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UNIVERSIDAD DE LA LAGUNA

INSTITUTO UNIVERSITARIO DE

BIO-ORGÁNICA "ANTONIO GONZÁLEZ" (IUBO-AG)

MEMORIA DE ACTIVIDADES 2014

Colabora en la Financiación el Cabildo Insular de Tenerife

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ÍNDICE

Página 1. Fines y Objetivos 3 2. Equipo Directivo 5 3. Comisión Permanente 5 4. Personal Investigador 6 5. Personal en Formación 7 6. Personal de Administración y Servicios 8 7. Investigadores, Profesores Invitados 9 8. Estancia de Investigadores en otros centros 11 9. Actos conmemorativos del 50 Aniversario del IUBO 12

MEMORIA CIENTÍFICA

10. Proyectos de Investigación 16 11. Publicaciones 37 12. Participaciones en Congresos 83 13. Tesis Doctorales Defendidas en 2013 133 14. Patentes y Modelos de Utilidad 134 15. Programas de posgrados, másteres, títulos propios y programas de

doctorado impartidos, organizados o promovidos por el instituto 135

16. Organización de Conferencias, Congresos, Seminarios y Jornadas de Divulgación

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17. Conferencias y cursos mpartidos 141 18. Convenios de Colaboración 143 19. Trabajo Fin de Grado y Trabajos Fin de Master realizados en el IUBO 144 20. Otras Actividades 145 21. Resumen Estadístico 146

MEMORIA ECONÓMICA

22. Subvención del Cabildo Insular de Tenerife 148 23. Subvención de la Universidad de La Laguna 149

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1. FINES Y OBJETIVOS

El Instituto Universitario de Bio-Orgánica Antonio González (IUBO-AG) es un centro

multidisciplinar orientado a la investigación en el campo de la Química Bio-Orgánica, Productos Naturales Bioactivos y Química Médica. El Instituto fue fundado en los años 60 con la necesidad de estudiar los metabolitos secundarios producidos por organismos marinos y terrestres, para proporcionar una nueva fuente de compuestos únicos. Actualmente, los objetivos del Instituto son el aislamiento, la biosíntesis, los cultivos de microorganismos, la biotecnología y la síntesis total de sustancias farmacológicamente activas procedentes de fuentes naturales. Además, son áreas de investigación de interés actual la evaluación biológica, el aislamiento y producción de toxinas, estudios NMR de procesos biológicos, insecticidas y repelentes naturales, etc.

Líneas de investigación IUBO-AG

Agentes anticancerígenos procedentes de fuentes naturales Varios productos naturales y sus derivados semisintéticos son producidos dentro de varios

proyectos comunes para el desarrollo de antitumorales con nuevos mecanismos de acción. Algunos productos recientemente han mostrado in vitro una reversión de la MDR (multirresistencia a fármacos) y efectos quimiopreventivos sobre el virus de Epstein-Barr.

Estudios de la relación entre Estructura-Actividad

Para entender la base estructural de la actividad biológica de una molécula y para dirigir el diseño de un fármaco más potente, el modelo cuantitativo tridimensional de la relación de la estructura-actividad (3D-QSAR) se realiza a partir de quimiotecas de compuestos relacionados.

Agentes antimicrobianos procedentes de fuentes naturales

Productos naturales procedentes de plantas y de derivados semisintéticos son de interés para luchar contra varios microorganismos y sus mecanismos de acción.

NMR en el estudio de procesos biológicos

Técnicas avanzadas de Resonancia Magnética Nuclear (NMR) se aplican para determinar interacciones enzima-inhibidor como una alternativa novedosa en la búsqueda de nuevos fármacos.

Organismos marinos y toxinas

Los dinoflagelados son organismos marinos responsables de las mareas rojas y el envenenamiento de moluscos. Entre otras, el ácido okadaico y las yessotoxinas son las toxinas más comunes presentes en crustáceos europeos. Desarrollamos sistemas de cultivos para proveernos de suficientes cantidades de toxinas para realizar estudios biológicos.

Insecticidas y repelentes

Se están aislando productos naturales para su uso contra plagas, especialmente las que afectan a la agricultura. Estos proyectos se llevan a cabo en colaboración con instituciones públicas y compañías agroquímicas de Europa y de América Latina.

Productos químicos y farmaquímicos

Nuestro instituto cuenta con una larga experiencia en el campo de la síntesis orgánica destinada a la síntesis de sustancias medicinales, especialmente enfocada en procesos

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asimétricos. Es de interés particular encontrar el desarrollo de nuevas metodologías para la síntesis total de sustancias activas biológicamente como toxinas, aminoácidos, análogos de la esfingosina, alcaloides, etc.

Catálisis metálica sostenible

En el actual contexto socioeconómico, el concepto de sostenibilidad ha irrumpido con mucha fuerza. Para el ser humano, la sostenibilidad consiste en satisfacer las necesidades de la actual generación sin sacrificar la capacidad de futuras generaciones. Dicho concepto tiene implicaciones medioambientales, económicas y sociales.

Actualmente se consumen muchos recursos, se encarecen los precios, mientras la sociedad demanda procesos más respetuosos con el medio ambiente.La catálisis posee el potencial para convertirse en una de las claves tecnológicas del siglo XXI. Así se podrán llevar a cabo nuevas reacciones y se desarrollarán procesos que permitan un ahorro de energía. Se podrán desarrollar nuevas metodologías sintéticas que tengan el menor impacto medioabmiental. Sin embargo muchos de los catalizadores empleados hoy en día son metales de transición caros, poco abundantes en cantidades que garanticen un total suministro en épocas venideras. Dentro de este contexto, estamos interesados en el desarrollo de nuevas metodologías sintéticas orientadas a la obtención de heterociclos (oxigenados y nitrogenados) de diversos tamaños, con potencial actividad biológica. Aplicar dicha metodología en la síntesis de productos naturales bioactivos y derivados utilizando una catálisis metálica sostenible. Por todas estas razones el hierro es una excelente alternativa a los metales preciosos en catálisis. Es uno de los metales más abundantes, es accesible, con bajo precio y respetuoso con el medio ambiente. Varias sales de hierro y complejos de hierro son accesibles comercialmente a gran escala o fáciles de sintetizar. Es importante destacar que el hierro forma parte de sistemas biológico como elemento esencial. El incremento en el número de reacciones catalizadas por hierro que se han publicado reflejan una mayor demanda de la química sostenible.

Descubrimiento fenotípico de compuestos antiproliferativos

Nuestra aproximación se fundamenta en el uso de estrategias convergentes para la identificación precoz de la diana terapéutica de cada molécula bioactiva mediante la aplicación de una estrategia global. Los compuestos que se analizan provienen no solo de grupos de investigación de la Universidad de La Laguna, sino de colaboraciones estables que mantenemos con grupos químicos nacionales e internacionales.

Farmacología e investigaciónes biomédicas

El IUBO-AG participa activamente en programas de investigación en colaboración con los hospitales y centros de investigación biomédicos de Canarias. El resultado de esta iniciativa es la constitución del CIBITEN (Centro de Investigación Biomédica de Tenerife) diseñado hacia el desarrollo en conjunto en los distintos aspectos de las Ciencias Biomédicas y de la Salud en Tenerife y Canarias.

Micromorfología y biomarcadores arqueológicos Al igual que hoy en día, la actividad humana en el pasado se desarrollaba en torno a materiales orgánicos (comida, vestimenta, el paisaje natural...etc.). A pesar de ello, el registro arqueológico orgánico es desconocido en su mayor parte debido a su bajo potencial de conservación. Nuestra línea de investigación se basa en el análisis microscópico y molecular de sedimento arqueológico para la identificación de partículas orgánicas y biomarcadores que nos permitan generar una visión más completa del pasado humano.

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2. EQUIPO DIRECTIVO

Director: Dr. D. Manuel Norte Martín Categoría: Catedrático de Universidad Email: mnorte@ull.es

Subdirector: Dr. D. José Javier Fernández Castro Categoría: Profesor Titular de Universidad Email: jjfercas@ull.es

Secretaria: Dra. Dña. Ana Estévez Braun Categoría: Profesora Titular de Universidad Email: aestebra@ull.es

3. COMITÉ EJECUTIVO

Director: Dr. D. Manuel Norte Martín Categoría: Catedrático Email: mnorte@ull.es

Subdirector: Dr. D. José Javier Fernández Castro Categoría: Profesor Titular Email: jjfercas@ull.es

Secretaria: Dra. Dña. Ana Estévez Braun Categoría: Profesora Titular Email: aestebra@ull.es

Vocal: Dr. D. Víctor S. Martín García Categoría: Catedrático Email: vmartin@ull.es

Vocal: Dr. D. Jesús María Trujillo Vázquez Categoría: Catedrático Email: jtruvaz@ull.es

Vocal: Dra. Dña. Isabel López Bazzocchi Categoría: Profesor Titular Email: ilopez@ull.es

Representante de Personal en Formación: D. Sixto José Pérez Moreno Categoría: Licenciado en Química – Becario Email: sjperez@ull.es

Representante del PAS: D. Ángel López Ruiz Categoría: Grupo IV Email: alopriz@ull.es

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4. PERSONAL INVESTIGADOR

Nombre y apellidos Categoría Correo electrónico

Ana Estévez Braun TU aestebraull.es

Ana Raquel Díaz Marrero Investigador Proy. IMBRAIN adiazmar@ull.es

Antonio M. Hernández Daranas Investigador Proy. IMBRAIN adaranas@ull.es

Carolina Mallol Duque Investigador Ramón y Cajal cmallol@ull.es

Celina Elena García González PCD Tipo 1 cgargon@ull.es

Fernando Pinacho Crisóstomo Investigador Proy. IMBRAIN fpinacho@ull.es

Ignacio Antonio Jiménez Díaz TU ignadiaz@ull.es

Isabel López Bazzocchi TU ilopez@ull.es

Jesús M. Trujillo Vázquez CU jtruvaz@ull.es

Jesús Manuel González Díaz TU jglezdll.es

José Adrián Gavín Sazatornil CU jgavin@ull.es

José Antonio Palenzuela López CU jpalenz@ull.es

José Javier Fernández Castro TU jjfercas@ull.es

José Manuel Padrón Carrillo PCD Tipo 1 jmpadron@ull.es

Juan Ignacio Padrón Peña Científico Titular CSIC jmpadron@ipna.csic.es

Manuel Norte Martín CU mnorte@ull.es

María del Mar Afonso Rodríguez TU mmafonso@ull.es

Mª Josefina Rodríguez Enríquez TU jenrique@ull.es

María Luisa Souto Súarez PC Tipo 1 msouto@ull.es

Matías López Rodríguez CU malopez@ull.es

Miguel Ángel Ramírez Muñoz TU mramirez@ull.es

Ricardo Borges Jurado CU rborges@ull.es

Rita Hernández Molina TU rrhernan@ull.es

Ricardo Guillermo Álvarez TU riguial@ull.es

Romen Carrillo Fumero Investigador Proy. IMBRAIN rocarril@ull.es

Tomás Martín Ruíz Científico Titular CSIC tmartin@ipna.csic.es

Víctor S. Martín García CU vmartin@ull.es

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5. PERSONAL EN FORMACIÓN

Nombre y apellidos Categoría Correo electrónico Adrian J. Santiago Benitez Becario Predoctoral ULL Ajsb_88@hotmail.com Alberto Jonatan Martín Rodríguez

Becario Predoctoral PLOCAN martin.rodriguez.aj@gmail.com

Ángel Amesty Arrieta Farmacéutico. Becario Universidad de Caracas

angelamesty@yahoo.es

Borja Hernández Martín Alumno de Grado en Química

Caterina Rodríguez de Vera Licenciada en C. Mar Becario FPU

caterina_rv@hotmail.com

Daniel Cruz Perdomo Becario FPI Diego Manuel Monzón Rodríguez

Estudiante Grado Química

Fátima del Pilar Pérez de la Rosa

Estudiante Máster Biomedicina

fatimapdelarosa@hotmail.com

Gema del Carmen Guedes de la Cruz

Licenciada en Químicas. Becaria Gobierno Autónomo

gemagc83@hotmail.com

Guillermo Díaz Crespín Becario MAE gdiazcrespin09@gmail.com Humberto José Domínguez Rodríguez

Becario FPU humbertodguez@gmail.com

Idaira Hueso Falcón Licenciada en Químicas. Becaria Contratada

idairahf@yahoo.es

José D. Machado Ponce Investigador Ramón y Cajal jdmacha@ull.es José Manuel López Sierra Becario CajaCanarias Jose G. Hernández Contratado CONSOLIDER jghdezj@gmail.com Julio Rodríguez López Becario FPI - Doctorando jrlopez@ull.es Lorena Cruz García TFG Marcelle Cadana Peretti Martín

Estudiante Master Biomedicina

mdperretti@gmail.com

María Fariña Ramos TFG Marta Rodríguez Pardo Contratada CONSOLIDER mahartha@yahoo.com Neldemary Arismendi Díaz Estudiante Fin de Grado Oliver Callies Licenciado en Química y

Biología, Universidad Albert-Ludwigs de Freiburg

callies.olliver@gmail.com

Patricia Alejandra Quintana Espinoza

Licenciada en Química. Becaria de Chile

patiquintana@gmail.com

Priscila López Rojas Estudiante Grado Química Rafael Ramírez Jiménez Alumno Grado Química rafa_carrizal@hotmail.com Ramón J. Alvarez Hernández

Proyecto Fin Carrera Ingeniería Química

Ricardo Liria Romero Alumno Grado Química Rodolfo Gastón Silveira Dorta

Becario Predoctoral ACIISI gastonsilveira@gmail.com

Rosalyn Peña Florez Licenciada en Química. Becaria CajaCanarias

rosalyn_pf@hotmail.com

Sandra María Oramas Royo Licenciada en Químicas. Becaria Gobierno Autónomo

soramasroyo@gmail.com

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6. PERSONAL DE ADMINISTRACIÓN Y SERVICIOS

Nombre Categoría

Dña. Pastora Izquierdo Herrera GIII Grupo III

D. Pedro Rodríguez Zuppo Grupo III

D. Antonio Díaz Herrera Grupo III

D. Gregorio Rois Grajal Grupo IV

D. Ángel López Ruiz Grupo IV

D. Nicolás Pérez Pérez Grupo III

Sandra Rodríguez Pérez Licenciada en Biología Alumno de Doctorado

Sara Tejera Díaz Estudiante postgrado stejera@ull.es Sergio Joaquín Álvarez Méndez

Licenciado en Química Becario FPU - Doctorando

salvmen@ull.es

Sixto José Pérez Moreno Becario FPU - Doctorando sjperez@ull.es Mónica Blanco Feijó Licenciada en Químicas.

Contratada por Proyecto PN

Pedro Martín Acosta Estudiante Doctorado Samuel Delgado Hernández Estudiante de Master alu01005511918@ull.edu.es Gabriela Brieba Plata Estudiante de Doctorado g.b.plata@gmail.com Rosalía González Brito Bacaria FPU gbrhgbrh@hotmail.com Adrián Morales Amador Alumno Doctorado Varkha Ramnani Gul Grado en Farmacia, ULL Del 15/07/14 hasta realizar

trabajo Fin de Grado Carmen Carro Sabina Grado en Química, ULL Del 04/02/14 hasta final curso

2013/14

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7. INVESTIGADORES Y PROFESORES INVITADOS

Nombre Procedencia Periodo de Estancia

Dr. Adrián Gutiérrez Cepeda Univ. Auton. de Santo Domingo, República Dominicana

Del 17/11/14 al 19/12/14

Dr. Ahmed Makhlouci Univ. Bechar, Algeria Del 12/03/14 al 29/03/14 Dr. Alex Adonai Osorio Landaverde

Universidad de El Salvador Del 25/09/14 al 3/12/14

Aline Zancheti Ameni Univ. de Sao Paulo Del 16/10/14 al 7/3/15 Carlos E. Tonn (Dr.) Univ. Nacional de San Luis Del 1/10/2014 al 29/10/14 Carmen Carro Sabina Grado en Química, ULL Del 04/02/14 hasta final

curso 2013/14 Claudia Rodríguez Sánchez Alumna Grado en Farmacia,

ULL Desde 03/02/14, previsto 2 meses

Larbi Ben Larbi (Dr.) Univ. Bechar, Algeria Del 12/03/14 al 29/03/14 Erica Marzaro University of Padova, Italia Del 10/01/14 al 10/10/14 Dr. Francisco A. Cen Pacheco Universidad Veracruzana,

Veracruz, México Del 15/12/14 al 5/1/15

Isabel Cristina Gómez Betancur

Univ. de Antioquia, Colombia Del 04/02/14 al 24/04/14

Jan Marius Willruth School of Life Science Del 01/09/14 al Dra. Jelena Dinic Instit. for Biological Research,

Serbia Del 25/09/14 al

Jorge Israel Ávila Alonso Trabajo Fin de Grado, F. Biología, ULL

Meses de junio y julio 2014

Laura Janeth Díaz Rubio Univ. Autónoma de Baja California

Del 13/11/14 al 19/12/14

Dr. Marvin José Núñez Rivas Univ. de El Salvador Dra. Olivia Márquez Fernández (Dra.)

Univ. Veracruzana Del 11/09/14 al 10/12/14

Paula Nueves de la Fuente García

Grado en Química, ULL Del 04/02/14 hasta final de curso 2013/14

Pavel Abramov Inst. de Química Inorgánica, Novosibirsk, Rusia

Desde 16/09/14, previsto un mes

Rafael Ramírez Jiménez Grado en Química, ULL Dic. 2013 hasta final curso 2013/14

Rossana Georgina Juárez Montiel

Univ. Nacional San Agustín de Arequipa

Del 21/09/14 hasta 21/11/14

Samuel Delgado Hernández Estudiante de Máster, ULL Del 01/11/2013 hasta junio 2014

Saoudi Salma Biology Engeneering, INSAT Tunisia

Del 13/10/2014 al 2/12/2014

Dr. Juan Pedro José Ceñal Univ. Nacional de San Luis, Argentina

Del 17/09/14 al 27/11/14

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8. ESTANCIAS DE INVESTIGACIÓN EN OTROS CENTROS Investigador: Antonio Manuel Hernández Daranas. Lugar: Imperial College London Grupo: Dr. John C. Lindon Fechas: Julio-Agosto 2014 Investigador: Alberto Jonathan Martín Rodríguez. Lugar: Estación Experimental del Zaidín Grupo: Dr. Tino Krell Fechas: Septiembre-Octubre 2014 Investigador:. María Josefina Rodríguez Enríquez Lugar: Plant Sciences Department University of Oxford UK Fechas: 20 de Junio del 2013 al 26 de Enero de 2015

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9. ACTOS INSTITUCIONALES DEL 50 ANIVERSARIO DEL IUBO

El Consejo de Instituto del IUBO decidió conmemorar los 50 años del comienzo de las investigaciones en el campo de los Productos Naturales en la ULL. En efecto, en 1964 se ponía en funcionamiento el Instituto de Investigaciones Químicas de Tenerife como un instituto dependiente del Cabildo Insular de Tenerife, que fue el primero que apoyó al Profesor Antonio González y González en la creación de un instituto de estas características en Tenerife. Con el paso del tiempo, este instituto terminó integrado en las estructuras orgánicas de la ULL como Instituto Universitario de Bioorgánica “Antonio González”.

A lo largo de los días 6 y 7 de Octubre de 2014, desarrollamos en el IUBO unas jornadas conmemorativas presididas por el Excmo y Mgfco Sr. Rector de la ULL y que contó con la participación de investigadores sudamericanos que se doctoraron en el IUBO, que han mantenido relación con nuestro Instituto a los largo de los años y que, tal y como se recoge en el programa, ocupan puestos de responsabilidad en sus universidades de origen. Por razones obvias, la mayor parte de ellos participaron a través de vídeos con sus testimonios y los Dres Carlos Tonn (San Luis, Argentina); Esteban Ferro (Asunción, Paraguay) y Angel Trigos (Jalapa, México) nos honraron con su presencia. De los colegas españoles contamos con la máxima representación institucional posible, el Presidente de la Real Sociedad Química de España, Dr. Jesús Jiménez y el Presidente del Grupo Especializado en Productos Naturales de dicha sociedad, Dr. Isidro González. Junto con ellos, nos honraron con su presencia los Profesores Honorarios Dres José Barluenga y Luis Castedo de la Universidad de la Universidad de Oviedo y de Santiago de Compostela, respectivamente. Finalmente, y como no podía ser de otra manera dada la íntima relación que existe con el IUBO, contamos con la presencia el Excmo Cabildo Insular de Tenerife, tanto en la inauguración como en la clausura, de representantes del Cabildo de Tenerife en las personas de los consejeros insulares D. José Joaquín Bethencourt y D. Antonio García.

El primer día se dedicó a un recorrido por la trayectoria del Instituto durante estos cincuenta años y su influencia en Iberoamérica. El periodo comprendido entre1964-1988 y entre 1989-2014 fueron cubiertos por los Dres. Angel Gutiérrez y Victor Martín. La vocación iberoamericana fueron resaltadas por el Dr. Esteban Ferro y el Dr. Carlos Tonn.

El segundo día recogió una sesión científica que, en su primera parte, incluyó una conferencia del Dr. José Barluenga junto a la entrega de los Premios Nacionales del Grupo Especializado en Química de Productos Naturales de la Real Sociedad Española de Química. La jornada continuó con las conferencias de los Dres Jesús Jiménez Barbero, Nuria Ortega e Isidro González.

Estas jornadas fueron clausuradas por el Vicerrector de Investigación e Internacionalización en nombre del Rector de la ULL.

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De izquierda a derecha, el Director del IUBO Dr. Manuel Norte, el Rector de la ULL Dr. Eduardo Doménech, el Consejero Insular D. José Joaquín Bethencourt y el Presidente de la Real Sociedad de Española de Química Dr. D. Jesús Jimenez Barbero.

http://www.ull.es/viewullnew/institucional/prensa/Noticias_ULL/es/2588197

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MEMORIA CIENTÍFICA

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10. PROYECTOS DE INVESTIGACIÓN SUBVENCIONADOS

Síntesis de nuevas entidades químicas para cartografiar la bioactividad en el espacio químico Resumen Nuestra propuesta de investigación se centra en la síntesis de pequeñas moléculas para cartografiar la bioactividad en el espacio químico. El objetivo general del proyecto es diseñar y desarrollar metodologías sintéticas basadas en procesos catalíticos (orgánicos y metálicos) y/o dominó para la síntesis de colecciones moleculares de moléculas pequeñas, las cuales incluirán productos naturales y homólogos, motivos estructurales privilegiados y plataformas moleculares sintéticas. Haremos uso de estrategias sintéticas tales como síntesis orientada a una estructura (producto natural) (TOS), síntesis de estructuras homólogas a partir de intermedios avanzados comunes (DTS) y síntesis orientada a la diversidad como ejes de innovación para la construcción molecular y el descubrimiento de nuevos cabezas de serie. Las colecciones de pequeñas moléculas serán evaluadas de acuerdo a nuestra implementación de la aproximación denominada “Phenotypic Drug Discovery” (descubrimiento de fármacos basados en fenotipos), la cual permite explorar contextos de relevancia biológica sin conjeturar mecanismos de acción. Los módulos existentes de evaluación contribuirán a explorar áreas relevantes del espacio farmacológico (biológico) (antitumorales, antibióticos, anti-infamatorios), en busca de nuevas topologías químicas bioactivas. Utilizaremos los tres módulos de ensayos fenotípicos denominados Cáncer, Enfermedades Infecciosas y Lesión Pulmonar Aguda. Los cabezas de serie seleccionados en los ensayos primarios serán validados mediante ensayos secundarios y de confirmación para descubrir sus mecanismos de acción y así como la identificación de la diana biológica. En el contexto de este proyecto desarrollaremos un nuevo módulo de evaluación destinado al estudio de la actividad “antibiofouling” (el biofouling es la acumulación no deseada de depósitos, esencialmente microbiológicos, sobre una superficie artificial sumergida o en contacto con agua de mar). Synthesis of Novel Chemical Entities to Map Bioactivity In The Chemical Space Synocemabics Summary This research proposal relates to the synthesis of small molecules to map bioactivity in the chemical space. The general aim of the project is to design and develop synthetic methodologies based on domino and/or catalytic manifolds (organic and metallic) for the synthesis of libraries of small molecules including natural products, natural products-like,

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privileged structural motives and synthetic scaffolds. We will make use of front edge synthetic strategies such as target-oriented synthesis, diverted–oriented synthesis and diversity-oriented synthesis as innovation axes for molecular construction and lead discovery. The resulting small molecule libraries will be screened using our implementation of the so-called Phenotypic Drug Discovery approach, which allows interrogating relevant biological contexts without predisposed bias toward action mechanisms. Running screening modules will contribute to explore relevant areas of the pharmacological (biological) space (antitumor, antibiotics, anti-inflammatory) in the search for novel bioactive chemical topologies. Three phenotypic assay modules, namely Cancer, Infectious Diseases and Acute Lung Injury will be used. Primary assays will be used to select initial lead compounds that will be submitted to secondary and confirmatory assays to unravel their mechanism of action in addition to identification of the biological target. Within this project we will start a new module devoted to the evaluation of antibiofouling activity Número de investigadores/as: 6 Cód. según financiadora: CTQ2011-28417-C02-01 Fecha de inicio: 01/01/2012 , 3 años Fecha fin: 31/12/2015 Entidades participantes: Consejo Superior de Investigaciones Científicas; IUBO- AGUniversidad de La Laguna Cuantía subproyecto: 216.590 € IP: Dr. D. Victor Sotero Martín García

Compuestos Bioactivos de Organismos Marinos: estudios estructurales, farmacológicos y biotecnológicos Resumen Las microalgas marinas juegan un papel crucial en los ecosistemas debido a su actividad fotosintética y de entre ellas, nuestro proyecto se interesa por el grupo de los dinoflagelados capaces de originar afloramientos o “blooms” conocidos como “mareas rojas”. Éstas se clasifican habitualmente en función de los efectos toxicológicos en humanos. Por otro lado, los dinoflagelados marinos podrían llegar a ser auténticas “factorías celulares” de importantes sustancias bioactivas con diferentes aplicaciones farmacológicas. Estudiaremos a gran escala especies de Prorocentrum orientados a los metabolitos más polares, apoyándonos en los hallazgos en el IUBO de Belizeanolido y Ácido Belizeanóico, dos ejemplos de los denominados “SuperCarbonChain compounds (SCC)” y otros ejemplos de lactonas macrocíclicas. Dado el interés de estos dinoflagelados como productores, en la UAL se propone establecer las

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condiciones para su cultivo semi-industrial y productivo. El objetivo es adaptar y poner a punto fotobiorreactores de decenas de litros trabajando el escalado para la máxima producción de toxinas y de biomasa en el cultivo externo para los dinoflagelados seleccionados. Moléculas de esta complejidad generan nuevos problemas que han de resolverse. En este sentido se está desarrollando una metodología por RMN directa y simple para establecer la configuración de los centros quirales en sistemas de anillos de cinco miembros muy comunes en este tipo de estructuras y de establecer el origen biosintético de estas estructuras. El interés de estas sustancias también radica en su potente actividad inhibitoria de proteínas fosfatasas, y hoy en día sigue suponiendo un gran reto la búsqueda de nuevos inhibidores selectivos. En el IUBO se realizarán estudios de inhibición in vitro; estudios estructurales y conformacionales del AO y análogos; cálculos teóricos de docking para determinar su modo de unión a los enzimas y establecer los requisitos estructurales necesarios para la inhibición selectiva de PP1 y PP2A. Los datos de inhibición in vitro serán contrastados en la UO con los de cultivos de cerebelo, para identificar los motivos estructurales asociados a la efectividad inhibidora en células vivas, la cual, dada la gran complejidad estructural de las PPs y su regulación, puede diferir significativamente de la actividad in vitro. Se estudian también otros poliéteres de algas rojas del género Laurencia para información de moléculas y motivos estructurales más simples con actividad inhibitoria. En la UAL, se estudian sus interacciones con células inmunitarias, evaluando la toxicidad y la función biológica de estas células ante la toxina o bioproducto. En el caso de linfocitos T, su capacidad para reconocer inmunógenos. Dada la gran sensibilidad del SNC a la acción a largo plazo de estos compuestos usaremos cultivos celulares primarios y organotípicos de SNC. Las propiedades eléctricas neuronales permiten aproximaciones únicas de determinación de efectos fisiológicos subtóxicos como los registros extracelulares con matrices de microeléctrodos. El estudio de las vías bioquímicas estará orientado especialmente a la identificación de mecanismos neuroprotectores. Finalmente en este proyecto nos planteamos iniciar el estudio a pequeña escala de 50 especies de diferentes géneros de dinoflagelados de la colección del IEO (Vigo) para estudiar su bioactividad y elegir los adecuados para proseguir su escalado y futuros estudios Bioactive Molecules From Marine Organisms: Structural, Pharmacological And Biotechnological Studies Summary Among marine organisms, microalgae play a crucial role in ecosystems due to their photosynthetic activity. This group is characterized by their ability to produce blooms known as "red tides” and classified according to the toxicological effects provoked in humans. There is no doubt that marine dinoflagellates could become real "cell factories" of important bioactive substances with different biotechnological applications. Thus, on the basis of the results recently obtained from of P. belizeanum, in this project we propose to continue the development of large-scale cultures of Prorocentrum species focussed on the search of highly polar metabolites. Certainly, we have isolated and characterized two new examples of the so-called "SuperCarbonChain compounds,SCC)" named belizeanoic acid and belizeanolide. Furthermore we have detected similar metabolites that are still under study. In addition, we propose to undertake in the UAL further studies to find the optimal the conditions to produce massive cultures. The ultimate goal of our project would be to adapt and develop the culture of dinoflagellates in external photobioreactors. It is obvious that complex molecules create new problems to be solved. On our side, we are developing a simple NMR methodology to establish the configuration of stereogenic centers in five-membered rings, which are common in this kind of compounds. This approach includes the synthesis of models that will be used to

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confirm theoretical approaches and we also try to establish their biosynthetic origins. In addition, the interest of this group of substances is mainly based on their potent biological activities that include new modes of action. Regarding the inhibitory activity of protein phosphatases, the design of this kind of selective inhibitors is the main challenge in this field nowadays. Therefore, we have undertaken structural and conformational studies in solution of AO and analogues and theoretical docking calculations to determine a plausible binding mode. These studies will continue aiming to find simplified molecules fulfilling the necessary structural requirements to achieve a selective inhibition of PP1 and PP2A. Data from in vitro inhibitory activity obtained at IUBO will be compared and complemented with the evaluation of biochemical and toxicological effects in neuronal and glial cells cultures developed in UO, which will help us to establish structure-activity correlations and to identify those structural motifs that determine more effective inhibitors in living cells. However, given the structural complexity of protein phosphatases and the cellular regulatory mechanisms they control it may differ significantly from the inhibitory activity determined in the test tube. Furthermore, these studies will be extended to other types of polyethers found in red algae of the genus Laurencia. The group of UAL will study the interaction between animal immune cells and the isolated compounds, evaluating both their toxicity and biological function, for instance studying the ability to recognize immunogens of T cells. UO group will analyse the effects on the CNS using in vitro systems of primary cerebellar neurons, glial cells and organotypic cultures. We will study the biochemical pathways involved in the physiological and toxicological effects and on the development of novel neuroprotective therapies. Finally in this project we plan to start small-scale cultures of 50 species of dinoflagellates from IEO collection to assess their bioactivity and select the new organisms for future studies. Número de investigadores/as: 7 Cód. según financiadora: SAF2011-23338-C03-01 Fecha de inicio: 01/01/2012 , 3 años Fecha fin: 31/12/2015 Entidades participantes: Universidad de Oviedo, Universidad de Almería, IUBO-AG Universidad de La Laguna Cuantía subproyecto: 189.970,00 €IP: Dr. D. José Javier Fernández Castro

Diseño y síntesis de nuevas moléculas moduladoras de dianas terapéuticas a través de estructuras privilegiadas y síntesis orientada a la diversidad

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Resumen Este proyecto tiene como objetivo la búsqueda y desarrollo de nuevas entidades moleculares con actividad antiinflamatoria, cardioprotectora, antitumoral, antimicrobiana o antiparasitaria. El acceso a las moléculas bioactivas se realizará mediante estrategias eficaces en la ocupación de regiones biológicamente relevante del espacio químico: uso de “Estructuras Privilegiadas” de origen natural, uso de Reacciones Dominó generadoras de complejidad estructural y diversidad de esqueleto bajo una aproximación de Síntesis Orientada a la Diversidad, Síntesis Total Derivada, Quimiomodulación de bioactividades de cabezas de serie, y estudios de modelización molecular. La inflamación es un factor implicado en la patogénesis de diversas enfermedades cardiovasculares [aterosclerosis, daño por isquemia/reperfusión (I/R), miocarditis viral, etc.]. Resultados previos del grupo con diversos tipos estructurales de diterpenos indican su capacidad de actuar en distintas dianas del proceso inflamatorio, siendo NF-kB una vía de señalización común en la acción de estos compuestos. Además, hemos observado la actividad protectora “per se” en ausencia de inflamación que ejercen algunos de estos compuestos, describiendo su potencial como agentes cardioprotectores actuando sobre dianas moleculares implicadas en el control de la viabilidad celular (PI3K, Akt, AMPk, Bax…). En este proyecto se evaluará la capacidad de nuevas estructuras diterpénicas para proteger frente al daño cardiaco, en concreto, series químicas obtenidas a partir de diterpenos seleccionados por su actividad antiinflamatoria y/o cardioprotectora (derivados de hispanolona, ácido labdanólico y solidagenona). La actividad antiinflamatoria y/o cardioprotectora de estas moléculas será evaluada en ensayos de screening en cultivos primarios de macrófagos y cardiomiocitos, para el estudio de las dianas moleculares de actuación (vías de señalización a través de TLRs, vías de supervivencia, AMPk, apoptosis…). Estos ensayos nos permitirán seleccionar moléculas activas con actividad cardioprotectora, actividad que será finalmente validada en modelos de I/R tanto celulares como ex vivo: corazón perfundido de Lagendorff. Estas evaluaciones nos llevarán a identificar estructuras candidatas a ser evaluadas in vivo en modelos de patologías cardíacas y permitirán identificar grupos funcionales relevantes en la actividad cardioprotectora. En el campo de los antitumorales principalmente nos centraremos en la familia de proteinas “Signal Transducer and Activator of Transcription” (STAT) y los Receptores de Estrógenos (RE) que son factores de transcripción que regulan el crecimiento, la diferenciaciación, el metabolismo o la supervivencia de numerosos tipos celulares. Estas proteínas son importantes dianas farmacológicas, validadas por numerosos grupos académicos y empresas, en el tratamiento de determinados tipos de cáncer o enfermedades inmunológicas y metabólicas. En la actualidad, existe una elevada demanda por inhibidores potentes y selectivos de la ruta oncogénica Jak2-STAT así como por moduladores selectivos de los RE (SERMs) con mejor perfil clínico. Se evaluará nuevas moléculas procedentes de quimiotecas específicamente diseñada para descubrir nuevos inhibidores JAK2-STAT o SERM. En concreto se evaluarán triarilmetanos altamente funcionalizados y estructuras C6-C3-C6 como SERMs, así como diversos derivados quinónicos heterocíclicos como inhibidores de la ruta oncogénica JAK2-STAT. Se evaluará la eficacia y toxicidad de estas nuevas moléculas. En primer lugar, se utilizará sistemas de búsqueda a mediana escala basados en líneas celulares con sistemas reporteros de luciferasa. Esto permitirá identificar con rapidez a moduladores químicos que actúen a cualquier nivel de la cascada de señalización dependiente de STAT o de RE. Los ensayos E-SCREEN permitirán seleccionar los productos con actividades SERM. En segundo lugar, se evaluará la citotoxicidad en líneas dependientes de JAK2-STAT (HEL) o de RE (T47D) y en linfocitos primarios. En tercer lugar, se evaluará la eficacia de las moléculas más activas en relación con respuestas biológicas concretas (proliferación, apoptosis, migración, invasión celular, formación de colonias, producción de fosfatasa alcalina, calcificación). Finalmente, con las moléculas más activas se realizarán estudios mecanísticos detallados como son: a)

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fosforilación y translocación nuclear usando técnicas de immunoblotting, GEMSA y microscopia, b) actividad quinasa de Jak2 in vitro y especificidad sobre otras quinasas, c) apoptosis y ciclo celular, d) binding al RE, e) Fármaco-Toxicogenómica predictiva in vitro, y e) las evaluaciones biológicas orientadas, apoyadas en la mejora del diseño químico, permitirán seleccionar la molécula óptima para evaluar su eficacia y toxicidad in vivo. Dado que nuestro grupo muy recientemente ha patentado una serie de productos de origen natural con una potente actividad antimicrobiana en estirpes bacterianas del género Staphylococcus resistentes a meticilina (MRSA) y a vancomicina (HVRSA) que actualmente constituyen un grave problema en los centros hospitalarios, en la presente solicitud accederá a una serie de análogos mediante una aproximación de Síntesis Total Derivada. Por último también abordará la preparación de nuevos derivados de fenalenonas como agentes antiparasitarios. En base a los resultados de actividad biológica, provenientes del cribado frente a las distintas dianas terapéuticas, mejoraremos las propiedades biológicas y/o farmacológicas de las moléculas bioactivas por medio de estudios de relación estructura-actividad (SAR) así como estudios in silico que facilitará el diseño racional de nuevas entidades. Synthesis and design of new molecule modulators of therapeutic targets trough priviliged structures and Diversity Oriented Synthesis Abstract The main objective of the present research proposal is the discovery and development of new molecular entities displaying anti-inflammatory, cardioprotective, antitumour, antibacterial or antiparasitic activities. The access to bioactive molecules will carry out through efficient strategies to chart biologically relevant regions in the chemical space. We will use natural “Privileged Structures”, domino reactions to generate diverse molecular skeletons and molecular complexity following a ”Diversity Oriented Synthesis” approach, Diverted Total Synthesis, Chemomodulation of Bioactivies of lead compounds, and Molecular Modeling studies. Inflammation is an important contributor to the pathogenesis of cardiovascular diseases [atherosclerosis, ischemia/reperfusion (I/R) injury, viral myocarditis, etc]. Our previous findings with diterpenes indicate their capacity to interact with different targets of the inflammatory process, being NF- B a common signaling pathway in the action of these compounds. Moreover, we have also observed the “per se” protective activity, in the absence of inflammation exerted by these compounds, and we described their potential as cardioprotective agents, acting at molecular targets involved in the control of cell viability (Akt, PI3K, AMPk, Bax…). This project will evaluate the capacity of new diterpene derivatives for protection against cardiac injury. Chemical series of diterpenes will be prepared from selected diterpenes (hispanolone, labdanolic acid and solidagenone) with proven anti-inflammatory and cardioprotective activities. The anti-inflammatory and/or cardioprotective activities of these molecules will be evaluated by using cell-based screening systems (primary cultures of macrophages and cardiomyocytes), in order to determine molecular targets involved (signaling pathways through TLRs, survival pathways, AMPk, apoptosis…). These screening assays will allow us to choose active molecules with cardioprotective activity, which will be validated in both cellular and ex vivo I/R models, as Lagendorff-perfused heart. This pharmacological approach will led us to identify candidates to be evaluated in animal models of cardiovascular diseases and the relevant functional groups for cardioprotection. Concerning the antitumoral area we will analyze the activities of the "Signal Transducer and Activator of Transcription" (STAT) and the Estrogen Receptor (ER) which are transcription

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factors that regulate growth, differentiation, metabolism or the survival of many cell types. These proteins are important drug targets, validated by numerous companies and academic groups, for the treatment of certain types of cancer or immune and metabolic diseases. At present, there is a high demand for potent and selective inhibitors of Jak2-STAT oncogenic route as well as ER selective modulators (SERMs) with better clinical profile. Highly functionalized triarymethanes and structures type C6-C3-C6 will be evaluated as SERMs as well as a variety of designed quinonic heterocycles as JAK2-STAT inhibitors. The efficacy and toxicity of these new molecules will be evaluated by using medium scale searching methodology based on luciferase reporter cell lines. This will quickly identify chemical modulators that act at any level of the cascade of STAT- or ER-dependent signaling. E-SCREEN assays allow select products with SERM activity. Secondly, we will evaluate drug cytotoxicity on JAK2-STAT (HEL) or RE (T47D) dependent cells lines as well as primary lymphocytes. Third, we will evaluate the effectiveness of the active molecules in relation to specific biological responses (proliferation, apoptosis, migration, cell invasion, colony formation, alkaline phosphatase production, bone calcification). Finally, with will perform mechanistic studies by using the more active molecules: a) phosphorylation and nuclear translocation using immunoblotting, GEMSA and microscopy, b) in vitro kinase activity of Jak2 and specificity over other kinases, c) apoptosis and cell cycle, d) interaction with ER, e) pharmacogenomic and drug-predictive Toxicogenomic, and e) our molecular target-based screening, supported by improved chemical design, will allow us select the optimal molecule to assess its efficacy and toxicity in vivo. Recently, our grroup has patented diverse compounds from natural sources which have strong in vitro antibacterial activities against Gram-positive bacteria; including multiresistant Staphylococcus aureus clinical isolates. In the present Project, several analogues of these compounds will be synthesized following a Diverted Total Synthesis approach. We will also carry out the preparation of new fenalenones derivatives as antiparasitic agents. From the obtained results in the assays against the several therapeutic targets, we will improve the biological and pharmacological properties of the bioactive molecules through SAR (Structure-Activity relationships) and in silico studies. These types of studies will allow us the rational design of new molecules. Número de investigadores/as: 9 Cód. según financiadora: SAF2012-13296-C03-01 Fecha de inicio: 01/01/2013, 3 años Fecha fin: : 30/09/2015 Entidades participantes: IUBO-AG Universidad de la Laguna, Universidad de Las Palmas de Gran Canaria, Universidad Complutense de Madrid Cuantía subproyecto: 210.000.00 € IP: Dra. Dña. Ana Estevez Braun

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Receptores quirales de cationes y péptido-miméticos como modelos para el estudio de las interacciones no covalentes y sus implicaciones Resumen El proyecto propuesto pretende realizar un estudio de las interacciones no covalentes que actúan como factores esenciales que gobiernan el reconocimiento molecular y el plegamiento de las moléculas orgánicas y las consecuencias que se derivan de dichos fenómenos. Con el fin de comprender a fondo el papel que juegan dichas interacciones no covalentes, nuestro grupo de investigación, ha recurrido al diseño y desarrollo de modelos moleculares sencillos que permitan emular los procesos que ocurren en los distintos fenómenos biológicos, tales como: el reconocimiento quiral, el refuerzo del reconocimiento molecular y quiral, la cooperatividad, el plegamiento molecular y la catálisis asimétrica. Esto nos ayudara a estudiar, desentrañar y modular los mecanismos, los procesos y las interacciones que intervienen en estos eventos moleculares. Para conseguir estos objetivos hemos elegido como modelos de estudio: receptores quirales de cationes y péptidos no naturales basados ambos en unidades de azucares o análogos. De esta forma, la construcción de receptores de cationes y de peptidomiméticos con unidades de azucares permite la incorporación de elementos estructurales y funcionales necesarios para que se intensifiquen las interacciones y se favorezca su compatibilidad con el medio acuoso. Este conocimiento nos permitirá vislumbrar los mecanismos por los que los receptores biológicos llevan a cabo sus funciones y también aplicar ese conocimiento a preparar receptores de cationes más eficaces y selectivos que puedan ser compatibles con las condiciones en las que trabajan los sistemas biológicos. Por otro lado, el estudio de los plegamientos observados en los homopéptidos y heteropéptidos, nos conducirá al desarrollo de nuevos dipéptidos no naturales basados en ácidos que puedan ser utilizados como nuevos órgano-catalizadores quirales en reacciones de adición tipo Michael. Chiral receptors for cations and peptidomimetics as models for studying noncovalent interaction and their implications Summary The proposed project aims to conduct a study of noncovalent interactions that act as essential factors that govern the folding and molecular recognition of organic molecules and the consequences resulting from these phenomena. In order to fully understand the role of such non-covalent interactions, our research group has used the design and development of simple molecular models that emulate the processes occurring in various biological phenomena, such as chiral recognition, the reinforcement of molecular and chiral recognition, cooperativity, the molecular folding, and asymmetric catalysis. This will help us to explore and unravel the mechanisms, processes and interactions involved in these molecular events. To achieve these objectives we have chosen as study models: chiral receptors for cations and unnatural peptides, both based on units of sugars or analogues. Thus, the design and synthesis of cation receptors and peptidomimetics with sugar units allows the incorporation of structural and functional elements necessary for the intensification of the noncovalent interactions, and promotes the compatibility with the aqueous medium. This knowledge will allow us to discern the mechanisms by which biological receptors carry out their functions and apply that knowledge to make more efficient and selective receptors for cation that may be compatible with the conditions in which biological systems work. On the other hand, the study of folding observed in homopeptides and heteropeptides allows us to develop new unnatural dipeptides

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- -amino acids that can be used as new chiral organocatalysts in Michael type addition reactions. Número de investigadores/as: 3 Cód. según financiadora: CTQ2011-22653 Fecha de inicio: 01/01/2012 , 3 años Fecha fin: 31/12/2015 Entidades participantes: Consejo Superior de Investigaciones Científicas; IUBO-AG Universidad de La Laguna Cuantía subproyecto: 96.800 € IP: Dr. D. Tomás Martín Ruiz

Improving Biomedical Research and Innovation in the Canary Islands To unlock and develop the research and innovation potential of the Centre for Biomedical Research of the Canary Islands (CIBICAN), a coherent series of activities have been designed through the development of this project (IMBRAIN). From a recent SWOT analysis, several impediments have been identified that must be overcome to maximize our research capacities. They include the isolation from decisionexcessive cost and effort required to coordinate and collaborate in projects and to disseminate research achievements both into the science community and the society. In addition, despite the quality of the research teams and their focus on priority areas, the problems of recruiting experienced new researchers, technical staff and innovation managers remain a serious handicap that we are strongly committed to overcome. The main strategic objective of this project is to increase the quality of research at CIBICAN, and to build its innovation capacity to become a leading centre in Biomedicine and the Health Sciences. It will have a significant impact in promoting regional economic and social development, and in spreading of health knowledge into the outermost EU regions and the near African countries. This will be achieved through the following measures: 1) Exchange of know-how and experience with EU research partnering organizations; 2) Recruitment of experienced researchers, technical staff and innovation manager; 3) Upgrading of research equipment, based on existing infrastructure and core facilities; 4) Elaboration of a strategic IP development plan for IP management and protection and innovation capability building; 5) Dissemination of knowledge on health and increase the visibility of CIBICAN activities at regional, national and European levels. In addition, an exspecific strategy actions for long

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http://www.ull.es/view/institucional/ull/Cibican-Imbrain/es

MAREX: Exploring Marine Resources for Bioactive Compounds: From Discovery to Sustainable Production and Industrial Applications 2010-2014 Project description Biodiversity in the seas is only partly explored, although marine organisms are excellent sources for many industrial products. Through close co-operation between industrial and academic partners, the MAREX project will collect, isolate and classify marine organisms, such as micro- and macroalgae, cyanobacteria, sea anemones, tunicates and fish from the Atlantic, Pacific and Indian Oceans as well as from the Mediterranean, Baltic and Arabian Seas. Extracts and purified compounds of these organisms will be studied for several therapeutically and industrially significant biological activities, including anticancer, anti-inflammatory, antiviral and anticoagulant activities by applying a wide variety of screening tools, as well as for ion channel/receptor modulation and plant growth regulation. Chromatographic isolation of bioactive compounds will be followed by structural determination. Sustainable cultivation methods for promising organisms, and biotechnological processes for selected compounds will be developed, as well as biosensors for monitoring the target compounds. The work will entail sustainable organic synthesis of selected active compounds and new derivatives, and development of selected hits to lead compounds. The project will expand marine compound libraries. MAREX innovations will be targeted for industrial product development in order to improve the growth and productivity of European marine biotechnology. MAREX aims at a better understanding of environmentally conscious sourcing of marine biotechnology products and increased public awareness of marine biodiversity and potential. Finally, MAREX is expected to offer novel marine-based lead compounds for European industries and strengthen their product portfolios related to pharmaceutical, nutraceutical, cosmetic, agrochemical, food processing, material and biosensor applications. Número de investigadores/as: 9 Cód. según financiadora: KBBE-2009-3-245137 Fecha de inicio: 01/08/2010 , 3,5 años Fecha fin: 31/07/2014

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Entidades participantes: 19 Cuantía Global : 7,5 M € Cuantía subproyecto: 478.444.00 € IP: Dr. D. Manuel Norte Martín

Evaluación del contenido en estrógenos naturales y sintéticos en leche y derivados lácteos mediante técnicas analíticas avanzadas y nuevos procedimientos de extracción Resumen El análisis de estrógenos tanto naturales como sintéticos constituye un tema de especial relevancia en las muestras alimenticias, pues está ampliamente demostrado que un exceso de los mismos en las dietas producen multitud de desórdenes en los sistemas endocrinos que, en muchas ocasiones, además de producir diferentes enfermedades (obesidad, hiperactividad, diabetes, disminución de la fertilidad, etc), pueden degenerar en cáncer, sobretodo de próstata, ovario y pecho, por lo que estudiar el tipo y contenido de este tipo de compuestos en alimentos básicos constituyentes de nuestra dieta es crucial. El exceso de estrógenos y las modificaciones en el sistema endocrino están causados por una amplia variedad de factores, entre los que se pueden incluir: ingerir una dieta rica en carnes que contiene estrógenos sintéticos, tomar leche y derivados lácteos y comer alimentos envasados en cajas o embalajes plásticos. Hoy en día, el consumo de leche por niños y adultos constituye una parte muy importante en la alimentación de la humanidad, dado que supone cerca de 500 millones de toneladas/año, gracias al desarrollo y a los avances de la ganadería y, entre un 60 y 70% de la ingesta de este tipo de compuestos. Aunque existen estudios en los que se determinan los estrógenos en este tipo de alimento, éstos sólo se han hecho de cara a identificar los principales estrógenos naturales y en algunos casos los sintéticos, pero existe una laguna muy amplia en lo que respecta a la determinación de los metabolitos de los mismos (derivados metilados, hidroxilados y glicosilados), los cuales constituyen más del 85% de la ingesta. Esto ha sido debido a que los procedimientos de extracción de este tipo de productos suele ser muy complejos y tediosos, y a que a pesar de que se han producido grandes avances en el campo analítico no se han sido utilizados en el campo de análisis de alimentos, por lo que establecer métodos de extracción altamente selectivos, eficaces y rápidos utilizando nanotubos de carbono, líquidos iónicos convencionales y sintetizados en el laboratorio, microextracción en fase sólida o hollow fiber acoplados a técnicas avanzadas de análisis (fundamentalmente HPLC y CE) para su determinación, constituye un aspecto fundamental y que apenas ha sido explorado por la comunidad científica. El determinar este tipo de metabolitos así como establecer la cantidad de fuentes estrogénicas (procedentes de las leches y derivados) a las cuales está sometida la población ayudará no sólo a esclarecer los efectos que este tipo de

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compuestos ejerce sobre distintos tipos de enfermedades, sino que permitirá al sector lácteo realizar una evaluación eficaz de cara a la racionalización de este tipo de productos para la población, incrementando la seguridad en el consumo de dichos alimentos. Por tanto esta propuesta tiene como objetivo fundamental la determinación del contenido estrogénico (incluyendo estrógenos naturales, sintéticos, así como sus metabolitos, además de precursores de actividad estrogénica procedente de envases plásticos) en leches y derivados (yogur y quesos) mediante procedimientos de extracción altamente selectivos, económicos y rápidos para su posterior identificación y cuantificación mediante técnicas cromatográficas y electroforéticas. Se pretende aplicar dichas metodologías a un amplio abanico de muestras de leche de diferente naturaleza y con diferente contenido graso, así como a derivados lácteos (yogures y quesos en este caso fabricados en la Comunidad Autónoma Canaria) consumidas ampliamente por la población así como evaluar su contenido estrogénico. Estos estudios (desarrollo de metodologías de extracción, determinación y evaluación) que se enmarcan dentro del campo de seguridad alimentaria, permitirán hacer evaluaciones eficaces de los contenidos de los mismos y establecer medidas preventivas de cara a disminuir los efectos de este tipo de compuestos sobre la población y así prevenir desordenes y/o enfermedades. Summary The analysis of natural and synthetic estrogens in foods constitutes a topic of special concern, since it is widely demonstrated that their excessive dietary intake is responsible for a good number of disorders of the endocrine system. Such disorders can cause different illnesses i.e. obesity, hyperactivity, diabetes, infertility, etc. but may also be responsible for the appearance of certain types of cancer (ovarian, mammalian and prostate cancer). Such estrogenic excess in the diet, as well as the modifications of the endocrine system, are caused by several factors like high ingest of meat products with synthetic estrogens, drinking milk and its derivatives, eating plastic packed foods, etc. That is why the study of the estrogenic content of basic food products is of high interest. Nowadays, children and adults consumption of milk constitute a very important part of human’s nutrition since nearly 500 millions of tons per year are worldwide consumed (thanks to modern farming practices). Such important consumption also represents the intake of 60-70% of these compounds in the diet. Although there already exist several studies in which the determination of estrogens in milk has been carried out, they have been mainly focused on the identification of the most important natural estrogens (and in few cases synthetic). However, few works have focused on their metabolites analysis (methylated, hydroxilated and glicosilated), which constitute 85% of the dietary intake. The main reason of this hardly explored field has probably been the fact that the extraction procedures developed up to now for their analysis are very complex and tedious. In fact, modern analytical techniques employing highly selective, efficient and quick extraction methods using new materials like carbon nanotubes, ionic liquids or hollow fibers, as well as solid-phase microextraction, coupled to advanced separation techniques (mainly HPLC and capillary electrophoresis), have hardly been applied in this field. Therefore, estrogenic metabolite analysis in milk products will allow establishing relationships between their high dietary intake and illnesses, but also will awake the interest of milk industries in order to rationalize the consumption of these products. The main objective of this proposal is to determine the estrogenic content (natural, synthetic and their metabolites, as well as some food packings constituents which are precursors of estrogenic activity) in milk and milk products (yoghourt and cheese) using highly selective, economic and quick extraction procedures for the ulterior analysis using cromatographic and electrophoretic techniques. Samples of different nature and fat content will be analyzed, all of them manufactured in the Canary Islands. The objective of this project is therefore focused on the food safety field.

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Número de investigadores/as: 7 Entidad Financiadora: Ministerio de Ciencia e Innovación Cód. según financiadora: AGL-2011-24667/ALI Fecha de inicio: 01/01/2012, 3 años Fecha fin: 31/12/2014 Entidades participantes: Departamento de Química Analítica; IUBO- AG Universidad de La Laguna Cuantía proyecto: 76.000 € IP: Dr. D. Miguel Ángel Rodríguez Delgado

Mecanismo de Acción de Nuevos Compuestos Antitumorales Disruptores de la División Celular Resumen Esta propuesta de investigación se refiere a la farmacología molecular de nuevos compuestos antitumorales resultantes de nuestro programa de cribado basado en ensayos fenotípicos (PDD). El objetivo general de este proyecto es la evaluación a nivel molecular de pequeñas moléculas que incluyen productos naturales y sus análogos, motivos estructurales privilegiados y estructuras moleculares con un interés relevante en aquellos productos que afectan a la división celular. Se considerarán dos temas generales. A) Compuestos líderes existentes: Previamente hemos identificado diversos líderes (p.ej. el inhibidor de topoisomerasa II DTA0100) que requieren estudios mecanísticos adicionales. B) Compuestos líderes nuevos: Las librerías de pequeñas moléculas (provenientes de nuestras colaboraciones externas) serán evaluadas utilizando nuestra implementación de la aproximación PDD, que nos permite interrogar contextos biológicos relevantes sin predisposición hacia algún mecanismo de acción en particular. Tres módulos de ensayos fenotípicos desarrollados por el grupo solicitante contribuyen a explorar las áreas relevantes del espacio farmacológico (antitumoral, antibiótico, antiinflamatorio), denominados Cáncer, Enfermedades Infecciosas y Lesión Pulmonar Aguda. Los ensayos primarios se utilizarán para una selección inicial de compuestos líderes, que a su vez serán sometidos a ensayos secundarios y confirmatorios para descifrar su mecanismo de acción además de la identificación de la diana biológica. El módulo de Síntesis de Pequeñas Moléculas complementará el trabajo con todos los aspectos relacionados con el

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desarrollo como fármaco (escalado, propiedades de buen fármaco, etc.) que no son contemplados por los grupos de colaboradores externos. Summary This research proposal relates to the molecular pharmacology of novel antitumor compounds resulting from our ongoing Phenotypic Drug Discovery (PDD) screening program. The general aim of the project is the evaluation at a molecular level of small molecules (SMs) including natural products, natural products-like, privileged structural motives and synthetic scaffolds with a prominent interest in those that can affect cell division. Two main topics are considered. A) Ongoing lead compounds: Previously, we identified several leads (e.g. the topoisomerase II inhibitor DTA0100) that require further mechanistic studies. B) New lead compounds: The resulting SM libraries (available from long and short-term external collaborations) will be screened using our implementation of the PDD approach, which allows interrogating relevant biological contexts without predisposed bias toward mechanism of action. Three phenotypic assay modules developed by the applicant group contribute to explore relevant areas of the pharmacological space (antitumor, antibiotics, anti-inflammatory), namely Cancer, Infectious Diseases and Acute Lung Injury. Primary assays will be used to select initial lead compounds that will be submitted to secondary and confirmatory assays to unravel their mechanism of action in addition to identification of the biological target. The Small Molecule Synthesis module will fulfill with those drug development issues (scaling up, drug-like properties, etc.) that are not covered by the external collaborating synthetic groups. Número de investigadores/as: 4 Cód. según financiadora: PI11/00840 Fecha de inicio: 01/01/2012, 3 años Fecha fin: 31/12/2014 Entidades participantes: IUBO-AG Universidad de La Laguna Cuantía Global : 86.212.50 € IP: Dr. D. José Manuel Padrón Carillo

The Spanish ion channel initiative Resúmen Los canales iónicos son proteínas de membrana que realizan un papel clave en todas las normas de vida, presentando una estructura altamente conservada de bacterias a humanos. La actividad de los canales iónicos ha sido reconocida como un soporte importante de la homeostasis celular y el mantenimiento de la salud por más de medio siglo. Debido a su contribución a la fisiopatogenia de varias enfermedades, estas proteínas han sido el blanco de

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diversos fármacos, desde antiepilépticos a analgésicos. Es más, la disfunción de los canales iónicos es por si misma la causa de muchas dolencias, acuñadas con el nombre de canalopatías. Más de 40 canalopatías asociadas a mutaciones genéticas de canales iónicos han sido descritas. A pesar de la intensa investigación en este excitante campo, existen todavía un elevado número de preguntas que carecen de respuesta, como son: i) la composición y papel de los complejos de señalización de canales iónicos en salud y enfermedad; iii) la estructura atómica de las subunidades que forman el poro de los canales y de sus complejos proteicos; iii) el conocimiento de las bases moleculares, estructurales y celulares de muchas canalopatías; y, iv) el descubrimiento de moduladores específicos que puedan ser útiles como herramientas farmacológicas y/o candidatos para fármacos. El estudio de estas complejas cuestiones requiere el establecimiento de un programa integrado de investigación pluridisciplinar en canales iónicos que aúne las metodologías necesarias y las coordine para cubrir exitosamente estas lagunas de nuestro conocimiento. Este es precisamente el objetivo primordial de IECI, convertirse en una referencia en investigación y formación que reúna todos los aspectos relacionados con los canales iónicos, desde genes, proteínas, células, sistemas y organismos hasta comportamiento, desde ciencia básica a la clínica. Por tanto, IECI persigue la innovación mediante la integración. Los objetivos principales de IECI son: i) coordinar y facilitar programas de innovación científica que creen un centro virtual de excelencia en investigación integrada en canales iónicos; ii) formar a jóvenes investigadores en un amplio abanico de metodologías y técnicas en canales iónicos, incluyendo función, estructura, fisiopatología y farmacología; iii) estimular colaboraciones aportando los recursos, personal y equipamiento para proyectos conjuntos; iv) atraer nuevos grupos de investigación al campo de los canales iónicos; y, v) promover y fortalecer la interacción entre ciencia básica y clínica y la industria. Esta iniciativa integrada de investigación pluridisciplinar en canales iónicos está organizada en cuatro grupos/nodos basados en conocimiento que están altamente interrelacionados, a saber, función, estructura, fisiopatología y farmacología. Para conseguir sus objetivos, IECI reúne a un equipo multidisciplinar compuesto de fisiólogos, bioquímicos, biólogos moleculares y estructurales, biofísicos, farmacólogos, y químicos. Además, IECI no se crea como un consorcio cerrado sino que pretende ser una iniciativa abierta a todos aquellos grupos académicos, clínicos e industriales que Consolider 2008 deseen adherirse al programa. La aportación de IECI será la generación de conocimiento innovador en el campo de los canales iónicos que resultará en: i) tecnología novedosa transferible; ii) estrategias terapéuticas originales para el tratamiento de enfermedades mediadas por disfunción de los canales iónicos; y, iii) un programa de formación integrado en canales iónicos para estudiantes pre- y post-doctorales. Por tanto, IECI cumplirá los dos objetivos cardinales de un programa multidisciplinar e integrado, a saber, crear conocimiento y tecnología innovadora y transferible e impulsar un programa formativo integrado. Summary Ion channels are membrane proteins that play crucial roles in all forms of life and are highly conserved from bacteria to humans. The activity of ion channels has been recogized as a important to cellular homeostasis and health maintenance for more than half a century. Because of their contribution to the patophysiology of several human maladies, these proteins have been the target of diverse drugs, from antiepileptic to analgesics. Furthermore, ion cannel dysfunction is itself the cause of human diseases, a pathological condition coined by the term channelopathy. More than 40 different channelopathies caused by genetic defects in ion channels have been reported. Despite the intense research in this exciting field, a plethora of issues remain poorly understood. These include: i) the composition, structure and role of signalling channel complexes in health and disease; ii) the atomic structure of the pore forming subunits and the channel complexes; iii) the knowledge on the molecular and cellular basis of channelopathies, as well as the implication of ion channels in the aetiology of other human

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diseases; iv) the discovery of more selective channel modulators that could be useful as pharmacological tools or drug leads. Addressing these key and complex questions requires an integrative and pluridisciplinary ion channel program that brings together all of the required complementary skills and coordinates them in order to successfully fill these gaps in our knowledge. This is precisely the main objective of SICI: to become a reference research and training programme that embraces all aspects of ion channels from genes and proteins, cells, systems and organisms to behaviour, and from basic research to the clinic. Thus, SICI pursues innovation through integration. The main objectives of SICI are: i) to coordinate and facilitate innovative research programmes that build on a virtual centre of excellence in integrative ion channel research; ii) to educate talented young scientists in a range of multidisciplinary methodologies and technologies in integrative ion channel research including channel function, structure, physiopathology and pharmacology; iii) to foster collaborative efforts by providing core resources, personnel and equipment for concerted research; iv) to bring new research groups and technologies to the field of integrative ion channel research; and v) to promote and strengthen the links between basic science, clinic and industry. This integrative ion channel research initiative is functionally organized into four distinct but highly interrelated, knowledge-based working groups or nodes encompassing channel function, structure, physiopathology and pharmacology. To accomplish this goal, SICI assembles a multidisciplinary team comprised of physiologists, biochemists, biophysicists, structural biologists, chemists and pharmacologists. SICI is not envisioned as a restricted consortium but rather Consolider 2008 seeks to be an open program for academic, clinical and industrial partners that may wish to join the initiative at a later stage. The major outcome of SICI will be the generation of innovative knowledge in the ion channel arena that will result in: i) ground-breaking, transferable technology; ii) original ion channel therapeutics for the treatment of human disorders; and, iii) an integrated educational program on ion channels for graduated and postgraduate students. Thus, SICI will fulfil the two main goals of an integrated, pluridisciplinary project, namely, to create innovative, transferable and exploitable knowledge and technology and to foster integrative training. Entidad financiadora: Comisión Europea/MCT/CONSOLIDER (CSD2008-00005) Entidades participantes: Duración: Desde: 2009; Hasta: 2014 Cuantía: 6.000.000 €. (296.000€ a nuestro grupo) Investigador responsable: Antonio V. Ferrer Montiel Número de investigadores participantes: 26 Código: CSD2008-00005 Universidad o Centro de Investigación del investigador principal: Universidad de La Laguna Otros investigadores: Ricardo Borges Jurado

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Chemical programming of Toll like Receptor 4: Design, synthesis and biological studies of prostatecancer vaccines The IOF proposal, TLRPROSTATE, consists of a 24 month outgoing phase to The Scripps Research Institute in San Diego, California, and a 12 month return phase to the Instituto de Productos Naturales y Agrobiología (IPNA-CSIC) for a total of 36 months. TLRPROSTATE will use advanced methods in synthetic biology to develop synthetic vaccines against prostate cancer, which is the second most common cancer worldwide for men. The project will consist of the design, synthesis and biological evaluation of synthetic vaccines that will chemically stimulate the toll-like receptors and therefore create an immune response. This exciting research area will increase Miranda’s expertise and knowledge in the field of synthetic biology as well as in the synthesis of complex organic molecules. During the return phase, Miranda will integrate his research findings into the studies carried out by the research group at IPNA. The return of knowledge and skills to the Canary Islands, Spain, will take place at a time when there is an increasing support from the government and also European authorities for the development of the Canary Islands as a nerve center in Biomedical studies through research programs partially financed by European funding. Beneficiario: Dr. Pedro O. Miranda Chinea Cód. según financiadora: 623155-TLRPROSTATE Fecha de inicio: 05/01/2015 , 3 años Fecha fin: 05/01/2018 Entidades participantes: Consejo Superior de Investigaciones Científicas; The Scripps Research Institute Cuantía proyecto: 341.387,10 € Científico Responsable: Dr. Juan I. Padrón Peña

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Estudio fitoquímico en plantas nativas del estado de veracruz para la búsqueda de sustancias con aplicaciones terapéutica Si bien es cierto que en los últimos cincuenta años se han descubierto una gran gama de medicamentos contra el cáncer, actualmente no hay una cura efectiva contra todas las patologías del cáncer, por lo que se hace necesaria la continua búsqueda de nuevos fármacos que sean más potentes y/o menos tóxicos.6 Es evidente que un estudio fitoquímico de plantas nativas del estado de Veracruz, como el que se propone en este proyecto, iniciará una quimioteca de extractos y compuestos puros que en futuro podría sentar las bases para el desarrollo de nuevos fármacos anticancerígenos, esto representará un valioso recurso económico para México, al tiempo que permitirá un mejor conocimiento quimiotaxonómico de especies nativas del estado de Veracruz, evitando así posibles casos de biopiratería. Además de lo anterior, este proyecto permitirá sentar las bases para el desarrollo de la línea de investigación Productos Naturales en la Facultad de Bioanálisis-Campus Veracruz, la cual tiene todo el potencial para dar resultados muy importantes, debido a la privilegiada situación geográfica del estado de Veracruz. Número de investigadores/as: 4 Cód. según financiadora: UV-PTC-650 Fecha de inicio: 01/01/2013 , 1 año Fecha fin: 31/12/2014 Entidades participantes: Facultad de Bioanálisis Universidad Veracruzana; IUBO-AG Universidad de La Laguna Cuantía bproyecto: $ 323.637 equivale a 17.980 € IP: Dr. D. Francisco A. Cen Pacheco.

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Búsqueda de metabolitos bioactivos en sistemas de arrecifes veracruzanos: estudios estructurales, farmacológicos y biotecnológicos Si bien es cierto que en los últimos cincuenta años se han descubierto un gran número de medicamentos anticancerígenos, antimicrobianos y antifúngicos, se estima que más de la mitad de estas enfermedades aun no tienen un tratamiento satisfactorio, esto es debido al gran número de patologías existentes del cáncer, a los brotes de cepas fármaco-resistentes por el uso inmoderado de medicamentos y a la falta de respuesta del sistema inmune en pacientes inmunodeficientes, por lo que se hace evidente la necesidad de descubrir nuevos fármacos que posean mecanismos de acción más específicos y potentes. Desde el punto de vista de la búsqueda de inhibidores específicos sobre dianas enzimáticas, los procesos de fosforilación y desfosforilación catalizados por enzimas quinasas y fosfatasas están considerados como uno de los mecanismos más importantes en el control de los procesos intracelulares. Las fosfatasas poseen un rol importante en numerosos mecanismos de señalización celular asociados a enfermedades como el cáncer, la diabetes y el alzheimer, lo cual ha motivo a la comunidad científica a diseñar nuevos fármacos contra estas dianas. Por tal motivo, en este proyecto se propone la búsqueda de inhibidores de estas enzimas, particularmente las fosfatasas serina y treonina de tipo 1 (PP1) y 2A (PP2A), ya que son utilizadas como herramientas farmacológicas en el estudio de enfermedades como el cáncer, osteoporosis, diabetes y el alzheimer. Tradicionalmente las principales fuentes de sustancias bioactivas han sido organismos terrestres, su estudio ha permitido el aislamiento de más de la mitad de los principios activos que se comercializan en la actualidad, sin embargo su amplia exploración ha hecho que cada vez sea más difícil encontrar nuevas moléculas con actividades terapéuticas prometedoras. En comparación el mar está lejos de considerarse estudiado, un mundo duro y agresivo y en el que durante millones de años, innumerables formas de vida han evolucionado, originando que estos organismos produzcan una inmensa variedad de compuestos químicos con gran diversidad estructural y potentes actividades farmacológicas. En los últimos 20 años la llamada “Biotecnología Azul”, se ha ido convirtiendo en una de las principales fuentes de sustancias que están siendo usadas para curar de numerosas enfermedades. Este potencial se basa en que los océanos abarcan cerca del 70 % de la extensión del planeta y su diversidad biológica el 95 % de la biosfera. Número de investigadores/as: 6 Cód. según financiadora: CONACyT 220206Fecha de aprobación: 26/06/2014, 3 años Fecha fin: 26/06/2016

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Entidades participantes: Facultad de Bioanálisis, Facultad de Ciencias Biológicas y Agropecuarias y Centro de Estudio y Servicio en Salud de la Universidad Veracruzana; IUBO-AG de la Universidad de La Laguna. Cuantía proyecto: $ 1400.000 equivale a 77.778 € IP: Dr. D. Francisco A. Cen Pacheco.

Búsqueda de sustancias citotóxicas a partir de hongos microscópicos En este proyecto, se pretende iniciar una nueva línea de trabajo con búsqueda sistemática de sustancias citotóxicas a partir de hongos de diferentes ecosistemas, con la finalidad de aprovechar este potencial químico a partir de estos recursos bióticos prácticamente sin explotar en México. Para ello, se llevará a cabo el aislamiento de cepas fúngicas de tres diferentes tipos de hongos (fitopatógenos terrestres, marinos de algas, esponjas y corales y hongos endófitos de manglar). Después, se realizarán cultivos líquidos y a partir de éstos se harán extractos con cloroformo-metanol y así, seleccionar las cepas que presenten mayor actividad citotóxica en cada uno de los tres grupos. Una vez seleccionadas las tres cepas de interés, se realizarán sus cultivos masivos. Posteriormente, se trabajará con la extracción y purificación por técnicas cromatográficas de los metabolitos bioactivos de los cultivos masivos. Finalmente, los compuestos así obtenidos, serán identificados por técnicas espectroscópicas (RMN, MS, IR, RX, etc) y serán evaluados para determinar nuevamente su citotoxicidad. Entidad finanaciadora: Fondo Sectorial de Investigación para la Educación, Consejo Nacional de Ciencia y Tecnología (CONACYT) Convocatoria Ciencia Básica SEP/CONACYT 2012. (Vigente). CB-2012-01: 181820 Investigador Principal: Angel Trigos Landa,

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Generación de diversidad Esqueletal en lupanos como herramienta en la búsqueda de nuevos agentes anticancerosos Entidad finanaciadora: Fondo Sectorial de Investigación para la Educación, Consejo Nacional de Ciencia y Tecnología (CONACYT) y la Secretaría de Educación Pública (SEP) Méjico) (referencia: 221886) Entidades participantes: Universidad del Yucatan, IPNA-CSIC Duración: 01/01/2015 hasta 31/12/2017. Cuantía: 85.000€ Investigador Principal: Rubén Marrero Carballo, Juan I. Padrón

Caracterizacion quimica de los metabolitos secundarios obtenidos de las especies nativas de la región sur del Perú Según estudios científicos, los metabolitos secundarios obtenidos de recursos marinos son una fuente fundamental de diversidad química estructural por lo que es posible caracterizar y descubrir nuevas estructuras químicas interesantes en las algas Ankistrodesmus sp, Tetraselmis striata (microalgas), y la Lessonia trabeculata y Lessonia nigrescens (macroalgas). Entidad finanaciadora:Ministerio de la Producción. Programa Nacional de Innovación para la Competitividad y Productividad Convocatoria Ciencia Básica CONCYTEC 2014 Investigador Principal: Teresa Cano

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11. PUBLICACIONES

Chem. Commun., 2014, 50, 3685-3688

-Hydroxy- -lactones as nucleophiles in the Nicholas reaction for the synthesis of oxepene rings. Enantioselective formal synthesis of (-)-isolaurepinnacin and (+)-rogioloxepane A

-Lopez, Nuria Ortega, and Tomas Martín

The enantioselective formal synthesis of ( )-isolaurepinnacin and (+)-rogioloxepane A has been achieved. The key steps are an intermolecular Nicholas reaction with a b-hydroxy-c-lactone as the nucleophile, to form branched linear ethers, and an olefin ring-closing metathesis to obtain the oxepene core.

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Synlett 2014, 25, 12-32 Strategies for the Synthesis of Cyclic Ethers of Marine Natural Products Tomás Martín, Juan I. Padrón and Víctor S. Martín

This account describes our studies addressed to the synthesis of natural products containing cyclic ethers in their structure. An overview of the main methodologies and several total syntheses developed by the group will be described. Also will discuss new applications based on the use of Prins and Nicolas reactions used as key steps in the preparation of oxygenated heterocyclic compounds.

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Synthesis 2014, 46, 2451-2462 Oxazole/Thiazole and Triazole Hybrids Based on -Amino Acids Guillermo Valdomir, Juan I. Padrón, José M. Padrón, Víctor S. Martín, Danilo Davyt

The Cu(I)-catalyzed Hüisgen [3+2] cycloaddition is the basis of click chemistry to synthesize triazole derivatives by coupling azides with ethynyl blocks. In the development of new compounds inspired by bioactive natural products, the synthesis of new oxazole building blocks containing azide moiety and coupling them with aromatic alkynes via triazole linker is described. These oxazole building blocks are synthesized using amino acids as chiral and inexpensive starting materials. Using this approach, 16 new triazole-oxazole hybrids were synthesized.

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Medicinal Chemistry 2014, 10, 571-579 Antiproliferative Evaluation of N-sulfonyl-2-alkyl-six Membered Azacycles. A QSAR Study Rubén M. Carballo, Leticia G. León, Ramiro F. Quijano-Quiñones, Gonzalo J. Mena-Rejón, Víctor S. Martín, José M. Padrón, Juan I. Padrón

A series of functionalized N-sulfonyl-piperidines and N-sulfonyl-tetrahydropyridines were evaluated for their antiproliferative activity against the representative panel of human solid tumor cells A2780 (ovarian), SW1573 (non-small cell lung) and WiDr (colon). The SAR study showed for WiDr cells a correlation between the biological activity and the length of the N-sulfonyl group, the nature of the substituents and the type of alkyl side chain. Further QSAR studies indicate that the size and nature of the N-sulfonyl group, the atomic polarizability (MP) and the partition coefficient are the most important descriptors for the activity. The major contribution is the size (F05C-S) of the N-sulfonyl group

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J. Org. Chem., 2014, 79, 6775–6782 Direct Stereoselective Synthesis of Enantiomerically Pure anti- - Amino Alcohols

-Dorta, Osvaldo J. Donadel, Víctor S. Martín, and José M.

Enantiomerically pure anti- -amino alcohols -(N,N-

-amino acids, by the sequential reduction to aldehyde with DIBAL-H at anti- -amino alcohols, anti-2-amino-1,3- diols and anti-3-amino-1,4-diols were obtained in good yields (60with free hydroxyl groups present in the substrate. To demonstrate the versatility of the method, spisulosine and sphinganine were synthesized in two steps from the appropriate N,N-dibenzyl-L-aminobenzyl ester in 42% and 45% yield, respectively .

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RSC Advances 2015, 5, 6647-6651 A practical, catalytic and selective deprotection of a Boc group in N,N´-diprotected amines using iron(III)-catalysis Juan M. López-Soria, Sixto J. Pérez, J. Nicolás Hernández, Miguel A. Ramírez, Víctor S. Martín, and Juan I. Padrón

A selective, catalytic and practical method for removing a Boc group from several N, N´-diprotected amino acids and amine derivatives using iron(III) salts as sustainable catalysts is described. The process is clean, not being necessary a purification step. A theoretical study rationalizing the results with several metals is presented. .

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Mar. Drugs 2014, 12, 5503-5526 Inhibition of Bacterial Quorum Sensing by Extracts from Aquatic Fungi: First Report from Marine Endophytes Alberto J. Martín-Rodríguez, Fernando Reyes, Jesús Martín, Juan Pérez-Yépez, Milagros León-Barrios, Alan Couttolenc, César Espinoza, Ángel Trigos, Víctor S. Martín, Manuel Norte and José J. Fernández

In our search for quorum-sensing (QS) disrupting molecules, 75 fungal isolates were recovered from reef organisms (endophytes), saline lakes and mangrove rhizosphere. Their QS inhibitory activity was evaluated in Chromobacterium violaceum CVO26. Four strains of endophytic fungi

characterization, based on the internal transcribed spacer (ITS) region sequences (ITS1, 5.8S and ITS2) between the rRNA of 18S and 28S, identified these strains as belonging to four genera: Sarocladium (LAEE06), Fusarium (LAEE13), Epicoccum (LAEE14), and Khuskia (LAEE21). Interestingly, three came from coral species and two of them came from the same organism, the coral Diploria strigosa. Metabolic profiles obtained by Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) suggest that a combination of fungal secondary metabolites and fatty acids could be the responsible for the observed activities. The LC-HRMS analysis also revealed the presence of potentially new secondary metabolites. This is, to the best of our knowledge, the first report of QS inhibition by marine endophytic fungi.

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Mar. Drugs 2014, 12, 5188-5196 New Oxidized Zoanthamines from a Canary Islands Zoanthus sp. Francisco Cen-Pacheco, Manuel Norte Martín, José Javier Fernández and Antonio Hernández Daranas

Three new norzoanthamine-type alkaloids, named 2-hydroxy-11-ketonorzoan thamide B (1), norzoanthamide B (2) and 15-hydroxynorzoanthamine (3), were isolated from Zoanthus sp. specimens collected at the Canary Islands. Their structures were determined by interpretation of NMR and HR-ESIMS data. Relative configurations of their chiral centers were proposed on the basis of ROESY spectra and by comparison of their spectroscopic data with those of the well-known compound, norzoanthamine.

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Mar. Drugs 2014, 12, 4031-4044 Stereochemical Determination of Five-Membered Cyclic Ether Acetogenins Using a Spin-Spin Coupling Constant Approach and DFT Calculations Adrián Gutiérrez-Cepeda, Antonio Hernández Daranas, José J. Fernández, Manuel Norte, and María L. Souto

Five-membered rings are of particular interest, due to their presence in some of the most common molecules in chemistry and biology. Despite their apparent simplicity, the structural resolution of these rings is complex, due to their inherent conformational flexibility. Here, we describe an application of a recently reported simple and efficient NMR protocol based on the measurement of spin-spin coupling constants to achieve the challenging relative configurations of five new halogenated C15 tetrahydrofuranyl-acetogenins, marilzafurollenes A–D (1–4) and 12-acetoxy-marilzafurenyne (5), isolated from the red alga, Laurencia marilzae. Although DFT chemical shift calculations were used to connect remote stereocenters, the NMR-based approach seems advantageous over computational techniques in this context, as the presence of halogens may interfere with reliable calculations.

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Mar. Drugs 2014, 12, 176-192 Stereochemistry of Complex Marine Natural Products by Quantum Mechanical Calculations of NMR Chemical Shifts: Solvent and Conformational Effects on Okadaic Acid Humberto J. Domínguez, Guillermo D. Crespín, Adrián J. Santiago-Benítez, José A. Gavín, Manuel Norte, José J. Fernández and Antonio Hernández Daranas

Marine organisms are an increasingly important source of novel metabolites, some of which have already inspired or become new drugs. In addition, many of these molecules show a high degree of novelty from a structural and/or pharmacological point of view. Structure determination is generally achieved by the use of a variety of spectroscopic methods, among which NMR (nuclear magnetic resonance) plays a major role and determination of the stereochemical relationships within every new molecule is generally the most challenging part in structural determination. In this communication, we have chosen okadaic acid as a model compound to perform a computational chemistry study to predict 1H and 13C NMR chemical shifts. The effect of two different solvents and conformation on the ability of DFT (density functional theory) calculations to predict the correct stereoisomer has been studied.

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Org. Lett., 2014, 16, 2880–2883 Zoaramine, a Zoanthamine-like Alkaloid with a New Skeleton Francisco Cen-Pacheco, Manuel Norte, José J. Fernández, and Antonio Hernández Daranas

Chemical investigation of an Atlantic variety of Zoanthus sp. led to the isolation of two new metabolites, zoaramine and zoarenone. Their structures were deduced by the use of NMR spectroscopy and computational calculation of 1H and 13C chemical shifts. The core of these novel compounds resembles the structure of norzoanthamine alkaloids, and their isolation represents an important step toward a better understanding of the biogenetic origin of this group of antiosteoporotic molecules.

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Org. Lett., 2014, 16, 4546–4549 Belizentrin, a Highly Bioactive Macrocycle from the Dinoflagellate Prorocentrum belizeanum Humberto J. Domínguez, José G. Napolitano, M. Teresa Fernández-Sánchez, David Cabrera-García, Antonello Novelli, Manuel Norte, José J. Fernández, and Antonio Hernández Daranas

Belizentrin (1), a novel 25-membered polyketide-derived macrocycle, was isolated from cultures of the marine dinoflagellate Prorocentrum belizeanum. This metabolite is the first member of an unprecedented class of polyunsaturated and polyhydroxylated macrolactams. The structure of 1 was primarily determined by NMR and computational methods. Pharmacological assays with cerebellar cells showed that 1 produces important changes in neuronal network integrity at nanomolar concentrations.

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BMC Microbiology 2014, 14:102 On the influence of the culture conditions in bacterial antifouling bioassays and biofilm properties: Shewanella algae, a case study Alberto J Martín-Rodríguez, Alejandro González-Orive, Alberto Hernández-Creus, Araceli Morales, Roberto Dorta-Guerra, Manuel Norte, Víctor S Martín and José J Fernández

Both the medium and the temperature significantly influenced the total cell densities and biofilm biomasses in 24-hour cultures. Likewise, the IC50 of three antifouling standards (TBTO, tralopyril and zinc pyrithione) was significantly affected by the medium and the initial cell density. Four media (Marine Broth, MB; 2% NaCl Mueller-Hinton Broth, MH2; Luria Marine Broth, LMB; and Supplemented Artificial Seawater, SASW) were selected to explore their effect on the morphological and nanomechanical properties of 24-h biofilms. Two biofilm growth patterns were observed: a clear trend to vertical development, with varying thickness and surface coverage in MB, LMB and SASW, and a horizontal, relatively thin film in MH2. The Atomic Force Microscopy analysis showed the lowest Young modulii for MB (0.16 ± 0.10 MPa), followed by SASW (0.19 ± 0.09 MPa), LMB (0.22 ± 0.13 MPa) and MH2 (0.34 ± 0.16 MPa). Adhesion forces followed an inverted trend, being higher in MB (1.33 ± 0.38 nN) and lower in MH2 (0.73 ± 0.29 nN). All the parameters significantly affected the ability of S. algae to grow and form biofilms, as well as the activity of antifouling molecules. A detailed study has been carried out in order to establish a biofilm model for further assays. The morphology and nanomechanics of S. algae biofilms were markedly influenced by the nutritional environments in which they were developed. As strategies for biofilm formation inhibition and biofilm detachment are of particular interest in antifouling research, the present findings also highlight the need for a careful selection of the assay conditions.

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PLOS ONE 2014, 9, e101045 The Neanderthal Meal: A New Perspective Using Faecal Biomarkers Ainara Sistiaga, Carolina Mallol, Bertila Galva, Roger Everett Summons

Neanderthal dietary reconstructions have, to date, been based on indirect evidence and may underestimate the significance of plants as a food source. While zooarchaeological and stable isotope data have conveyed an image of Neanderthals as largely carnivorous, studies on dental calculus and scattered palaeobotanical evidence suggest some degree of contribution of plants to their diet. However, both views remain plausible and there is no categorical indication of an omnivorous diet. Here we present direct evidence of Neanderthal diet using faecal biomarkers, a valuable analytical tool for identifying dietary provenance. Our gas chromatography-mass spectrometry results from El Salt (Spain), a Middle Palaeolithic site dating to ca. 50,000 yr. BP, represents the oldest positive identification of human faecal matter. We show that Neanderthals, like anatomically modern humans, have a high rate of conversion of cholesterol to coprostanol related to the presence of required bacteria in their guts. Analysis of five sediment samples from different occupation floors suggests that Neanderthals predominantly consumed meat, as indicated by high coprostanol proportions, but also had significant plant intake, as shown by the presence of 5b-stigmastanol. This study highlights the applicability of the biomarker approach in Pleistocene contexts as a provider of direct palaeodietary information and supports the opportunity for further research into cholesterol metabolism throughout human evolution.

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Science 2014, 345, 1609 Early Levallois technology and the Lower to Middle Paleolithic transition in the Southern Caucasus D. S. Adler, K. N. Wilkinson, S. Blockley, D. F. Mark, R. Pinhasi,B. A. Schmidt -Magee, S. Nahapetyan, C. Mallol, F. Berna, P. J. Glauberman, Y. Raczynski -Henk, N. Wales, E. Frahm, O. Jöris, A. MacLeod, V. C. Smith, V. L. Cullen, B. Gasparian

The Lower to Middle Paleolithic transition (~400,000 to 200,000 years ago) is marked by technical, behavioral, and anatomical changes among hominin populations throughoutAfrica and Eurasia. The replacement of bifacial stone tools, such as handaxes, by tools made on flakes detached from Levallois cores documents the most important conceptual shift in stone tool production strategies since the advent of bifacial technology more than one million years earlier and has been argued to result from the expansion of archaic Homo sapiens out of Africa. Our data from Nor Geghi 1, Armenia, record the earliest synchronic use of bifacial and Levallois technology outside Africa and are consistent with the hypothesis that this transition occurred independently within geographically dispersed, technologically precocious hominin populations with ashared technological ancestry.

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Archaeol Anthropol Sci 2014, DOI 10.1007/s12520-014-0217-0 Radiometric dates and micromorphological evidencefor synchronous domestic activity and sheep penningin a Neolithic cave: Cueva de El Toro (Málaga, Antequera, Spain) Natalia Égüez & Carolina Mallol & Dimas Martín-Socas & M. Dolores Camalich

We present radiocarbon dates and preliminary mi- cromorphological information from the Neolithic cave site of Cueva del Toro (Antequera, Málaga, Spain). This site has yielded a rich early and late Neolithic archaeological record. The late Neolithic assemblage reflects specialized handcraft activity including in situ ceramic manufacture, textile produc- tion, and food processing along with sheep and goat penning, suggesting that the cave occupants and their domestic animals shared the same living space. Until now, dating of the strati- graphic sequence was incomplete, and the function of the combustion activities carried out at the cave remained unclear. New absolute dates from the main late Neolithic domestic activity area, corresponding to the most intense Neolithic occupation of the cave, allow us to place the entire sequence between 5320 and 5170 BP (or 4250–results show that many combustion fea- tures from this site represent recurrently burnt episodes on sheep/goat stabling deposits all along the sequence, corrobo- rating human-goat/sheep cohabitation. This practice had not been previously documented in southern Spain for such early dates. Our results exemplify the importance of characterizing archaeological deposits at a microstratigraphic scale of observation.

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Journal of Human Evolution 2014, 75, 16-27 New evidence of early Neanderthal disappearance in the Iberian Peninsula Bertila Galván, Cristo M. Hernández, Carolina Mallol, Norbert Mercier, Ainara Sistiaga, Vicente Soler

The timing of the end of the Middle Palaeolithic and the disappearance of Neanderthals continue to be strongly debated. Current chronometric evidence from different European sites pushes the end of the Middle Palaeolithic throughout the continent back to around 42 thousand years ago (ka). This has called into question some of the dates from the Iberian Peninsula, previously considered as one of the last refuge zones of the Neanderthals. Evidence of Neanderthal occupation in Iberia after 42 ka is now very scarce and open to debate on chronological and technological grounds. Here we report thermolumi- nescence (TL) and optically stimulated luminescence (OSL) dates from El Salt, a Middle Palaeolithic site in Alicante, Spain, the archaeological sequence of which shows a transition from recurrent to sporadic human occupation culminating in the abandonment of the site. The new dates place this sequence within MIS 3, between ca. 60 and 45 ka. An abrupt sedimentary change towards the top of the sequence suggests a strong aridification episode coinciding with the last Neanderthal occupation of the site. These results are in agreement with current chronometric data from other sites in the Iberian Peninsula and point towards possible breakdown and disappearance of the Neanderthal local population around the time of the Heinrich 5 event. Iberian sites with recent dates (<40 ka) attributed to the Middle Palaeolithic should be revised in the light of these data.

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Journal of Human Evolution 2014, 75, 16-27 Neanderthals from El Salt (Alcoy, Spain) in the context of the latest Middle Palaeolithic populations from the southeast of the Iberian Peninsula María Dolores Garralda, Bertila Galván, Cristo M. Hernández, Carolina Mallol, José A. Gómez, Bruno Maureille

We present a bioanthropological study of dental remains recovered from El Salt Middle Palaeolithic site (Alcoy, Alicante, Spain). The dental remains were found in a sedimentary layer representing a calm depositional environment within a freshwater spring system. The corresponding archaeological context comprises a Middle Palaeolithic faunal and lithic assemblage that represents the last documented evi- dence of human occupation at the site, dating to between 47.2 ` 4.4 and 45.2 ` 3.4 ka (thousands of years ago). This evidence is overlain by an archaeologically sterile deposit dated to 44.7 ` 3.2 ka. Results show that the teeth belong to a single juvenile or young adult individual with morphological and metric features falling within the Neanderthal range of variability, although the considered traits are not taxonomically highly discriminant. The reported fossils are representative of the latest Middle Palae- olithic groups in the region and may be considered in the ongoing debate on the disappearance of Neanderthals and the end of the Middle Palaeolithic.

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Menga. Revista de prehistoria de andalucía no 05. 2014. Pp. 270-273. Issn 2172-6175 Revista Mainake, 33 (Tema Monográfico), Servicio de Publicaciones, Centro de Ediciones de la Diputación de Málaga, 2011-2012, 284 páginas, ISSN: 0212-078-X Neanderthales en Iberia: Últimos avances en la investigación del Paleolítico Medio Ibérico Carolina Mallol Desde hace varias décadas, la península ibérica ha sido un foco de atención de la investigación en torno al mundo neandertal, y en especial los últimos milenios de vida de esta población prehistórica. Por su situa- ción geográfica, la península ha sido considerada como cul de sac; una región periférica de interacción entre neandertales y humanos anatómi- camente modernos. Atendiendo alas hipótesis tradicionales sobre el Paleolítico Medio final peninsular,la zona suroccidental actuó como refugio neandertal (Finlayson etal., 2008; Jennings et al., 2011), el Ebro representó una barrera que separaba a la población neandertal (al sur) de los primeros grupos del Paleolítico Superior, que venían del norte (Zilhao, 2006) y en el norte peninsular, los últimos neanderta- les acabaron por retirarse a zonas montañosas marginales (Baena Preysler et al., 2012). Sin embargo, en los últimos años, y a partir deuna revisión exhaustiva de datacio- nes radiométricas a escala europea (Higham, 2011), se ha reavivado el debate en torno a la transición del Paleolítico Medio al Superior y el ocaso de los neandertales en Euro- pa, la cual ahora se sitúa en torno a 42 ka BP, un par de milenios atrás de lo que se conocía anteriormente. Con respecto al contexto peninsular, las últimas dataciones también retrasan varios milenios el final del Paleolíti- co Medio (Maroto et al., 2012; Wood et al., 2013; Galván et al., 2014), lo cual resulta significativo para los yacimientos más representativos de las hipótesis de perduración (e.g., Jarama VI y Zafarraya).

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PNAS 2014, 111, 14394–14399 Early modern human settlement of Europe north of the Alps occurred 43,500 years ago in a cold steppe-type environment Philip R. Nigsta, Paul Haesaertsc, Freddy Damblonc, Christa Frank-Fellnerd, Carolina Mallol, Bence Viola, Michael Götzinger, Laura Niven, Gerhard Trnka, and Jean-Jacques Hublin

The first settlement of Europe by modern humans is thought to have occurred between 50,000 and 40,000 calendar years ago (cal B.P.). In Europe, modern human remains of this time period

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are scarce and often are not associated with archaeology or originate from old excavations with no contextual information. Hence, the behavior of the first modern humans in Europe is still unknown. Aurignacian assemblages—demonstrably made by modern humans—are com- monly used as proxies for the presence of fully behaviorally and anatomically modern humans. The site of Willendorf II (Austria) is well known for its Early Upper Paleolithic horizons, which are among the oldest in Europe. However, their age and attribution to the Aurignacian remain an issue of debate. Here, we show that archaeological horizon 3 (AH 3) consists of faunal remains and Early Aurignacian lithic artifacts. By using stratigraphic, paleoenvironmen- tal, and chronological data, AH 3 is ascribed to the onset of Green- land Interstadial 11, around 43,500 cal B.P., and thus is older than any other Aurignacian assemblage. Furthermore, the AH 3 assem- blage overlaps with the latest directly radiocarbon-dated Neander- thal remains, suggesting that Neanderthal and modern human presence overlapped in Europe for some millennia, possibly at rather close geographical range. Most importantly, for the first time to our knowledge, we have a high-resolution environmental con- text for an Early Aurignacian site in Central Europe, demonstrating an early appearance of behaviorally modern humans in a medium- cold steppe-type environment with some boreal trees along valleys around 43,500 cal B.P.

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Journal of Archaeological Science 2014, 41, 813-817 Steroidal biomarker analysis of a 14,000 years old putative human coprolite from Paisley Cave, Oregon A. Sistiaga, F. Berna, R. Laursen, P. Goldberg

Lipid components of a putative human coprolite sample from the Paleoindian site of Paisley Cave, Oregon (12,300 14C yr BP) were analyzed using GC/MS to explore its origin in light of controversial data obtained from mitochondrial DNA, cross-immunoelectrophoresis, trisodium phosphate rehydration, and micro- morphology analyses. Results show the predominant presence of 5b-stigmastanol, the biomarker of herbivore fecal matter, supporting micromorphological identification of the coprolite as herbivore. This study highlights the potential of the biomarker approach in coprolite studies devoted to research on the first presence of humans in North America.

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European Journal of Medicinal Chemistry 2014, 73, 265-279 Synthesis and biological activity of polyalthenol and pentacyclindole analogues Isidro S. Marcos, Rosalina F. Moro, Isabel Costales, Pilar Basabe, David Díez, Ana Gil, Faustino Mollinedo, Fátima Pérez-de la Rosa, Eduardo Pérez-Roth, José M. Padrón

A series of indole sesquiterpenes analogues of polyalthenol and pentacyclindole have been synthesized starting from ent-halimic acid in order to test their biological activity. These analogues include diverse oxidation levels at the sesquiterpenyl moiety and different functionalization on the indole ring. All synthetic derivatives were tested against a representative panel of Gram positive and Gram negative bacterial strains, and the human solid tumour cell lines A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon). Overall, the compounds presented activity against the cancer cell lines. The resulting lead, displaying a polyalthenol scaffold, showed GI50 values in the range 1.2e5.7 mM against all cell lines tested.

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European Journal of Medicinal Chemistry 2014, 77, 176-184 QSAR on antiproliferative naphthoquinones based on a conformation-independent approach Pablo R. Duchowicz, Daniel O. Bennardi, Daniel E. Bacelo, Evelyn L. Bonifazi, Carla Rios-Luci, José M. Padrón, Gerardo Burton, Rosana I. Misico

The antiproliferative activities of a series of 36 naphthoquinone derivatives were subjected to a Quan- titative StructureeActivity Relationships (QSAR) study. For this purpose a panel of four human cancer cell lines was used, namely HBL-100 (breast), HeLa (cervix), SW-1573 (non-small cell lung) and WiDr (colon). A conformation-independent representation of the chemical structure was established in order to avoid leading with the scarce experimental information on X-ray crystal structure of the drug interaction. The 1179 theoretical descriptors derived with E-Dragon and Recon software were simultaneously analyzed through linear regression models based on the Replacement Method variable subset selection technique. The established models were validated and tested through the use of external test sets of compounds, the Leave-One-Out Cross Validation method, Y-Randomization and Applicability Domain analysis.

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European Journal of Medicinal Chemistry 2014, 82, 68-81 Antiproliferative and quinone reductase-inducing activities of withanolides derivatives Manuela E. García, Viviana E. Nicotra, Juan C. Oberti, Carla Ríos-Luci, Leticia G. León, Laura Marler, Guannan Li, John M. Pezzuto,Richard B. van Breemen, José M. Padrín, Idaira Hueso-Falcón, Ana Estévez-Braun

Two new and five known withanolides (jaborosalactones 2, 3, 4, 5, and 24) were isolated from the leaves of Jaborosa runcinata Lam. We also obtained some derivatives from jaborosalactone 5, which resulted to be the major isolated metabolite. The natural compounds as well as derivatives were evaluated for their antiproliferative activity and the induction of quinone reductase 1 (QR1; NQ01) activity. Structureeac- tivity relationships revealed valuable information on the pharmacophore of withanolide-type com- pounds. Three compounds of this series showed significantly higher antiproliferative activity than jaborosalactone 5. The effect of these compounds on the cell cycle was determined. Furthermore, the ability of major compounds to induce QR1 was evaluated. It was found that all the active test compounds are monofunctional inducers that interact with Keap1. The most promising derivatives prepared from jaborosalactone 5 include (23R)-4b,12b,21-trihydroxy-1,22-dioxo-12,23-cycloergostan-2,5,17,24-tetraen- 26,23-olide (18) and (23R)-21-acetoxy-12b-hydroxy-1,22-dioxo-12,23-cycloergostan-2,5,17,24-tetraen- 26,23-lactame (20).

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Behavioural Brain Research 2015, 278, 98–106 Mice lacking chromogranins exhibit increased aggressive and depression-like behaviour Daniel Pereda, Marta R. Pardo, Yezer Morales, Natalia Dominguez, Maria Rosa Arnau, Ricardo Borges

Chromogranins are acidic proteins; both chromogranins A and B constitute the main protein component in the vesicular matrix of large dense core vesicles. Chromogranins are a natural source of peptides with different physiological activities that have been associated with vascular and neurological diseases. We have used three different genetic mutant models of mice lacking chromogranin A, chromogranin B and both all on the same C57BL/6J background, to characterize the physiological roles of these proteins using metabolic, cardiovascular and behavioural tests. In mice from 3 to 18 months of age, the lack of any chromogranin promoted age-dependent hypersensitivity to insulin, while the lack of both chromogranins provoked progressive lack of response to stress, as restriction did not promote tachycardia in old mice. Moreover, the lack of chromogranin B produced a depressive-like and aggressive phenotype, while the lack either or both chromogranins increased barbering behaviour. In addition, we observed no effects on light–dark box or RotaRod tests. Mice lacking chromogranin B exhibited lower exploratory activity. Based on this extensive phenotyping with more than 2800 mice, these findings support roles of chromogranins, or the peptides derived from them, in the control of aggressive behaviour along with changes in their metabolic profile beyond their previously described activities in the secretory pathway.

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BMJ 2014; 348:g1806 doi: 10.1136/bmj.g1806 PERSONAL VIEW

We need a global system to help identify new uses for existing drugs A centralised, worldwide system, similar to the existing “yellow cards” collected for adverse drug events, could amass the huge numbers of data needed, writes Ricardo Borges “Identification of potential therapeutic targets for new drugs” is a phrase commonly used in grant proposals in both basic and clinical research. Every year drug companies produce and patent hundreds of new drugs that have been assessed in preclinical tests. However, despite this enormous effort and cost, the number of new drugs in the formularies and available to clinicians is ever declining, and the general feeling is that this will persist. Many drugs are already used for therapeutic purposes that are different from those that were initially intended. Examples include the use of antidepressants as analgesics,2 antiepileptics such as topiramate for migraine prevention,3 antihistamine drugs as over the counter sleep aids, sildenafil for sexual impotence,4 and methotrexate for arthritis.5 Several drugs used to treat diseases of the central nervous system have other uses, after clinical improvements were seen that were unrelated to the disease originally targeted. Examples include promethazine6 and imipramine,7 and tetrabenazine and its derivatives, which were recently approved for chorea associated with Huntington’s disease. …../….

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European Journal of Medicinal Chemistry 2014, 86, 724-739 Chalcones as positive allosteric modulators of a7 nicotinic acetylcholine receptors: A new target for a privileged structure Beatriz Balsera, José Mulet, Asia Fernandez-Carvajal, Roberto de la Torre-Martínez, Antonio Ferrer-Montiel, José G. Hernández-Jiménez d, Judith Estévez-Herrera,Ricardo Borges, Andiara E. Freitas, Manuela G. López e, M. Teresa García-López a, Rosario González-Muñiz, María Jesús Pérez de Vega, Luis M. Valor, Lucie Svobodova, Salvador Sala, Francisco Sala, Manuel Criado

The a7 acetylcholine nicotine receptor is a ligand-gated ion channel that is involved in cognition dis- orders, schizophrenia, pain and inflammation among other diseases. Therefore, the development of new agents that target this receptor has great significance. Positive allosteric modulators might be advan- tageous, since they facilitate receptor responses without directly interacting with the agonist binding site. Here we report the search for and further design of new positive allosteric modulators having the relatively simple chalcone structure. From the natural product isoliquiritigenin as starting point, chal- cones substituted with hydroxyl groups at defined locations were identified as optimal and specific promoters of a7 nicotinic function. The most potent compound (2,4,20 ,50 -tetrahydroxychalcone, 111) was further characterized showing its potential as neuroprotective, analgesic and cognitive enhancer, opening the way for future developments around the chalcone structure.

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The FASEB Journal 2014, 28, 4657-4667 The interaction between chromogranin A and catecholamines governs exocytosis Natalia Dominguez, Judith Estevez-Herrera, Ricardo Borges, and Jose D. Machado

Chromogranins (Cgs) are acidic proteins that have been described in the large, dense core vesicles (LDCVs) of adrenal chromaffin cells and that have been shown to promote LDCV formation, even in nonsecretory cells. Catecholamines (CAs) are adsorbed by Cgs in vitro, and the absence of Cgs modifies the storage and exocytosis of CAs in chromaffin cells. In this study, we set out to assess the role of CgA in the accumulation and exocytosis of CAs in cells when the levels of CgA and CA are manipulated. We overex- pressed CgA in nonsecretory HEK293 cells and in secretory PC12 cells, to study the formation, move- ment, and exocytosis of newly formed granules by evanescent wave microscopy. We analyzed the associa- tion of Cgs/CA by HPLC and amperometry and their role in the accumulation and exocytosis of amines, both under resting conditions and after L-DOPA overload- ing. To our knowledge, this is the first demonstration that CgA expression in a nonsecretory cell line facili- tates the storage and exocytosis of CA. In addition, CgA overexpression causes a doubling of the accumulation of CA, although it slows down exocytosis in PC12 cells. We propose a model to explain how the CgA/CA complex governs the accumulation and exocytosis of secreted amines.—Dominguez, N., Estevez-Herrera, J., Borges, R., Machado, J. D. The interaction between chromogranin A and catecholamines governs exocyto- sis

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Bioorg. Med. Chem. Lett. 2014, 24, 2105–2109 Cytotoxic diterpenes from roots of Crossopetalum gaumeri, a Celastraceae species from Yucatan Peninsula Gumersindo Miron-Lopez, Isabel L. Bazzocchi, Ignacio A. Jimenez-Diaz, Laila M. Moujir, Ramiro Quijano-Quiñones, Leovigildo Quijano, Gonzalo J. Mena-Rejon

Four new diterpenes, crossogumerins A–D (1–4) along with six known ones (5–10) were isolated from the root bark of Crossopetalum gaumeri, an endemic medicinal plant from the Yucatan Peninsula. Their structures were elucidated on the basis of 1D and 2D NMR techniques, including HMQC, HMBC, and ROESY experiments. Compounds 1–5, 8–10 were evaluated for cytotoxicity against HeLa (carcinoma of the cervix) and Hep-2 (lung carcinoma) human tumor cells lines and against normal Vero cells (African green monkey kidney) in lag and log phase of growth. Podocarpane diterpenes, crossogumerin B (2) and nimbiol (10), exhibited the highest activity against HeLa cells (IC50 values of 3.1 and 8.1 lM, respectively), but also selectivity on Vero cells (SI 22.6 and 7.5, respectively). The preliminary SAR studies suggest that an epoxy moiety in ring B and a hydrogen bond-donor group strategically positioned in the diterpene core are important requirements for cytotoxicity and selectivity.

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Journal of Natural Products 2015, 78, pp 736–745 Restoration of Chemosensitivity in P-Glycoprotein -Dependent Multidrug-Resistant Cells by Dihydro- -agarofuran Sesquiterpenes from Celastrus vulcanicola Oliver Callies, María P. -Cañete, FranciscoGamarro, IgnacioA. , Santiago Castanys, and Isabel L. Bazzocchi

Multidrug resistance (MDR) caused by theoverexpression of ABC drug transporters is a major obstacle inclinical cancer chemotherapy and underlines the urgent needdevelopment of new, potent, and safe reversal agents.Toward this goal, reported herein are the structure elucidationand biological activity of nine new (1dihydro- -agarofuran sesquiterpenes, isolated fromthe leaves of Celastrus vulcanicola, as reversers of MDRm ediated by human P-glycoprotein expression. The structures of these compounds were elucidated by extensive NMR spectroscopic and mass spectrometric analysis, and their absolute configurations were determined by circular dichroism studies, chemical correlations (1a, 8a, and 8b), and biogenetic means. Four compounds from this series were discovered as potent chemosensitizers for MDR1-G185 NIH-3T3 murine cells (3, 4, 6, and 7), showing higher efficacies than the classical P- glycoprotein inhibitor verapamil, a first-generation chemosensitizer, when reversing resistance to daunomycin and vinblastine at the

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Phytochemistry 2014, 105, 60–67 Elaeodendron orientale as a source of cytotoxic cardenolides Alex A. Osorio, Manuel R. López, Ignacio A. Jiménez, Laila M. Moujir, Matías L. Rodríguez, Isabel L. Bazzocchi

In the present study, we report six cardiac glycosides (1–6) along with four known ones (7–10) isolated from the leaves and fruits of Elaeodendron orientale. Their stereostructures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR, and the absolute configuration of 1 was determined by X-ray diffraction analysis. The compounds were evaluated for growth inhibitory activity against a panel of human cancer cell lines, HeLa, A-549, MCF-7 and HL-60, and normal Vero cells. Four compounds from this series (5 and 7–9, IC50 values ranging from 0.01 to 0.07 lM) exhibited cytotoxicity against three of the cancer cell lines assayed that was similar to or higher than the well-known therapies digoxin and digitoxigenin. Taking into account the narrow safety range of cardiac glycosides used in clinic, this series shows a selectivity index higher than 3 for three of the cancer cell lines assayed, increasing their interest for further study.

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Phytomedicine 2014, 21, 1689–1694 In vitro effects of triterpenic acids from olive leaf extracts on the mitochondrial membrane potential of promastigote stage of Leishmania spp Ines Sifaoui, Atteneri López-Arencibia, Carmen Ma Martín-Navarro,Juan Carlos Ticona, María Reyes-Batlle, Mondher Mejri, Antonio Ignacio Jiménez, Isabel Lopez-Bazzocchi, Basilio Valladares, Jacob Lorenzo-Morales,Manef Abderabba , José E. Piñero

Protozoan diseases, such as leishmaniasis, are a cause of considerable morbidity throughout the world, affecting millions every year. In this study, two triterpenic acids (maslinic and oleanolic acids) were isolated from Tunisian olive leaf extracts and their in vitro activity against the promastigotes stage of Leishmania (L.) infantum and Leishmania (L.) amazonensis was investigated. Maslinic acid showed the highest activity with an IC50 of 9.32 ± 1.654 and 12.460 ± 1.25 g/ml against L. infantum and L. amazo- nensis, respectively. The mechanism of action of these drugs was investigated by detecting changes in the phosphatidylserine (PS) exposure, the plasma membrane permeability, the mitochondrial membrane potential and the ATP level production in the treated parasites. By using the fluorescent probe SYTOX® Green, both triterpenic acids showed that they produce a time-dependent plasma membrane perme- abilization in the treated Leishmania species. In addition, spectrofluorimeteric data revealed the surface exposure of PS in promastigotes. Both molecules reduced the mitochondrial membrane potential and decreased the ATP levels to 15% in parasites treated with IC90 for 24 h. We conclude that the triterpenic acids tested in this study, show potential as future therapeutic alternative against leishmaniasis. Further studies are needed to confirm this.

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Electrophoresis 2014, 35, 2479–2487 Determination of estrogens in environmental water samples using 1,3-dipentylimidazolium hexafluorophosphate ionic liquid as extraction solvent in dispersive liquid–liquid microextraction Bárbara Socas-Rodríguez, Javier Hernández-Borges, María Asensio-Ramos, Antonio V. Herrera-Herrera, Jose A. Palenzuela, Miguel Ángel Rodríguez- Delgado

In this work, the potential of a symmetric dialkyl-substituted ionic liquid (IL), 1,3- dipenthylimidazolium hexafluorophosphate ([PPIm][PF6]), as extraction solvent in dis- persive liquid–liquid microextraction (DLLME) has been studied for the analysis of a group of three natural (estriol, 17b-estradiol, and 17 -estradiol) and four synthetic (17b- ethynylestradiol, diethylstibestrol, dienestrol, and hexestrol) estrogenic compounds as well as one mycotoxin with estrogenic activity (zearalenone) in different types of water samples (Milli-Q, mineral, and wastewater). Separation, determination, and quantification were developed by HPLC-DAD and a fluorescence detector (FD) connected in series. Factors influencing the IL-DLLME procedure (sample pH, amount of IL, type and volume of dis- perser solvent, ionic strength, and assistance of vortex agitation) were investigated and optimized by means of a step-by-step approach. Once the optimum extraction conditions were established (10 mL of water at pH 8, 60 mg of [PPIm][PF6], 500 L of ACN as dis- perser solvent and vortex agitation for 1 min), the calibration curves of the whole method (IL-DLLME-HPLC-DAD/FD) were obtained and precision and accuracy were evaluated. It was demonstrated that the developed methodology was repeatable, accurate, and selective with limits of detection in the 0.30–0.57 ug/L and 13.8–37.1 ug/L range for FD and DAD, respectively. Relative recovery values were higher than 85% for the different types of water samples and the Student’s t test demonstrated that there were not significant differences between the added and the found concentration.

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Organic Letters 2014, 16, 552 – 555 Artículo destacado en el Synfacts 2014, 10, 370 Expedient Synthesis of C3-Symmetric Hexasubstituted Benzenes via Nicholas Reaction/[2 + 2 + 2] Cycloaddition. New Platforms for Molecular Recognition Romen Carrillo, Tomás Martín, Matías López-Rodríguez, and Fernando Pinacho Crisóstomo.

An expedient methodology to synthesize macrocyclic compounds in one step based on the Nicholas reaction is disclosed. The key step features two intermolecular reactions followed by an intramolecular reaction from the starting dicobalt hexacarbonyl–propargylic complex. The macrocycles obtained were modified through [2 + 2 + 2] cycloaddition, generating two new C3-symmetric hexasubstituted benzene structures suitable for molecular recognition purposes.

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Acta Cryst. B, 2014, 70, 19 – 27 Three new europium(III) methanetriacetate metal-organic frameworks: the influence of synthesis on the product topology Laura Cañadillas-Delgado, Óscar Fabelo, Jorge Pasán, Mariadel Déniz, Carla Martínez-Benito, Pau Díaz-Gallifa, Tomás Martín and Catalina Ruiz-Pérez. Three new metal-organic framework structures containing EuIII and the little explored methanetriacetate (C7H7O6

3 ,mta3 ) ligand have been synthesized. Gel synthesis yields a two-dimensional framework with the formula [Eu(mta)-(H2O)3]n·2nH2O, (I), while two polymorphs of the threedimensional framework material [Eu(mta)(H2O)]n·nH2O, (II) and (III), are obtained through hydrothermal synthesis at either 423 or 443 K. Compounds (I) and (II) are isomorphous with previously reported GdIII compounds, but compound (III) constitutes a new phase. Compound (I) can be described in terms of dinuclear [Eu2(H2O)4]6+ units bonded through mta3 ligands to form a two-dimensional framework with topology corresponding to a (6,3)-connected bimodal (43)(466683)-kgd net, where the dinuclear [Eu2(H2O)4]6+ units are considered as a single node. Compounds (II) and (III) have distinct three-dimensional topologies, namely a (41263)(4966)-nia net for (II) and a (41065)(41164)-K2O2; 36641 net for (III). The crystal density of (III) is greater than that of (II), consistent with the increase of temperature, and thereby autogeneous pressure, in the hydrothermal synthesis.

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Angew. Chem. Int. Ed, 2014, 53, 2181 – 2185 Artículo destacado en el Synform 2014/05 y en el Synfacts 2014, 10, 454 Ascorbic Acid as an Initiator for the Direct C-H Arylation of (Hetero)arenes with Anilines Nitrosated In Situ Fernando Pinacho Crisóstomo, Tomás Martín, Romen Carrillo.

Ascorbic acid (vitamin C) has been used as a radical initiator in a metal-free direct C-H arylation of (hetero)arenes. Starting from an aniline, the corresponding arenediazonium ion is generated in situ and immediately reduced by vitamin C to an aryl radical that undergoes a homolytic aromatic substitution with a (hetero)arene. Notably, neither heating nor irradiation is required. This procedure is mild, operationally simple, and constitutes a greener approach to arylation.

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Chem. Eur. J., 2014, 20, 4007 – 4022 Synthesis and Conformational Analysis of Cyclic Homooligomers from

–Sugar Amino Acids Andrés Feher-Voelger, Jorge Borges-González, Romen Carrillo, Ezequiel Q. Morales, Javier González-Platas, Tomás Martín.

New pyranoid -sugar amino acids were designed as building blocks, in which the carboxylic acid and the amine groups were placed in positions C2 and C3 with respect to the tetrahydropyran oxygen atom. By using standard solution-phase coupling procedures, cyclic homooligomers containing pyranoid -sugar amino acids were synthesized. Conformation analysis was performed by using NMR spectroscopic experiments, FTIR spectroscopic studies, X-ray analysis, and a theoretical conformation search. These studies reveal that the presence of a methoxy group in the position C4 of the pyran ring produces an important structural change in the cyclodipeptides. When the methoxy groups are present, the structure collapses through interresidue hydrogen bonds between the oxygen atoms of the pyran ring and the amide protons. However, when the cyclodipeptide lacks the methoxy groups, a U-shape structure is adopted, in which there is a hydrophilic concave face with four oxygen atoms and two amide protons directed toward the center of the cavity. Additionally, we found important evidence of the key role played by weak electrostatic interactions, such as the five-membered hydrogen-bonded pseudocycles (C5) between the amide protons and the ether oxygen atoms, in the conformation equilibrium of the macrocycles and in the cyclization step of the cyclic tetrapeptides.

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Tetrahedron 2014, 70, 8480-8487 Indium catalyzed solvent-free multicomponent synthesis of cytotoxic dibenzo[a,h]anthracenes from aldehydes, 2-hydroxy-1,4-naphthoquinone, and 2-naphthol Idaira Hueso-Falcón a, Ángel Amesty, Patricia Martín, Matías López-Rodríguez, Leandro Fernández-Pérez b, Ana Estévez-Braun

A series of dibenzo[a,h]anthracene derivatives were synthesized through a straightforward, one-pot protocol based on a three-component reaction with 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes, and 2-naphthol as synthetic inputs, using InCl3 a catalyst under solvent-free conditions. Most of the obtained ortho-quinonic adducts were cytotoxic against HEL and MCF-7 tumoral cell lines.

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Clin Transl Oncol 2015, 17, 74–84 A new family of choline kinase inhibitors with antiproliferative and antitumor activity derived from natural products A. Estévez-Braun, A. G. Ravelo, E. Pérez-Sacau , J. C. Lacal Background Choline kinase alpha (ChoKa) is a critical enzyme in the synthesis of phosphatidylcholine, a major structural component of eukaryotic cell membranes. ChoKa is overexpressed in a large variety of tumor cells and has been proposed as a target for personalized medi- cine, both in cancer therapy and rheumatoid arthritis. Materials and methods Triterpene quinone methides (TPQ) bioactive compounds isolated from plants of the Celastraceae family and a set of their semisynthetic derivatives were tested against the recombinant human ChoKa. Those found active as potent enzymatic inhibitors were tested in vitro for antiproliferative activity against HT29 colorectal adenocarcinoma cells, and one of the active compounds was tested for in vivo antitumoral activity in mice xenographs of HT29 cells.natural and semisynthetic TPQs tes- ted in an ex vivo system, 14 were highly active as inhibitors of the enzyme ChoKa with IC50 \10 lM. Nine of these were potent antiproliferative agents (IC50 \10 lM) against tumor cells. At least one com- pound was identified as a new antitumoral drug based on its in vivo activity against xenographs of human HT-29 colon adenocarcinoma cells. Conclusions The identification of a new family of natural and semisynthetic compounds with potent inhibitory activity against ChoKa and both in vitro antiproliferative and in vivo antitumoral activity supports further research on these inhibitors as potential anticancer agents. Their likely role as antiproliferative drugs deserves further studies in models of rheumatoid arthritis.

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Bioorganic & Medicinal Chemistry 2014, 22, 3341–3350 Preparation, anticholinesterase activity and molecular docking of new lupane derivatives María Julia Castro, Victoria Richmond, Carmen Romero, Marta S. Maier, Ana Estévez-Braun, Ángel G. Ravelo, María Belén Faraoni, Ana Paula Murray

A set of twenty one lupane derivatives (2–22) was prepared from the natural triterpenoid calenduladiol (1) by transformations on the hydroxyl groups at C-3 and C-16, and also on the isopropenyl moiety. The derivatives were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcho- linesterase (BChE) and some structure–activity relationships were outlined with the aid of enzyme kinetic studies and docking modelization. The most active compound resulted to be 3,16,30-trioxolup- 20(29)-ene (22), with an IC50 value of 21.5 lM for butyrylcholinesterase, which revealed a selective inhibitor profile towards this enzyme.

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Journal of Natural Products 2014, aceptado y en prensa Structure and Antimicrobial Activity of Phloroglucinol Derivatives from Achyrocline satureioides Carina Casero, F Machín, -Álvarez, Mirta Demo, Ángel G.Ravelo, Nury - , PedroJoseph-Nathan, and Ana -Braun

-pyrones 1the known 23-methyl-6-O-demethylauricepyrone (5), achyrofuran (6), and 5,7-dihydroxy-3,8-dimethoxyflavone (gnaphaliin A), were isolated from the aerial parts of Achyrocline satureioides. Their structures were determined by 1D and 2D NMR spectroscopic studies, while the absolute configuration of the sole stereogenic center of 1 was established by vibrational circular dichroism measurements in comparison to density functional theory

-methylbutyryl chain attached to the phloroglucinol nucleus was assumed for compounds 2 6 based on biogenetic considerations. Derivatives 7of the isolated metabolites and some of the semisynthetic derivatives against a selected panel of Gram-positive and Gram-negative bacteria, as well as a set of yeast molds, were determined

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Biochemical Pharmacology 2014, 92, 206–219 Yeast cytotoxic sensitivity to the antitumour agent b-lapachone depends mainly on oxidative stress and is largely independent of microtubule- or topoisomerase-mediated DNA damage Cristina Ramos-Pérez, Isabel Lorenzo-Castrillejo, Oliver Quevedo, Jonay García-Luis, Emiliano Matos-Perdomo, Chaxiraxi Medina-Coello, Ana Estévez-Braun, Félix Machín

-Lapachone ( -lap) is a promising antitumour drug currently undergoing clinical trials. Although it is known that b-lap generates reactive oxygen species (ROS), its actual mechanism of action is still controversial. Especially important is to determine whether concomitant DNA or microtubule damage is the key target of its antitumour properties and whether DNA damage is mediated by topoisomerases as previously suggested. Here, we have searched for determinants of b-lap cytotoxicity in the model organism Saccharomyces cerevisiae through a mechanism-driven approach whereby several pathways of the DNA and microtubule integrity responses, as well as the anti- oxidant response, were downregulated and the outcome of b-lap treatment examined. We also included in the analysis several -lap derivatives expected to modify drug bioavailability and activity. We found that neither topoisomerase II nor microtubules contributed to yeast sensitivity to b-lap and its equitoxic derivative 3-bromo-b-lapachone. Instead, we found that oxidative and related environmental stresses were primarily responsible for toxicity. Accordingly, Yap1, the central transcription factor in the antioxidant response in yeast, together with several components involved in stress tolerance (i.e., Snf1 and Hog1) and chromatin remodelling (i.e., the SWR1 and RSC complexes), played major roles in protection against b-lapachone. Critically, we show that dioxygen enhanced toxicity and that ROS scavengers protected cells from it. Furthermore, we show that both quinones resulted in cell death in a manner which cytologically resembled apoptosis/necrosis. We thus conclude that b-lap is toxic to yeast through massive ROS production that either directly kills the cells or else triggers programmed cell death.

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Journal of Natural Products 2014, 77, 1853

-Agarofurans and Sesquiterpene Pyridine Alkaloids from Maytenus spinosa

-Nicolas, Juan C. Oberti, Ángel G.Ravelo, and Ana -Braun

-dihydroagarofurans (1 four new sesquiterpene pyridine alkaloids (10were isolated from the leaves of Maytenus spinosa. Their structures were determined mainly by 1D- and 2D-NMR spectroscopic studies. The absolute configuration of compound 6 was established using CD spectroscopy. Several derivatives (14sesquiterpene 13. Most of the sesquiterpenoids were tested for anti-HIV activity, but only compound 1 was found to be active.

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J Clust SciDOI 10.1007/s10876 -014-0720-6 Linkage Isomerism in [Mo3(l3-S)(l2-SSe)3(dtp)3]Cl: Preparation and Characterization of Two Isomers with Different Coordination Mode of the l2-SSe Ligand Rita Hernández-Molina, Artem Gushchin, Cristian Vicent, Pedro Gili

Two geometrical isomers of the composition [Mo3S4Se3(dtp)3]Cl (dtp is O,O0-diethyldithiophosphate) have been prepared and characterized by multinuclear NMR, electrospray ionization mass spectrometry (ESI–MS) and quantum chemical calculations. The first isomer was prepared by reaction of the aqua cluster ([Mo3(l3- S)(l2-Se)3(H2O)9]4?) with a large excess of P4S10/EtOH in 2 M HCl. Its structure corresponds to [Mo3(l3-S)(l2-Seax-Seq)3(dtp)3]Cl (1). The second isomer, [Mo3(l3- S)(l2-Sax-Seeq)3(dtp)3]Cl (2) was prepared by the reaction of [Mo3S7Cl6]2- with SePPh3 followed by treatment with a stoichiometric amount of P4S10/EtOH. The reason for the isomerism is that the l2-SSe ligand is coordinated asymmetrically, so that one chalcogen atom is almost coplanar with the Mo3 plane (called equatorial) and the other one is strongly out of the plane (axial). Alternative occupancy of these positions by S or Se leads to a rare kind of linkage isomerism. Each isomer has distinctive spectro- scopic signature and fragmentation pattern in ESI–MS. Isomer 2 with l2-SaxSeeq.

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Chem. Eur. J. 2015, 21, 2835 – 2844 Mechanism of [3+2] Cycloaddition of Alkynes to the [Mo3S4(acac)3(py)3] [PF6] Cluster Jose Ángel Pino- -Trujillo, Rita Hernández-Molina, Cristian Vicent, Andrés G. Algarra, and Manuel G. Basallote

A study, involving kinetic measurements on test opped-flow and conventional UV/Vis timescales, ESI-MS, NMR spectroscopy and DFT calculations, has been carried out to understand the mechanism of the reaction of [Mo3S4(acac)3(py)3][PF6] ([1]PF6 ; acac = acetylacetonate, py = pyridine) with two RC=CR alkynes (R = CH2OH (btd), COOH (adc)) in CH3CN. Both reactions show polyphasic kinetics, but experimental and computational data indicate that alkyne activation occurs in a single kinetic step through a concerted mechanism similar to that of organic [3 + 2] cycloaddition re- actions, in this case through the interaction with one Mo(m- S) moiety of [1]+. The rate of this step is three orders of 2 magnitude faster for adc than that for btd, and the products initially formed evolve in subsequent steps into compounds that result from substitution of py ligands or from reorgani- zation to give species with different structures. Activation strain analysis of the [3 + 2] cycloaddition step reveals that the deformation of the two reactants has a small contribu- tion to the difference in the computed activation barriers, which is mainly associated with the change in the extent of their interaction at the transition-state structures. Subse- quent frontier molecular orbital analysis shows that the car- boxylic acid substituents on adc stabilize its HOMO and LUMO orbitals with respect to those on btd due to better electron-withdrawing properties. As a result, the frontier mo- lecular orbitals of the cluster and alkyne become closer in energy ; this allows a stronger interaction

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Journal of Structural Chemistry 2014, 55, 1478-1483 Synthesis and structure -methyl-2-phenylpiridine)2]with intermolecular stacking interactions R. Hernández Molina, A. Agirretxu, and J. González-Platas

The preparation of a copper(I) iodide complex with a N-donor ligand 3-methyl-2-phenylpyridine of formula [CuI(3-methyl-2-phenylpiridine)2] is described. The isolated complex was characterized by elemental analyses, IR spectroscopy and crystallographic studies. Single crystal X-Ray diffraction analysis of the complex reveal their monomeric tri-coordinated nature. The coordination polyhedron around the copper center may be described as a distorted trigonal planar geometry. The Cu–N distances for this compound are 1.984(7) Å and 1.982(7) Å, while the Cu–I distance is 2.5507(9) Å.