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Nouveaux Ligands De Quadruplexes. Approches in Silico Et in Vitro

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Nouveaux Ligands De Quadruplexes. Approches in Silico Et in Vitro THESE DE DOCTORAT DES UNIVERSITÉS BORDEAUX I ET BORDEAUX SEGALEN Ecole Doctorale Sciences de la Vie et de la Santé Spécialité : Biochimie Présentée par Daimel CASTILLO GONZÁLEZ Pour obtenir le grade de Docteur de l’Université de Bordeaux Nouveaux ligands de quadruplexes. Approches in silico et in vitro . Thèse dirigée par le Dr. Jean-Louis MERGNY Soutenue le 14 novembre 2013 devant le jury composé de: Pr. Mathy Froeyen KU. Leuven, Belgique Président Dr. Jacques Chomilier UPMC, Paris, France Rapporteur Dr. Genevieve Pratviel Université de Toulouse, France Rapporteur Pr. Sandro Cosconati Université de Naples, Italie Examinateur Pr. Maria Natália Dias Soeiro Université de Porto, Portugal Examinateur Dr. Jean-Louis Mergny Université de Bordeaux, France Directeur de thèse DEDICO ESTE TRABAJO A Ernesto, por su luz, por la fuerza, por la vida. A Gladys, por el apoyo, la inspiración, la constancia, la confianza, la incondicionalidad. A Luis y Morbila, por el amor, la ternura, los cuidados, madrugones, la educación y todas las leches con azúcar, café y sal. A Alain, por la humanidad, por las manos amigas siempre a tiempo y salvadoras. AGRADECIMIENTOS “Honrar, honra”, escribió hace más de un siglo José Martí, el más universal de los cubanos. Quisiera, pues, agradecer a los que de alguna manera han contribuido al desarrollo de la presente investigación. Al concilio interuniversitario flamenco (Bélgica), por financiar el proyecto “Strengthening postgraduate education and research in Pharmaceutical Sciences” de la cual esta investigación es parte. Al proyecto de la AECID (España) “Montaje de un laboratorio de química computacional, con fines académicos y científicos, para el diseño racional de nuevos candidatos a fármacos en enfermedades de alto impacto social (D/024153/09)” y a INSERM U869. Al doctor Jean-Louis Mergny, no solo por recibirme en su laboratorio y facilitarme el uso de sus instalaciones, sino también por dejarme hacer e innovar, sintiendo siempre su respaldo y su guía. A los profesores doctores Miguel Ángel Cabrera y Gisselle Pérez Machado, quienes asesoraron los primeros pasos de esta labor científica en la Universidad de Las Villas (Cuba). En la misma institución, a los profesores Dr. Luis Bravo, Dr. Leisy Nieto, Dr. Mirta Mayra González, Dr. Julio Omar Prieto, MSc. Luis Torres y MSc. Enoel Hernández. Y a mis colegas y amigos cubanos del Grupo de Diseño de Fármacos: Reynaldo, Aliuska, Maikel X, Chiqui y el Guille. A Guy, Josefa y María, por su facilitación logística, siempre a tiempo. A quienes más tarde, en los laboratorios europeos, continuaron ofreciéndome el mismo apoyo desinteresado y decisivo: los profesores doctores Arthur van Aerschoft, Teresa María Garriguez Pelufo y María Teresa Varea. A los especialistas y técnicos del laboratorio INSERM U869, en Burdeos por ser compañeros y amigos: Aurore, Amandine, Anne, Samir, Gilmar, Katy, Thao, Amina, Rui, Abdelazziz y Souheila. Al profesor doctor Mathy Froeyen, por sus oportunas revisiones, apreciables críticas y sabios consejos. A los doctores Prof. Sandro Cosconati, Prof. Maria Natália Dias Soeiro, Prof. Mathy Froeyen, Dr. Jacques Chomilier y Dr. Genevieve Pratviel, que aceptaron evaluar mi trabajo e integrar el tribunal para su defensa. A Ronal Ramos, por estar en la génesis de esta labor. A Maikel Pérez: dondequiera que estés, ojalá puedas ver estos resultados. A los jesuitas de la comunidad Campanar, en Valencia: Jesús, Mariano, Ramiro, Tony, Pedro y Joaquín. A Encarna. A Liane, por la hermandad, la complicidad, la alegría, el apoyo. A los amigos de toda la vida, los nuevos y los viejos, por tolerarme, ayudarme y, sobre todo, por hacerme reír: Aramís, Durán, Maylén, el Tyler, las Roxsis, Yaíma, Lesbia, Pilar, Misael, Alain, Rafa, Gelsy... Gracias por estar y por ser tan especiales. A mi familia, pues siempre me ha acompañado en la luz y en la sombra: mamá, mami, papi, tigre, Andrés, pompón, Laura Pi, Luis Enrique, tío Carlos, Brian y Misdelkis. A todos, mi agradecimiento sincero. ACKNOWLEDGEMENTS “To honor do us honor”, wrote José Martí about a century ago, who has been considered the most universal of the Cubans. Following this lead I would like to thank all the people that in many ways contributed to this research. I am thankful to the Flemish Interuniversity Council (VLIR/UOS) for funding the project: “Strengthening postgraduate education and research in Pharmaceutical Sciences”, of which this research is part. Likewise I am grateful to the AECID project: “Montaje de un laboratorio de química computacion al, con fines académicos y científicos, para el diseño racional de nuevos candidatos a fármacos en enfermedades de alto impacto social (D/024153/09)” and INSERM U869 for the financial support provided to this research . I would also like to express a deep sense of gratitude to Dr. Jean-Louis Mergny not only for the warm welcome that he gave me in his laboratory, providing me with all kind of equipment I needed for my research, but also for allowing me to innovate and work in an independent way, knowing that I could always count on his support and the guide of his scientific experience. In this sense it is also a pleasure for me to recognize the contribution of Prof. Dr Miguel Ángel Cabrera and Dr. Gisselle Pérez Machado from Universidad Central de Las Villas (UCLV), who advised me in the first steps of this research. I would also like to thank to Dr. Luis Bravo, Dr. Leisy Nieto, Dr. Mirta Mayra González, Dr. Julio Omar Prieto, MSc. Luis Torres and MSc. Enoel Hernández from the same institution for their support. I am deeply grateful to my colleagues from the Molecular Simulation and Drug Design (MSDD) group of UCLV in Cuba: Aliuska, Maikel X, Reynaldo, Chiqui and Guille for sharing with me their friendship, ideas and knowledge. I offer my sincerest gratitude to Guy, Josefa and Maria for their guidance in the laboratory. It is also very important for me to thank the persons that later in the European laboratories were very supportive for me: Prof. Dr Arthur Van Aerschot, Prof. Dr. Teresa María Garriguez Pelufo, Prof. Dr. María Teresa Varea as well as a whole team of friendly and capable specialists and technicians Aurore, Amandine, Anne, Samir, Gilmar, Katy, Thao, Amina, Rui, Abdelazziz and Souheila. I would like to thank Prof. Dr. Mathy Froeyen for providing remarks that stimulated me to improve the discussion of the results and all the thesis committee members for accepting to assess the results of my work done during the last 4 years and finalize this thesis. I offer my utmost appreciation to Ronal Ramos for being the genesis of this work and to Maykel Perez, who encouraged me in the beginning of this investigation; wishing you would have seen the results. I have many friends I would like to thank for their unselfish support in my most difficult times, like the Jesuit from the Campanar community in Valencia: Jesús, Mariano, Ramiro, Tony, Pedro and Joaquín. Thanks Encarma. Thanks Liane for the friendship, your joy, complicity and unselfish support. I am thankful to the friends, the ones that have been there all my life and the new ones Aramís, Durán, Maylén, el Tyler, the Roxsis, Yaíma, Lesbia, Pilar, Misael, Alain, Rafa, Gelsy for helping me to get through my moments of frustrations and making my years of PhD more smooth and amusing. Last but not least I would like to express special gratitude to my family that has always been there for me: mamá, mami, papi, tigre, Andrés, pompón, Laura Pi, Luis Enrique, tío Carlos, Brian and Misdelkis. To all of you my most sincere thanks. Contents Abbreviations……………………………………………………………………………….…….… I Key words/Mots-clés ….…………………………………………………………………………… III Abstract……………………………………………………………………………………...……… IV Résumé étendu en français ………………...………………………………………………………. VI Introduction ……………………...………………………………………………………………..... 1 Chapter 1. Telomeres, telomerase, and guanine qu adruplexes. Main concepts….…………….. 16 1.1 Formation of G-quadrupl exes by DNA……………………………………………………... 16 1.2 Telomeres structure and function…… .…………………………………………………..….. 17 1.3 Telomerase: Role in the cellular senes cence and cancer…… ... ……………………..……… 18 1.4 Cellular senescence and t elomerase…………… ... ……………………………..…………… 22 1.5 Role of telomerase in cellular immortalization………………… .………………...………… 22 1.6 Genetic disorders, telomeres, an d telomerase………………………………………..……… 23 1.7 Elongation of telomeres independent ly of telomerase…………………….………………… 24 1.8 Prevalence of guanine-rich sequences in genomic regions………………… .………….…… 25 1.9 G-quadruplex structures as therapeutic targets in telomerase-positive cell lines …… ... ……. 26 1.10 Comparison of different G-quadruplex targeted anticancer strategies… .…………………. 30 Chapter 2. Concepts and useful parameters for in silico studies..…………………………….… 32 2.1 Molecular Descript ors…… .……….…..……………………………………………….……. 32 2.2 Chemome trics………………………………… .……………………………………………. 37 2.2.1 Cluster anal ysis..…… .……………………………………………………..…………. 37 2.2.2 Classi fication…… .……………………………………………………………………. 37 2.2.3 Parameters for measuring the quality of discriminant analysis…………… .. …..……. 38 2.2.4 Regression a nalysis…… .………………………………………………………..……. 39 2.2.5 Regression p arameters………………………………………………………..………. 40 2.2.6 Goodness o f prediction…… .…………………………………………………………. 42 2.3 Genetic algorithm (GA) for the sele ction of variables………… .……… .…… .……….……. 42 2.4 Valida tion techniques… .………………………………………………………………….…. 43 2.5 Enrichment Analysis………………………………………………………………………… 46 Chapter 3. Search for new compounds with G-quadruplex binding activity using computational
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