Synthesis and Cytotoxicity evaluation of small 1,4 - triazolic derivatives against B16 melanoma cell lines and a methodolgy study on the synthesis of propargyl ethers from their corresponding propargyl esters without catalyst and under microwave irradiations Shiva Kalhor Monfared To cite this version: Shiva Kalhor Monfared. Synthesis and Cytotoxicity evaluation of small 1,4 - triazolic derivatives against B16 melanoma cell lines and a methodolgy study on the synthesis of propargyl ethers from their corresponding propargyl esters without catalyst and under microwave irradiations. Organic chemistry. Université Pierre et Marie Curie - Paris VI, 2014. English. NNT : 2014PA066235. tel- 01133657 HAL Id: tel-01133657 https://tel.archives-ouvertes.fr/tel-01133657 Submitted on 20 Mar 2015 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THESE DE DOCTORAT DE L’UNIVERSITE PIERRE ET MARIE CURIE Spécialité Chimie Organique Ecole doctorale de Chimie Moléculaire Paris Centre Présentée par Mme Shiva Kalhor-Monfared Pour obtenir le grade de DOCTEUR de l’UNIVERSITÉ PIERRE ET MARIE CURIE Sujet de la thèse : Synthesis and Cytotoxicity evaluation of small 1,4-triazolic derivatives against B16 melanoma cell lines and a methodolgy study on the synthesis of propargyl ethers from their corresponding propargyl esters without catalyst and under microwave irradiations soutenue le 18 septembre 2014 devant le jury composé de : Mr F. Chemla, Examinateur Mr G. Prestat, Rapporteur Mr B. Vauzeilles, Rapporteur Mme Valérie Bénéteau, Examinatrice Mme Sandrine Sagan, Examinatrice Mr C. Girard, co-Directeur de thèse Mr J. Herscovici, Directeur de thèse Préparée à l’École Nationale Supérieure de Chimie de Paris 2 Synthesis and Cytotoxicity evaluation of small 1,4-triazolic derivatives against B16 melanoma cell lines and a methodology study on the synthesis of propargyl ethers from their corresponding propargyl esters without catalyst and under microwave irradiations By Shiva KALHOR MONFARED Dissertation Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Molecular Chemistry in the graduate college of 406 University of Pierre et Marie Curie prepared at Ecole Nationale Supérieure de Chimie de Paris Defense scheduled for 18 September 2014. Doctoral committee: Professor Fabrice Chemla, Examinor Professor Guillaume Prestat, Referee Doctor Boris Vauzeilles, Referee Doctor Sandrine Sagan, Examinor Doctor Valérie Bénéteau, Examinor Doctor Christian Girard, Ph.D. co-director Doctor Jean Herscovici, Ph.D. director 3 4 Acknowledgement I would like to take this time to thank Doctoral College 406 for all of the funding they were able to provide to me in order to make this thesis possible. I would also to express my special appreciation and thank to my advisor Dr. Christian Girard, you have been a tremendous mentor for me. I would like to thank you for encouraging my research and for following to grow as a research scientist. Your advice on both research as well as on my career have been priceless. I cannot forget Dr. Jean Herscovici, our previous lab director also my PhD directtor. However after only some months of my thesis you got retired, but even this short period let me to profit from your years of experience in organic synthesis, and I appreciate you for your availability in the lab even it was your last workdays. I would like also to special thank to Dr. Claire Beauvineau who was like my second advisor. I appreciate her voluntaries to help me through my project and give me good advices. You were not only a good advisor for my PhD work, but also you were like a consultant who helped me through the moments that I was not happy, you were always available to hear me, I really thank to you from the bottom of my heart. I would like also to thank my committee members, Pr. Fabrice Chemla, Pr. Giullaume Prestat, Dr. Boris Vauzeilles, Dr. Sandrine Sagan and Dr. Valérie Bénéteau. I extremely appreciate you to accept to be a member of my thesis committee. 5 I would like also to thank our colleagues in faculty of pharmacy, Dr. Johanne Seguin, Lionel Quentin and Dr. Guy Chabot who helped me to perform biological test on my molecules. Thanks a lot for your availability to answer my questions around biology and your guides. I, as a chemist was not ever able to do this work without your helps. Except these guys who helped me in my project, there were also other people in our research group who, with their presence made good moments for me in the lab. I would like to thank Dr. Fethi Bédioui, the responsible of our lab, Pr. Anne Varenne, Dr. Sophie Griveau, Dr. Mathiew Lazerge, Dr. Fanny Dorlye and Dr. Bich-Thuy Doan. Special thank to you Bich-Thuy for your guides in NMR. I won’t ever forget other people of the lab including PhD students and Postdocs or others, Riadh, Camille, Amandine, Abed, Gonzalo, Duc, Baptiste, Grégory, Abdelilah and Patrick (thank you Patrick. You were always smiley and trying to make me smile too. I was so happy because of your presence), and other temporary PhD students or trainings who worked for a short time with us. Thank to you to try to make the lab environment as funny as possible by organizing lab parties specially Mexican and Vietnamese ones that will stay forever in my mind. At the end, a special thank to my family. Words cannot express how grateful I am to my mother, and father for all of the sacrifices that you’ve made on my behalf. However you were not physically beside me, but your prayer for me was what sustained me thus far. I would also to thank my brothers Shahab and Shayan, and all of my friends who supported me during my PhD, and incented me to strive towards my goal. Thank you to all. 6 Table of contents General introduction………………………………………………………………………………17 Chapter 1: Diversity Oriented Synthesis and Click Chemistry………………………….......... 31 I. Introduction…………………………………………………………………………………...33 I.1.1. Source of small molecules for use in biological screens……………………………… 33 I.1.2. What is Diversity Oriented Synthesis……………………………………………..........34 I.1.2.1. Comparing DOS, TOS, and combinatorial chemistry……………………………...35 I.1.2.2. Molecular diversity…………………………………………………………………35 I.1.2.3. Skeletal diversity…………………………………………………………………...37 I.1.3. Screening small molecules for biological activity……………………………………...37 I.1.4. Discovering bioactive small molecules using DOS………………………………........39 I.1.4.1. Protein-protein interactions (PPIs)……………………………………………........39 1.1.5. Diversity Oriented Synthesis and chemical space……………………………………..40 I.2. Click Chemistry………………………………………………………………………….........41 I.2.1. Mechanism of Cu-catalyzed azide-alkyne cycloaddition…………………………........43 I.2.2. Physicochemical properties of organic azides…………………………………….........45 I.2.2.1. Reactions of organic azides……………………………………………………........47 I.2.2.2. Applications of azides…………………………………………………………........48 I.2.3. Applications of click chemical reactions………………………………………….........52 I.2.3.1. Therapeutics polymer………………………………………………………….........53 I.2.3.2. Drug delivery systems………………………………………………………............54 I.2.3.3. Bioconjugation………………………………………………………………….......56 I.2.3.3.1. Radiolabelling……………………………………………………………...........57 I.2.3.3.2. Polysaccharides………………………………………………………………….58 I.2.3.3.3. Tagging of live organisms and proteins……………………………………........59 I.2.3.3.4. Activity based protein profiling (ABPP)……………………………………......59 I.2.3.3.5. Labeling of DNA…………………………………………………………..........60 I.2.4. Synthesis of lead discovery libraries……………………………………………….......60 I.2.5. Limitations of Click Chemistry…………………………………………………….......61 I.2.6. Biologically active 1,2,3-triazoles………………………………………………….......62 I.2.7. Biologically active 1,2,3-triazoles synthesized without copper catalyst……………….62 I.2.8. Click reactions and the pharmacological applications of 1,2,3-triazoles………………63 I.2.8.1. Anticancer………………………………………………………………………......64 I.2.8.2. In vivo tumor cell targeting with ‘Click’ nanoparticles…………………………......66 Chapter II: Synthesis of triazolic derivatives departing from aldehydes and by use of a solid supported catalyst (A-21.CuI) and study their biological activity……………………………...69 II. Solid supported catalyst……………………………………………………………………...71 II.1. Synthesis of triazolic derivatives on a solid supported catalyst………………………....72 II.2. Amberlyst copper (I)-A-21 (A-21.CuI)……………………………………………….....76 II.2.1. Stability of Amberlyst A-21.CuI……………………………………………………..79 II.2.2. Limits of the Amberlyst A-21.CuI…………………………………………………...79 II.3. Synthesis of 1,2,3-triazoles derivatives from alkynes or propargylic alcohols……….....85 II.3.1. Terminal alkynes……………………………………………………………………..85 II.3.1.1. Seyferth-Gilbert homologation…………………………………………………...86 II.3.1.2. Mechanism of the Seyferth-Gilbert homologation……………………………….86 II.3.1.3. Bestmann-Ohira Reagent (BOR) reaction………………………………………..90 II.3.1.4. Mechanism of the alkynylation of an aldehyde with BOR………………………90 7 II.3.1.5. Some applications of Bestmann-Ohira reagent…………………………………..91 II.3.1.6. Synthesis of alkynes……………………………………………………………...96 II.3.1.6.1.