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Potential Irreversible Inhibitors of Cysteine Proteases Based on Sultam and Naphthoquinone Scaffolds

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Potential Irreversible Inhibitors of Cysteine Proteases Based on Sultam and Naphthoquinone Scaffolds UNIVERSIDADE DE LISBOA, FACULDADE DE FARMÁCIA Potential Irreversible Inhibitors of Cysteine Proteases based on Sultam and Naphthoquinone Scaffolds Cláudia Sofia dos Santos Valente DOUTORAMENTO EM FARMÁCIA (QUÍMICA FARMACÊUTICA) 2007 UNIVERSIDADE DE LISBOA, FACULDADE DE FARMÁCIA Potential Irreversible Inhibitors of Cysteine Proteases based on Sultam and Naphthoquinone Scaffolds Cláudia Sofia dos Santos Valente Tese orientada pelo Professor Doutor Rui Moreira Dissertação apresentada à Faculdade de Farmácia da Universidade de Lisboa, com vista à obtenção do grau de Doutor em Farmácia (Química Farmacêutica) Lisboa 2007 Este trabalho foi desenvolvido sob orientação científica do Professor Doutor Rui Moreira, no Centro de Estudos de Ciências Farmacêuticas da Faculdade de Farmácia da Universidade de Lisboa. O trabalho foi apoiado financeiramente pela Fundação para a Ciência e a Tecnologia e pelo Fundo Social Europeu, no âmbito do III Quadro Comunitário de Apoio − Bolsa de Doutoramento (SFRH/BD/10815/2002). ACKNOWLEDGEMENTS I respectfully acknowledge my supervisor, Professor Rui Moreira. To Professor Jim Iley from The Open University, UK, I am grateful for the thoughtful suggestions throughout these studies and also for the NMR and ESI-MS analyses. I wish to express my gratitude to Professor Maria José Umbelino Ferreira, who first believed in me and gave me the opportunity to do research. I gratefully acknowledge Professor Kenneth Douglas for kindly receiving me at the University of Manchester, UK, and to the members of his lab for all the assistance, in particular to Tim and João Neres. To Professor Philip J. Rosenthal from the University of California, San Francisco, I thank for the antimalarial testing of the compounds. I want to thank Professor Rita C. Guedes for performing the Molecular Orbital Calculations and the Molecular Modelling work of this thesis. To Dr. Célia Fernandes, from the ITN, for the elemental analyses, and to Eng. Ana Isabel Rodrigues, from the INETI, for making possible the access to the polarimeter and for all the assistance. I am also thankful to Professor Maria José Brito and Professor Paula Ferreira, both from Faculdade de Ciências, Universidade de Lisboa, for their support and advice in the handling of the NMR spectrometer. I would like to express my gratitude to Professor José Nascimento, who helped me to understand some publications in german, which were very useful in the initial stage of this work. I am also thankful to Professor Ana Paula Leandro for her invaluable guidance during the dialysis assays, and to Professor Fátima Cabral, Professor Judite Costa, Dr. Isabel Joglar and Dr. Virginia Carvalho, for all the availability and technical help during some equipment problems in the last steps of my experimental work. For those who gave me their support, sympathy and patience on a daily basis: research assistants and technical staff of my department (some of you saw me “growing up”!) and also my fellows. I will always keep you on my mind. To the ones I have the privilege to call friends, especially Analisa, Catarina, Marina, Raquel, Rui and Zé. “You raise me up…” Most of all, to my family, for whom a thousand words would not be enough. I will never be able to compensate my “absence”. GENERAL INDEX INDEX OF FIGURES.......................................................................................................................... iv INDEX OF SCHEMES........................................................................................................................ vi INDEX OF TABLES.......................................................................................................................... viii ABSTRACT.......................................................................................................................................... xi KEYWORDS........................................................................................................................................ xi RESUMO ............................................................................................................................................ xiii PALAVRAS CHAVE......................................................................................................................... xiii ABBREVIATIONS AND SYMBOLOGY ........................................................................................ xv 1. INTRODUCTION............................................................................................................................. 1 1.1 Cysteine proteases....................................................................................................................... 1 1.1.1 Update................................................................................................................................... 1 1.1.2 Potential therapeutic targets............................................................................................... 2 1.1.3 Structural differences.......................................................................................................... 5 1.1.4 Catalytic mechanism ........................................................................................................... 6 1.2 Inhibitors of cysteine proteases.................................................................................................. 9 1.2.1 Irreversible versus reversible action .................................................................................. 9 1.2.2 Epoxysuccinyl derivatives.................................................................................................10 1.2.3 Vinyl sulfones and analogues............................................................................................ 14 1.2.3.1 As inhibitors of cysteine proteases............................................................................ 14 1.2.3.2 Synthesis...................................................................................................................... 18 1.3 Introductory remarks on quinones ......................................................................................... 20 1.4 Aims of the thesis ...................................................................................................................... 25 2. DIPEPTIDE VINYL SULTAMS................................................................................................... 29 2.1 Synthesis .................................................................................................................................... 29 2.1.1 Overall strategy ................................................................................................................. 29 2.1.2 Strategies for sultam scaffolds.......................................................................................... 30 2.1.2.1 β-Sultams .................................................................................................................... 30 2.1.2.2 γ- and δ-Sultams ......................................................................................................... 36 2.1.3 Synthesis of sultams core .................................................................................................. 37 2.1.3.1 β-Sultams .................................................................................................................... 38 N-Phenyl-β-sultam............................................................................................................. 38 N-Benzyl-β-sultam ............................................................................................................. 44 2.1.3.2 γ-Sultams..................................................................................................................... 46 2.1.3.3 δ-Sultams..................................................................................................................... 48 2.1.4 Synthesis of dipeptide vinyl sultams ................................................................................ 50 2.1.4.1 Aminoacid and dipeptidyl aldehydes........................................................................ 50 2.1.4.2 Aldol-type reaction of sultam carbanions ................................................................ 53 2.1.4.3 Sultam phosphonates ................................................................................................. 54 2.1.4.4 Horner-Wadsworth-Emmons reaction .................................................................... 56 2.1.4.5 Dipeptide vinyl sultams.............................................................................................. 59 Deprotection (removal of Boc protecting group) ............................................................ 59 Coupling with aminoacids and endcapping of the dipeptide moiety............................. 60 i NMR Spectral characterisation ........................................................................................ 62 2.1.5 Synthesis of vinyl sulfonamides ........................................................................................ 70 2.2 Kinetic study of the reaction with cysteine ............................................................................. 73 2.2.1 Introductory remarks........................................................................................................ 73 2.2.2 Results and Discussion....................................................................................................... 74 2.3 Inhibitory activity against papain, falcipain-2 and
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