A Doença de Chagas é uma protozoose causada pelo parasita hemoflagelado Trypanosoma cruzi. Classificada pela Organização Mundial de Saúde como extremante negligenciada, essa doença é endêmica em 21 países da América Latina, entretanto podem ser encontrados, ainda, casos nos EUA, Canadá, Europa e Japão devido a movimentos migratórios. Segundo estimativa da Organização Mundial da Saúde, no ano de 2012 havia de 8 a 10 milhões de pessoas infectadas mundialmente e cerca de 25 milhões de pessoas sob risco de contrair a doença de Chagas, ainda sim, havia a ocorrência de 56 mil novos casos da doença e cerca de 12 mil mortes por ano, recorrente de complicações da doença. Diante destes números, essa parasitose se apresenta com um sério problema de saúde pública mundial. A terapêutica antichagásica disponível apresenta apenas dois fármacos o Nifurtimox e o Benznidazol, que atuam somente na fase aguda da doença e provocam sérios efeitos adversos, sendo necessária a busca por novos fármacos eficazes contra o parasita. Os métodos modernos de planejamento de fármacos antiparasitários envolvem a seleção de vias metabólicas específicas a serem bloqueadas, nesse contexto se encontram diferentes proteases, enzimas envolvidas em processos essenciais para a sobrevivência do parasita, entre elas a cruzaína, principal cisteíno-protease do T. cruzi, a qual é responsável pela sobrevivência, replicação celular e invasão do parasita à célula hospedeira, se apresentando como um excelente alvo bioquímico na pesquisa de novos agentes antichagásicos. Partindo do estudo do nitrofural (5-nitro-2-furfurilidenossemicarbazona), antibacteriano também conhecido por sua ação inibitória da cruzaína, adotamos-o como protótipo na pesquisa de fármaco contra a doença. No presente trabalho, utilizou-se o bioisosterismo como estratégia de modificação molecular no planejamento de compostos antichagásicos, inibidores da cruzaína. Foram sintetizados 27 derivados sulfonil-hidrazônicos, para os quais foi determinada a pureza por CLAE e caracterizados por faixa de fusão, espectroscopia no UV e RMN 1H e RMN 13C. Os compostos sintetizados foram avaliados frente às formas celulares epimastigota do T. cruzi, apresentando atividade inibitória de crescimento celular entre 20 e 100% a 100 µM. Nos ensaios frente a cruzaína, os derivados nitrados se mostraram ativos com IC50 em torno de 100 µM. Visto os resultados, podemos sugerir que o grupo nitro presente em alguns compostos pode ser o responsável pela atividade tripanomicida. Face a indicação de toxicidade do grupo nitro, os derivados não nitrados, Ie, IIf e IIIe, podem ser considerados promissores, visto sua atividade intermediária como tripanomicida, entre 45 e 60% à 100 µM, sendo que o composto IIf também apresentou atividade inibidora da cruzaína, 23,4% à 100 µM, podendo assim serem utilizados como ponto de partida na busca de eficazes agentes antichagásicos. / Chagas disease, a protozoonosis caused by the hemoflagellate parasite Trypanosoma cruzi, is classified as an extremely neglected disease by World Health Organization. It is an endemic disease in 21 countries on Latin America and cases in the USA, Canada, Europe and Japan were also reported as a consequence of migratory activity. In the last five years, it is estimated that around 8 to 10 million people worldwide were affect by this disease, with nearly 12,000 deaths due to disease complications and approximately 25 million people being at risk of contracting it. Chagas disease is therefore a worldwide public health problem. There are only two available antichagasic therapeutic drugs, nifurtimox and benznidazol, which act only in the acute phase of the disease and cause serious adverse effects, making it necessary to search novel, more effective drugs against this parasite. The newer methods of antiparasitic drug design involve the selection of specific metabolic pathways to be blocked. Many proteases, enzymes involved in essential processes to the survival of the parasite, such as cruzain, are thought of as potential therapeutic targets. Cruzain, the major cysteine protease of T. cruzi, is responsible for cellular replication, survival and invasion of the host cell, being an excellent biochemical target for the drug discovery of new antichagasic agents. Starting from the knowledge of nitrofural (5-nitro-2-furaldehyde semicarbazone) as an antibacterial agent and as a known cruzain inhibitor, we used it as a template for the search of new drugs against Chagas disease. In the present work, bioisosteric modifications were used as a strategy to design new compounds as potential cruzain inhibitors. 27 sulfonilhydrazones derivatives were synthesized, had their purity assessed by HPLC and were characterized through their melting point, UV spectroscopy and NMR 1H and 13C. The synthesized compounds were evaluated against epimastigote strains of T. cruzi, showing inhibitory activity on cellular growth between 20 and 100% at 100 µM. In the cruzain enzymatic assays, the nitro derivatives showed activity around 50% of inhibition at 100 µM, and IC50 around 100 µM. By the results, we can suggest that the presence of the nitro group in some compounds should be responsible for triponocidal activity. Given the known toxicity of nitro compounds, the derivatives without the nitro goup, Ie, IIf and IIIe, may be considered promising given their intermediate inhibitory activity on cruzain, among 45% and 60% at 100 µM. The coumpound IIf also showed 23,4% inhibitory activity at 100 µM. Therefore, these compounds could be employed as starting points on the search of new effective antichagasic agents.

A capsaicina é um componente pungente das pimentas do gênero capsicum que possui atividade antitumoral. Na busca por compostos antineoplásicos mais eficazes e seletivos em relação aos disponíveis atualmente, foi desenvolvido um análogo sulfonamídico sintético da capsaicina, o RPF101, que apresentou atividade citotóxica superior em linhagens de adenocarcinoma de mama. Face ao exposto, o objetivo deste trabalho foi otimizar a atividade do RPF101 a partir da síntese de análogos sulfonil-hidrazônicos planejados por bioisosterismo. Treze análogos foram sintetizados em três etapas, baseando-se na reação entre cloreto de sulfonila e hidrato de hidrazina para obtenção do intermediário sulfonil-hidrazida; oxidação do álcool piperonílico para obtenção do piperonal; e reação de adição nucleofílica entre sulfonil-hidrazida e piperonal ou vanilina, que apresentaram rendimentos entre 23 e 85%. Os compostos foram caracterizados por metodologias de RMN 1H/13C, faixa de fusão e análise elementar e avaliados quanto sua capacidade citotóxica em células de adenocarcinoma de mama (MDA-MB-231 e MCF-7) pelo método do MTT. Dois análogos mostraram-se ativos nas duas linhagens, dos quais o mais promissor, RPF906 (IC50 em MDA-MB-231 = 104,6 µM) foi submetido a estudos de elucidação mecanística, onde observou-se indução de apoptose, causando interrupção do ciclo celular na fase G0/G1. Os resultados obtidos mostraram que o grupo benzodioxol favorece a atividade biológica quando comparado ao grupo metilcatecol. Estudos de modelagem molecular sugerem que uma maior hidrofilicidade esteja relacionada com uma atividade superior. Embora menos ativas que seu protótipo, as sulfonil-hidrazonas apresentaram efeito biológico e mostram-se promissoras no desenvolvimento de compostos com potencial antitumoral. Novas modificações moleculares devem ser planejadas com o intuito de otimizar a atividade e seletividade destes compostos. / Capsaicin is a primary pungent compound in red peppers, which has antitumor activity. In view of demand for more selective and less toxic anticancer agents, our group reported a synthetic sulfonamide capsaicin-like analogue, RPF101, which presents higher cytotoxicity in adenocarcinoma cell line than its prototype. Thus, the aim of this work is to optimize RPF101 activity by the synthesis of sulfonylhydrazone analogues, using the bioisosterism as molecular modification strategy. Thirteen analogues were synthesized in three reaction steps: oxidation of piperonyl alcohol to the piperonyl aldehyde; nucleophilic substitution reaction between sulfonyl chloride and hydrazine hydrate to obtain the intermediate sulfonylhydrazide; nucleophilic addition reaction between sulfonylhydrazide and piperonal of vanilin to obtain sulfonylhydrazones, which showed yields between 23 and 85%. All compounds were characterized by NMR 1H/13C, melting point and elemental analisys and evaluated for their cytotoxic activity in breast tumor cell lines (MDA-MB-231 and MCF-7). Two analogues showed cytotoxic effect although RPF906 (IC50 in MDA-MB-231= 104.6 µM) had been the most promising and was further evaluated about its mechanistic properties. This compound induced apoptosis and cell cycle arrest at the G0/G1 phase. Results showed that the introduction of benzodioxol group increases cytotoxicity. Molecular modeling studies suggests that superior hydrophilicity is related to superior activity. Sulfonyl-hydrazone analogues were less cytotoxic than their prototype, but they are still promising compounds. Molecular modifications strategies should be done to optimize the activity and selectivity of these compounds.

Yes / The aldo-keto reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles were designed to simultaneously interact with both subpockets 1 and 2 in the active site of AKR1C3, larger for AKR1C3 than other AKR1Cs isoforms. Through computational design and iterative rounds of synthesis and biological evaluation, novel compounds are reported, sharing high selectivity (up to 230-fold) for AKR1C3 over 1C2 isoform and minimal COX1 and COX2 off-target inhibition. A docking study of compound 8, the most interesting compound of the series, suggested that its methoxybenzyl substitution has the ability to fit inside subpocket 2, being involved in π-π staking interaction with Trp227 (partial overlapping) and in a T-shape π-π staking with Trp86. This compound was also shown to diminish testosterone production in the AKR1C3-expressing 22RV1 prostate cancer cell line while synergistic effect was observed when 8 was administered in combination with abiraterone or enzalutamide. / University of Turin (Ricerca Locale grant 2014 and 2015) and Prostate Cancer UK grant S12-027

A tripanossomíase sul-americana, também conhecida como Doença de Chagas é uma enfermidade endêmica da América Latina.A doença é causada pelo protozoário Trypanosoma cruzi, cuja transmissão em seres humanos e outros mamíferos ocorrem, principalmente, através das fezes do inseto \"barbeiro\" (triatoma infestans) infectado.Desde a descoberta já foram realizadas inúmeras tentativas de tratamento sem obter quimioterapia eficaz. Hoje o tratamento é realizado pelo uso do fármaco nitroheterocíclico benznidazol. Porém esse composto só é utilizado na fase aguda da doença e tem sua eficácia variada de acordo com a área geográfica, provavelmente como consequência de variação de cepas do parasita e apresenta graves efeitos colaterais. Uma ferramenta interessante em Química Medicinal é o uso do bioisosterismo para a síntese de moléculas análogas, que por possuírem propriedades biológicas relacionáveis geralmente atuam no mesmo alvo farmacológico como agonistas ou antagonistas. Por outro lado, as reações relacionadas às condensações de cicloadição 1,3 dipolar catalisadas por Cu(I), envolvendo estratégias de \"click chemistry\" tem como pontos positivos o fato de geralmente não formarem subprodutos, serem de fácil execução e apresentarem rendimentos elevados. Partindo de dois compostos comerciais (benzilamina e cloreto de cloro acetila) efetuou-se a síntese de uma biblioteca de vinte e três compostos análogos ao benznidazol através de uma rota sintética curta e de fácil execução. Foram realizados ensaios de atividade tripanocida envolvendo a cepa Tulahuen de T.cruzi, bem como ensaios de citotoxicidade. / The South American trypanosomiasis, also known as Chagas\' disease is an endemic disease in Latin America. The disease is caused by the protozoan Trypanosoma cruzi, whose transmission in humans and other mammals occur primarily through the faeces of the insect \"barbeiro\" (triatoma infestans) infection. Since the discovery already been carried out many attempts to obtain effective chemotherapy treatment. Today\'s treatment is accomplished through the use of the drug nitro-heterocyclic benznidazole. However this compound is only used in the acute phase of the disease and its effectiveness is varied in accordance with the geographical area, probably as a consequence of the variation of strains of the parasite and presents serious side effects. An interesting tool in medicinal chemistry is the use of bioisosterism for the synthesis of analogous molecules, which possess biological properties relatable generally act on the same target as pharmacological agonists or antagonists. Moreover, the reactions related to condensations of 1.3 dipolar cycloaddition catalyzed by Cu(I), involving strategies \"click chemistry\" has the strengths of the fact usually do not form byproducts, being easy to perform and present high yields. Starting from two commercial compounds benzylamine and chloro acetyl chloride) we performed the synthesis of a library of twenty-three analog compounds to benznidazole via a synthetic route short and easy to perform. Tests of trypanocidal activity involving Tulahuen strain of T. cruzi, and cytotoxicity assays.

Les protéines kinases représentent le groupe d'enzymes qui servent d'intermédiaire pour la phosphorylation de protéines - le transfert d'un groupe phosphate de l'adénosine triphosphate(ATP) sur des chaînes latérales correspondantes de tyrosine, de serine ou de thréonine des acides aminées. La phosphorylation de protéines est un des outils les plus importants pour la régulation de l'activité cellulaire. La « signalisation » cellulaire par le récepteur de tyrosine kinase VEGFR2 (KDR) appartient aux réactions biochimiques clés influençant la croissance de tumeurs. L'inhibition thérapeutique de cette réaction à l'aide des composés de faible poids moléculaire spécifiques est devenue une stratégie utile dans le cadre des thérapies anticancéreuses. Ce travail a amené à la découverte de 16 substances biologiquement actives sur la base N,5-diaryloxazol-2-amine (IC50, VEGFR2 TK). D'excellents résultats ont été atteints notamment dans le cas des substances 189, 191, 211, 214, 220, 221, 223 et 4 qui montrent une activité inhibitrice inférieure à 500 nM. / Protein kinases represent a group of enzymes responsible for phosphorylation - transfer of aphosphate group from adenosine triphosphate (ATP) to tyrosine or serine/threonine residues. Protein phosphorylation is one of the most important tools regulating a cell activity. A cell "signalization" through an endothelial receptor tyrosine kinase VEGFR2 TK (KDR) is the important pathway influencing growth of a tumor. Small-molecule inhibitors of VEGFR2 TK (VEGFR2 TKls) have become an important tool for the treatment of various types of cancer. This dissertation thesis resulted in a discovery of 16 biologically active N,5-diaryloxazol-2-amines (IC50, VEGFR2 TK). Very good results were achieved especially with compounds 189, 191, 211, 214, 220, 221, 223 and 4 exhibiting the activity under 500 nM.

Made available in DSpace on 2015-05-14T13:21:24Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2922562 bytes, checksum: 9db6c2993f51e11e2568c6fc42b4d668 (MD5) Previous issue date: 2009-11-27 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This work was designed using the concept of classical bioisosterism where isoelectronic OH groups were replaced by the CH3 group, aimed at finding a relationship between the lipossolubility of the adducts Morita-Baylis-Hillman (AMBH) and its biological activity. Was developed in this work, synthetic methodologies for the preparation of 16 AMBH unprecedented (47-62), getting good and high yields. Initially was synthesized AMBH 8 using the 2-hydroxyethyl Acrylate 45 as Michael acceptor, giving the adducts 47 (2-hydroxyethyl [2-(hydroxy( 2-nitrophenyl)methyl)] acrylate, 71%), 48 (2-hydroxyethyl [2-(hydroxy( 3-nitrophenyl)methyl)] acrylate, 50%), 49 (2-hydroxyethyl [2-(hydroxy(4- nitrophenyl)methyl)] acrylate, 62%), 50 (2-hydroxyethyl [2-(hydroxy(pyridin-2- yl)methyl)] acrylate, 94%), 51 (2-hydroxyethyl [2-(hydroxy(pyridin-3-yl) methyl)] acrylate, 83%), 52 (2-hydroxyethyl [2-(hydroxy(pyridin-4-yl)methyl)] acrylate, 80%), 53 (2-hydroxyethyl [2-((4-bromophenyl)(hydroxy)methyl)] acrylate, 67%), 54 (2-hydroxyethyl [2-(hydroxy(naphthalen-2-yl)methyl)] acrylate, 71%). The second step of the synthesis was the preparation of Propyl Acrylate (46), from acrylic acid and propanol (yield 98%), which was later used as Michael acceptors in the synthesis of AMBH 55 (Propyl [2-(hydroxy(2-nitrophenyl) methyl)] acrylate, 68%), 56 (Propyl [2-(hydroxy(3-nitrophenyl)methyl)] acrylate, 73%), 57 (Propyl [2-(hydroxy(4-nitrophenyl)methyl)] acrylate, 97%), 58 (Propyl [2-(hydroxy(pyridin-2-yl)methyl)]acrylate, 70%), 59 (Propyl [2- (hydroxy(pyridin-3-yl)methyl)acrylate], 80%), 60 (Propyl [2-(hydroxy(pyridin-4- yl)methyl)] acrylate, 66%), 61 (Propyl [2-((4-bromophenyl)(hydroxy)methyl)] acrylate, 64%), 62 (Propyl [2-(hydroxy(naphthalen-2-yl)methyl)] acrylate, 60%). All of these adducts were bioavailiated in vitro against the parasite Leishmania amazonensis, their cytotoxicity in macrophages were studied and their therapeutic indices calculated. Unlike expected, the bioisosteric modification not presented a direct relationship between the lipossolubility (Log P) of these compounds and their biological activity. All adducts showed strong activity antipromastigote, being the compounds 47, 55, 49, 57, 53, 54 and 62 the most actives in L. amazonensis, all with IC50 less than 60μM. Among them the AMBH 47 was the most active and that presented the higher therapeutic index, which is the prototype substance of this work. / Este trabalho foi idealizado utilizando o conceito de bioisosterismo clássico, onde grupos isoeletrônicos OH foram substituídos pelo grupo CH3, visando encontrar uma relação entre a lipossolubilidade dos Adutos de Morita-Baylis- Hillman (AMBH) e sua atividade biológica. Foram desenvolvidos neste trabalho, metodologias sintéticas para a preparação de 16 AMBH inéditos (47-62), em bons a altos rendimentos. Inicialmente foi sintetizado 8 AMBH utilizando o Acrilato de 2-hidroxietila (45) como aceptor de Michael, obtendo os adutos 47(Acrilato de [2-(hidroxi(2-nitrofenil)metil)] de 2-hidroxietila, 71%), 48 (Acrilato de [2-(hidroxi(3-nitrofenil)metil)] de 2-hidroxietila, 50%), 49 (Acrilato de [2-(hidroxi(4-nitrofenil)metil)] de 2-hidroxietila, 62%), 50 (Acrilato de [2-(hidroxi( piridin-2-il)metil)] de 2-hidroxietila, 94%), 51(Acrilato de [2-(hidroxi(piridin- 3-il)metil)] de 2-hidroxietila, 83%), 52 (Acrilato de [2-(hidroxi(piridin-4-il)metil)] de 2-hidroxietila, 80%), 53 (Acrilato de [2-((4-bromofenil)(hidroxi)metil)] de 2- hidroxietila, 67%), 54 (Acrilato de [2-(hidroxi(naftalen-2-il)metil) de 2-hidroxietila, 71%). A segunda etapa de síntese foi a preparação do Acrilato de propila (46), a partir do ácido acrílico e do propanol (rendimento de 98%), que posteriormente foi utilizado como aceptor de Micheal na síntese dos AMBH 55(Acrilato de [2-(hidroxi-(2-nitrofenil)metil)] de propila, 68%), 56 (Acrilato de [2-(hidroxi-(3-nitrofenil)metil)] de propila 73%), 57 (Acrilato de [2-(hidroxi-(4- nitrofenil)metil)] de propila, 97%), 58 (Acrilato de [2-(hidroxi-(piridin-2- il)metil)] de propila, 70%), 59 (Acrilato de [2-(hidroxi-(piridin-3-il)metil)] de propila, 80%), 60 (Acrilato de [2-(hidroxi-(piridin-4-il)metil)] de propila, 66%), 61(Acrilato de [2-((4-bromofenil)(hidroxi)metil)] de propila, 64%), 62 (Acrilato de [2-(hidroxi(nafthalen-2-il)metil)] de propila, 60%). Todos estes adutos foram bioavaliados in vitro contra o parasita Leishmania amazonensis, suas citotoxicidades em macrófagos foram estudadas e seus índices terapêuticos calculados. Diferentemente do esperado, a modificação bioisostérica não apresentou uma relação direta entre a lipossolubilidade (Log P) destes compostos e a sua atividade biológica. Todos os adutos apresentaram forte atividade antipromastigota, sendo os compostos 47, 55, 49, 57, 53, 54 e 62 os mais ativos em L. amazonensis, todos com IC50 menores que 60QM. Entre eles o AMBH 47 foi o mais ativo e o que apresentou o maior índice terapêutico, sendo este a substância protótipo deste trabalho.

A tripanossomíase sul-americana, também conhecida como Doença de Chagas é uma enfermidade endêmica da América Latina.A doença é causada pelo protozoário Trypanosoma cruzi, cuja transmissão em seres humanos e outros mamíferos ocorrem, principalmente, através das fezes do inseto \"barbeiro\" (triatoma infestans) infectado.Desde a descoberta já foram realizadas inúmeras tentativas de tratamento sem obter quimioterapia eficaz. Hoje o tratamento é realizado pelo uso do fármaco nitroheterocíclico benznidazol. Porém esse composto só é utilizado na fase aguda da doença e tem sua eficácia variada de acordo com a área geográfica, provavelmente como consequência de variação de cepas do parasita e apresenta graves efeitos colaterais. Uma ferramenta interessante em Química Medicinal é o uso do bioisosterismo para a síntese de moléculas análogas, que por possuírem propriedades biológicas relacionáveis geralmente atuam no mesmo alvo farmacológico como agonistas ou antagonistas. Por outro lado, as reações relacionadas às condensações de cicloadição 1,3 dipolar catalisadas por Cu(I), envolvendo estratégias de \"click chemistry\" tem como pontos positivos o fato de geralmente não formarem subprodutos, serem de fácil execução e apresentarem rendimentos elevados. Partindo de dois compostos comerciais (benzilamina e cloreto de cloro acetila) efetuou-se a síntese de uma biblioteca de vinte e três compostos análogos ao benznidazol através de uma rota sintética curta e de fácil execução. Foram realizados ensaios de atividade tripanocida envolvendo a cepa Tulahuen de T.cruzi, bem como ensaios de citotoxicidade. / The South American trypanosomiasis, also known as Chagas\' disease is an endemic disease in Latin America. The disease is caused by the protozoan Trypanosoma cruzi, whose transmission in humans and other mammals occur primarily through the faeces of the insect \"barbeiro\" (triatoma infestans) infection. Since the discovery already been carried out many attempts to obtain effective chemotherapy treatment. Today\'s treatment is accomplished through the use of the drug nitro-heterocyclic benznidazole. However this compound is only used in the acute phase of the disease and its effectiveness is varied in accordance with the geographical area, probably as a consequence of the variation of strains of the parasite and presents serious side effects. An interesting tool in medicinal chemistry is the use of bioisosterism for the synthesis of analogous molecules, which possess biological properties relatable generally act on the same target as pharmacological agonists or antagonists. Moreover, the reactions related to condensations of 1.3 dipolar cycloaddition catalyzed by Cu(I), involving strategies \"click chemistry\" has the strengths of the fact usually do not form byproducts, being easy to perform and present high yields. Starting from two commercial compounds benzylamine and chloro acetyl chloride) we performed the synthesis of a library of twenty-three analog compounds to benznidazole via a synthetic route short and easy to perform. Tests of trypanocidal activity involving Tulahuen strain of T. cruzi, and cytotoxicity assays.

Yes / The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data. / University of Turin (Ricerca Locale grant 2015-2017) and Prostate Cancer UK grant S12-027.

Lors de son développement, une tumeur ne peut survivre sans passer par une étape invasive afin de subvenir à ses besoins en nutriment et en oxygène. Cette étape, appelé angiogénèse tumorale, conduit à la formation de vaisseaux sanguins dits « tumoraux », différents des vaisseaux sanguins normaux. Afin de stopper la croissance de la tumeur, il est possible de détruire les vaisseaux sanguins tumoraux formés pendant l’angiogénèse tumorale grâce à des molécules antivasculaires. Ces molécules vont désorganiser la structure du vaisseau et diminuer le flux sanguin au sein de la tumeur pour mener à la nécrose de cette dernière. Parmi ces molécules antivasculaires,la prodrogue phosphate de la combrétastatine A-4 naturelle (CA-4) est le composé actuellement le plus efficace(en développement clinique de phase III contre le cancer de la thyroïde). L’isocombrétastatine A-4 (isoCA-4),possédant une structure de type 1,1-diaryléthylène, est un analogue très puissant développé au laboratoire. Cette molécule est isomère de la CA-4 et permet d’obtenir les mêmes activités biologiques que la CA-4. L’objectif de cette thèse est d’étudier ce motif 1,1-diaryléthylène dans le cadre de molécules cytotoxiques en synthétisant et en évaluant in vitro plusieurs séries de molécules de type « iso ». L’autre partie de cette thèse est dédiée à la synthèse d’analogues hétérocycliques de l’isoCA-4, qui permettront de réaliser les premières études de relation structure-activité sur l’isoCA-4, où son cycle B a été remplacé par un hétérocycle. Ce travail nous a permis de confirmer que la structure de l’isoCA-4 peut servir de base de travail pour développer d’autres agents antivasculaires. / For a tumor, the angiogenesis is a vital step for its development. The spread of the tumor is necessary characterized by an extension of the surrounding vasculature, in order to provide the nutriments and the oxygen required to the growth of the tumor. Resulting from the angiogenesis, the new tumorous blood vessels formed represent an excellent target to treat cancer by aiming specifically at the heart of the tumor. By means of vascular disrupting agents (VDA), it is possible to cut the tumor off the blood flow to trigger the necrosis within the tumor. Among the current VDA, the natural combretastatin A-4 (CA-4) is a strong compound that exhibits excellent antitumoral activities. An isomer of the CA-4, the isocombretastatin A-4 (isoCA-4), was developed inour laboratory to propose an alternative and a new family of VDA. The isoCA-4 is characterized by a 1,1-diarylethylene core, which we studied in this thesis, through 3 series of molecules related to this new structure inmedicinal chemistry. We also synthesized heterocyclic analogues of the isoCA-4, in order to explore the capacity of the isoCA-4 to serve as a basis for developing new antimitotic compounds.

La dépression est l’un des troubles mentaux les plus fréquents de nos jours. C’est une maladie liée en général à un déficit en neurotransmetteurs monoaminergiques (sérotonine, noradrénaline et dopamine). Les antidépresseurs actuels agissant via des mécanismes monoaminergiques présentent de nombreux effets secondaires et peuvent conduire à une accoutumance. L’une des approches impliquerait le ciblage des récepteurs mélatoninergiques afin de resynchroniser les rythmes circadiens qui sont perturbés dans certaines pathologies du système nerveux central, notamment la dépression. La conception de ligands non monoaminergiques et possédant des propriétés chronobiotiques constituerait une stratégie prometteuse.L’agomélatine (Valdoxan®) issue d’une collaboration entre le laboratoire de chimie thérapeutique (EA4481 - GRIIOT) et les laboratoires Servier est commercialisée depuis 2009 pour le traitement de la dépression majeure. Ce bioisoster naphtalénique de la mélatonine possède un mécanisme d’action innovant. Elle se distingue par ses propriétés agoniste non sélectif des récepteurs mélatoninergiques MT1 et MT2 et antagoniste des récepteurs 5-HT2c.L’objectif de ce travail réside dans la conception et la synthèse de nouveaux ligands successeurs de l’agomélatine présentant un profil pharmacologique et pharmacocinétique amélioré. Différentes pharmacomodulations ont été réalisées sur l’agomélatine. Les stratégies de «Drug Design» notamment le principe de bioisostérie ont été appliquées, nous permettant ainsi la synthèse de nouvelles familles de composés présentant des profils pharmacologiques intéressants. / Nowadays, depression related to a deficit in nonoaminergic neurotransmitters, is the most frequent mental illness. Available antidepressive drugs acting through monoamnergic mechanisms possess a lot of side effects and can lead to an addiction. One approach involves targeting melatoninergic receptors to resynchronize circadian rhythms, which are known to be perturbed in some pathology related to nervous central system as depression. So conception of non-monoaminergic ligands with chronobiotic properties would constitute a promising strategy.Agomelatine (Valdoxan®) a novel antidepressant developed by Servier and our laboratory (EA4481 - GRIIOT) was granted marketing authorization in 2009 for the treatment of major depressive disorder. This naphthalen analogous of melatonin possess an innovative mechanism. It acts as a non selective melatoninergic MT1/MT2 receptors agonist and a serotonin 5-HT2c receptor antagonist.The aim of this work is to design and synthesize new potential successors of agomelatine with an improved pharmacological and pharmacokinetic profile. Drug Design strategies such as bioisosterism were applied to allow the elaboration of new series of compounds with interesting pharmacological profiles.