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Doctoral Thesis
DOI
https://doi.org/10.11606/T.9.2019.tde-10122019-105212
Document
Author
Full name
Micael Rodrigues Cunha
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Parise Filho, Roberto (President)
Fernandes, João Paulo dos Santos
Kawano, Daniel Fabio
Reymond, Jean-louis
Title in English
Targeting the hTRPV6 with capsaicinoid inhibitors
Keywords in English
Bioisosterism
Capsaicin
Cytotoxicity
TRPV Channel
Abstract in English
Capsaicin is a substance produced by Capsicum peppers with extensive biological activity reported in the literature. Among these studies, it was suggested that the anti-tumor activity is related to modulation of the Transient Potential Receptor Vanilloid (TRPV) channels. Capsaicin is known to bind with very high affinity to TRPV1 (IC50 ≈ 7 nM), triggering the burning sensation followed by analgesia. However, recent studies have suggested that the pro-apoptotic effects of capsaicin are TRPV6-mediated. Herein we report the development of a novel inhibitor of the TRPV6 using two different strategies for compounds design. We generated a series of direct and chimeric capsaicinoids based on the literature compounds, capsaicin, and cis-22a. These analogs were probed against HEK-hTRPV6 and the hits were further optimized. Based on the previous SAR and chemical optimization, we found 56h, named MRC-130, a derivative that remarkably inhibited TRPV6 in the nanomolar range (IC50 = 83 ± 4 nM), possess high selectivity and stability in vitro, and lesser hERG inhibition compared to the reference compound, cis-22a. It is expected that these new molecules would contribute significantly to the study on the TRPV6 function and its role in tumor pathophysiology.
Title in Portuguese
Targeting the hTRPV6 with capsaicinoid inhibitors
Keywords in Portuguese
Bioisosterismo
Capsaicina
Citotoxicidade
Receptor TRPV
Abstract in Portuguese
Capsaicina é uma substância produzida por pimentas do gênero Capsicum com extensa atividade biológica relatada na literatura. Entre esses estudos, sugeriu-se que a atividade antitumoral esteja relacionada à modulação dos canais TRPV (do inglês, Transient Potential Receptor Vanilloid). Sabe-se que a capsaicina se liga com altíssima afinidade ao TRPV1 (IC50 ≈ 7 nM), desencadeando a sensação de queimação seguida de analgesia. No entanto, estudos recentes sugeriram que os efeitos pró-apoptóticos da capsaicina são mediados pelo TRPV6. Visando o exposto, este trabalho relata o desenvolvimento de um novo inibidor do TRPV6 usando duas estratégias diferentes para o planejamento dos compostos. Geramos séries de capsaicinoides diretos e quiméricos com base nos compostos da literatura, capsaicina e cis-22a. Esses análogos foram analisados contra HEK-hTRPV6 e os análogos mais promissores foram otimizados. Com base na REA e em otimizações químicas anteriores, encontramos 56h, chamado MRC-130, um derivado que inibiu notavelmente o TRPV6 na faixa nanomolar (IC50 = 83 ± 4 nM), possui alta seletividade e estabilidade in vitro e menor inibição de hERG em comparação com o composto de referência, cis-22a. Espera-se que essas novas moléculas contribuam significativamente para o estudo da função do TRPV6 e seu papel na fisiopatologia tumoral.
 
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Publishing Date
2019-12-13
 
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