Natural product inspired optimization of a selecti... - BV FAPESP
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Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor

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Autor(es):
Cunha, Micael Rodrigues [1, 2] ; Bhardwaj, Rajesh [3] ; Carrel, Aline Lucie [1] ; Lindinger, Sonja [4] ; Romanin, Christoph [4] ; Parise-Filho, Roberto [2] ; Hediger, Matthias A. [3] ; Reymond, Jean-Louis [1]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Univ Bern, Dept Chem & Biochem, Freiestr 3, CH-3012 Bern - Switzerland
[2] Univ Sao Paulo, Dept Pharm, Prof Lineu Prestes Ave 580, BR-05508000 Sao Paulo - Brazil
[3] Inselspital Bern, Univ Hosp Bern, Dept Hypertens & Nephrol, CH-3010 Bern - Switzerland
[4] Johannes Kepler Univ Linz, Inst Biophys, Gruberstr 40, A-4020 Linz - Austria
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: RSC MEDICINAL CHEMISTRY; v. 11, n. 9, p. 1032-1040, SEP 1 2020.
Citações Web of Science: 1
Resumo

Transient receptor potential vanilloid 6 (TRPV6) is a calcium channel implicated in multifactorial diseases and overexpressed in numerous cancers. We recently reported the phenyl-cyclohexyl-piperazinecis-22aas the first submicromolar TRPV6 inhibitor. This inhibitor showed a seven-fold selectivity against the closely related calcium channel TRPV5 and no activity on store-operated calcium channels (SOC), but very significant off-target effects and low microsomal stability. Here, we surveyed analogues incorporating structural features of the natural product capsaicin and identified 3OG, a new oxygenated analog with similar potency against TRPV6 (IC50= 0.082 +/- 0.004 mu M) and ion channel selectivity, but with high microsomal stability and very low off-target effects. This natural product-inspired inhibitor does not exhibit any non-specific toxicity effects on various cell lines and is proposed as a new tool compound to test pharmacological inhibition of TRPV6 mediated calcium flux in disease models. (AU)

Processo FAPESP: 13/19311-6 - Planejamento, síntese e avaliação do potencial antitumoral de compostos arilsulfonil-hidrazônicos
Beneficiário:Thais Batista Fernandes
Modalidade de apoio: Bolsas no Brasil - Mestrado
Processo FAPESP: 17/00689-0 - Potenciais agentes antineoplásicos: síntese, docking molecular e avaliação da atividade antitumoral de análogos capsaicinoides
Beneficiário:Roberto Parise Filho
Modalidade de apoio: Auxílio à Pesquisa - Regular