Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor

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]

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

• 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