Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor† †Electronic supplementary information (ESI) available: Tables S1–S3, Fig. S1–S4, protocols for FLIPR assays, confocal imaging and antiproliferative assays, preparation, crystal structure reports, HRMS results, 1H, 13C and 19F NMR spectra of all new compounds, and purity of final compounds. CCDC 1997201–1997205. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0md00145g
| Autor: | Rajesh Bhardwaj, Christoph Romanin, Jean-Louis Reymond, Aline Lucie Carrel, Roberto Parise-Filho, Micael Rodrigues Cunha, Matthias A. Hediger, Sonja Lindinger |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
TRPV6
TRPV5 Pharmaceutical Science 610 Medicine & health Biochemistry 03 medical and health sciences Transient receptor potential channel chemistry.chemical_compound 0302 clinical medicine Drug Discovery Calcium flux 540 Chemistry Ion channel 030304 developmental biology Pharmacology 0303 health sciences Natural product Voltage-dependent calcium channel Calcium channel Organic Chemistry CÁLCIO 3. Good health Chemistry chemistry 030220 oncology & carcinogenesis Biophysics Molecular Medicine 570 Life sciences biology |
| Zdroj: | RSC Medicinal Chemistry Rodrigues Cunha, Micael; Bhardwaj, Rajesh; Carrel, Aline Lucie; Lindinger, Sonja; Romanin, Christoph; Parise-Filho, Roberto; Hediger, Matthias A.; Reymond, Jean-Louis (2020). Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor. RSC Medicinal Chemistry, 11(9), pp. 1032-1040. Royal Society of Chemistry 10.1039/D0MD00145G Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 2632-8682 |
| Popis: | Natural product derived analogues were surveyed, and an oxygenated analog was identified as a potent and selective TRPV6 inhibitor, with high microsomal stability and low off-target effects. 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-piperazine cis-22a as 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 μM) 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. |
| Databáze: | OpenAIRE |
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