Capsaicin-like analogue induced selective apoptosis in A2058 melanoma cells: Design, synthesis and molecular modeling

Author(s):Show less -

Vasco Pereira, Gustavo Jose ^[1] ; Tavares, Mauricio Temotheo ^[1] ; Azevedo, Ricardo Alexandre ^[2] ; Martins, Barbara Behr ^[3] ; Cunha, Micael Rodrigues ^{[4, 1]} ; Bhardwaj, Rajesh ^[5] ; Cury, Yara ^[3] ; Zambelli, Vanessa Olzon ^[3] ; Barbosa, Euzebio Guimaraes ^[6] ; Hediger, Matthias A. ^[5] ; Parise-Filho, Roberto ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, Lab Design & Synth Bioact Subst LAPESSB, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Expt Oncol Unit UNONEX, Dept Microbiol Immunol & Parasitol, Sao Paulo - Brazil

^[3] Butantan Inst, Lab Pain & Signaling, Sao Paulo - Brazil

^[4] Univ Bern, Dept Chem & Biochem, Freiestr 3, CH-3012 Bern - Switzerland

^[5] Univ Bern, Inst Biochem & Mol Med, Natl Ctr Competence Res, NCCR TransCure, Buhlstr 28, CH-3012 Bern - Switzerland

^[6] Univ Fed Rio Grande do Norte, Dept Pharm, Natal, RN - Brazil

• Document type: Journal article
• Source: Bioorganic & Medicinal Chemistry; v. 27, n. 13, p. 2893-2904, JUL 1 2019.
• Web of Science Citations: 0

Abstract

The use of molecules inspired by natural scaffolds has proven to be a very promising and efficient method of drug discovery. In this work, capsaicin, a natural product from Capsicum peppers with antitumor properties, was used as a prototype to obtain urea and thiourea analogues. Among the most promising compounds, the thiourea compound 6g exhibited significant cytotoxic activity against human melanoma A2058 cells that was twice as high as that of capsaicin. Compound 6g induced significant and dose-dependent G(0)/G(1) cell cycle arrest in A2058 cells triggering cell death by apoptosis. Our results suggest that 6g modulates the RAF/MEK/ERK pathway, inducing important morphological changes, such as formation of apoptotic bodies and increased levels of cleaved caspase-3. Compared to capsaicin, 6g had no significant TRPV1/6 agonist effect or irritant effects on mice. Molecular modeling studies corroborate the biological findings and suggest that 6g, besides being a more reactive molecule towards its target, may also present a better pharmacokinetic profile than capsaicin. Inverse virtual screening strategy found MEK1 as a possible biological target for 6g. Consistent with these findings, our observations suggested that 6g could be developed as a potential anticancer agent. (AU)

• FAPESP's process: 13/19311-6 - Design, synthesis and antitumor activity of aryl-sulfonylhydrazone compounds
• Grantee: Thais Batista Fernandes
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/00689-0 - New antineoplastic agents: synthesis, molecular docking and antitumoral activity of capsaicinoids analogues
• Grantee: Roberto Parise Filho
• Support Opportunities: Regular Research Grants