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Bioorg Med Chem. 2019 Jul 1;27(13):2893-2904. doi: 10.1016/j.bmc.2019.05.020. Epub 2019 May 14.

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

Author information

1
Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
2
Experimental Oncology Unit (UNONEX), Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo, Brazil.
3
Laboratory of Pain and Signaling, Butantan Institute, São Paulo, Brazil.
4
Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil; Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland.
5
Institute of Biochemistry and Molecular Medicine, National Center for Competence in Research, NCCR TransCure, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland.
6
Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, Brazil.
7
Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: roberto.parise@usp.br.

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 G0/G1 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.

KEYWORDS:

Anticancer agents; Apoptosis; Cancer; Capsaicin; Chemotherapy; Drug design; Natural product; Peppers; Thiourea; Urea

PMID:
31104785
DOI:
10.1016/j.bmc.2019.05.020

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