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

Pereira, Gustavo José Vasco; Tavares, Maurício Temotheo; Azevedo, Ricardo Alexandre; Martins, Barbara Behr; Rodrigues Cunha, Micael; Bhardwaj, Rajesh; Cury, Yara; Zambelli, Vanessa Olzon; Barbosa, Euzébio Guimarães; Hediger, Matthias A.; Parise-Filho, Roberto (2019). Capsaicin-like analogue induced selective apoptosis in A2058 melanoma cells: Design, synthesis and molecular modeling. Bioorganic & medicinal chemistry, 27(13), pp. 2893-2904. Elsevier 10.1016/j.bmc.2019.05.020

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)

UniBE Contributor:

Rodrigues Cunha, Micael, Hediger, Matthias

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
500 Science > 540 Chemistry

ISSN:

0968-0896

Publisher:

Elsevier

Language:

English

Submitter:

Verena de Serra Frazao-Bill

Date Deposited:

23 Dec 2019 14:53

Last Modified:

05 Dec 2022 15:34

Publisher DOI:

10.1016/j.bmc.2019.05.020

PubMed ID:

31104785

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.137499

URI:

https://boris.unibe.ch/id/eprint/137499

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