Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 136, Issue -, Pages 305-314Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.05.023
Keywords
Medicinal chemistry; Anticancer therapy; Cellular death; DNA interaction; Topoisomerase inhibition
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Funding
- Brazilian agency Fundacao de Amparo Pesquisa do Estado de Pernambuco (FACEPE, Brazil)
- Brazilian agency Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
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In this study, we report the synthesis and structural characterization of a series of thiosemicarbazone and 4-thiazolidinones derivatives, as well as their in vitro antiproliferative activity against eight human tumor cell lines. For the most potent compound further studies were performed evaluating cell death induction, cell cycle profile, ctDNA interaction and topoisomerase II alpha inhibition. A synthetic three-step route was established for compounds (2a-e and 3a-d) with yields ranging from 32 to 95%. Regarding anti proliferative activity, compounds 2a-e and 3a-d showed mean GI(50) values ranging between 1.1 mu M (2b) 84.65 mu M (3d). Compound 2b was the most promising especially against colorectal adenocarcinoma (HT-29) and leukemia (K562) cells (GI(50) = 0.01 mu M for both cell lines). Mechanism studies demonstrated that 24 h-treatment with compound 2b (5 mu M) induced phosphatidylserine residues exposition and G2/M arrest on HT-29 cells. Moreover, 2b (50 mu M) was able to interact with ctDNA and inhibited topoisomerase II alpha activity. These results demonstrate the importance of thiosemicarbazone, especially the derivative 2b, as a promising candidate for anticancer therapy. 2017 Elsevier Masson SAS. All rights reserved.
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