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de Oliveira JF, Lima TS, Vendramini-Costa DB, de Lacerda Pedrosa SC, Lafayette EA, da Silva RM, de Almeida SM, de Moura RO, Ruiz A, de Carvalho JE, de Lima M
Thiosemicarbazones and 4-thiazolidinones indole-based derivatives: Synthesis, evaluation of antiproliferative activity, cell death mechanisms and topoisomerase inhibition assay
Eur J Med Chem (2017) 136:305-314.
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 IIalpha inhibition. A synthetic three-step route was established for compounds (2a-e and 3a-d) with yields ranging from 32 to 95%. Regarding antiproliferative activity, compounds 2a-e and 3a-d showed mean GI50 values ranging between 1.1 muM (2b) - 84.65 muM (3d). Compound 2b was the most promising especially against colorectal adenocarcinoma (HT-29) and leukemia (K562) cells (GI50 = 0.01 muM for both cell lines). Mechanism studies demonstrated that 24 h-treatment with compound 2b (5 muM) induced phosphatidylserine residues exposition and G2/M arrest on HT-29 cells. Moreover, 2b (50 muM) was able to interact with ctDNA and inhibited topoisomerase IIalpha activity. These results demonstrate the importance of thiosemicarbazone, especially the derivative 2b, as a promising candidate for anticancer therapy.
Publication Date: 2017-08-18.
Last updated on Wednesday, March 04, 2020