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de Oliveira JF , Lima TS , Vendramini-Costa DB , de Lacerda Pedrosa SCB , Lafayette EA , da Silva RMF , de Almeida SMV , de Moura RO , Ruiz Altg , de Carvalho JE , de Lima Mdca
Thiosemicarbazones and 4-thiazolidinones indole-based derivatives: Synthesis, evaluation of antiproliferative activity, cell death mechanisms and topoisomerase inhibition assay
Eur J Med Chem. 2017 Aug 18;136 :305-314
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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 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.
1768-3254 de Oliveira, Jamerson Ferreira Lima, Talitha Santos Vendramini-Costa, Debora Barbosa de Lacerda Pedrosa, Sybelle Christianne Batista Lafayette, Elizabeth Almeida da Silva, Rosali Maria Ferreira de Almeida, Sinara Monica Vitalino de Moura, Ricardo Olimpio Ruiz, Ana Lucia Tasca Gois de Carvalho, Joao Ernesto de Lima, Maria do Carmo Alves Journal Article France Eur J Med Chem. 2017 Aug 18;136:305-314. doi: 10.1016/j.ejmech.2017.05.023. Epub 2017 May 8.