Thiosemicarbazones and 4-thiazolidinones indole-based derivatives: Synthesis, evaluation of antiproliferative activity, cell death mechanisms and topoisomerase inhibition assay

European Journal of Medicinal Chemistry
Jamerson Ferreira de OliveiraMaria do Carmo Alves de Lima

Abstract

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 IIα 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 μM (2b) - 84.65 μM (3d). Compound 2b was the most promising especially against colorectal adenocarcinoma (HT-29) and leukemia (K562) cells (GI50 = 0.01 μM for both cell lines). Mechanism studies demonstrated that 24 h-treatment with compound 2b (5 μM) induced phosphatidylserine residues exposition and G2/M arrest on HT-29 cells. Moreover, 2b (50 μM) was able to interact with ctDNA and inhibited topoisomerase IIα activity. These results demonstrate the importance of thiosemicarbazone, especially the derivative 2b, as a promising candidate for anticancer therapy.

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Citations

Apr 2, 2019·Anti-cancer Drugs·Daiane M PerondiMaria C Santos-Silva
Sep 3, 2019·Archiv der Pharmazie·Merve ErtasŞeref Demirayak
Jan 17, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Van Hien PhamBinh Duong Vu
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Dec 29, 2020·International Journal of Biological Macromolecules·Josival Emanuel Ferreira AlvesSinara Mônica Vitalino de Almeida
Feb 17, 2021·Pharmacological Reports : PR·Íris T T JacobMaria C A de Lima
Feb 24, 2020·Journal of Inorganic Biochemistry·Raquel AlcarazCarlos García-Girón
Mar 26, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Nancy Y Guerrero-PepinosaJuan C Sepúlveda-Arias
Jan 26, 2018·Chemico-biological Interactions·Luana Maria Mariz Gomes da SilvaMonica Camelo Pessoa de Azevedo Albuquerque
Jul 20, 2019·International Journal of Biological Macromolecules·Francivaldo Araújo da Silva FilhoSinara Mônica Vitalino de Almeida

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