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

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. doi: 10.1016/j.ejmech.2017.05.023.
Jamerson Ferreira de Oliveira 1,  Talitha Santos Lima 1,  Débora Barbosa Vendramini-Costa 2,  Sybelle Christianne Batista de Lacerda Pedrosa 3,  Elizabeth Almeida Lafayette 4,  Rosali Maria Ferreira da Silva 5,  Sinara Monica Vitalino de Almeida 6,  Ricardo Olímpio de Moura 7,  Ana Lúcia Tasca Gois Ruiz 8,  João Ernesto de Carvalho 9,  Maria do Carmo Alves de Lima 10
Affiliations

Affiliations

  • 1 Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos (DANTI), 50670-901, Recife, PE, Brazil.
  • 2 Universidade Estadual de Campinas (Unicamp), Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), 13083-970, Campinas, SP, Brazil; Cancer Biology, Fox Chase Cancer Center, 19111, Philadelphia, PA, USA.
  • 3 Universidade Federal do Vale do São Francisco (UNIVASF), Colegiado de Ciências Farmacêuticas (CFARM), 56304-205, Petrolina, PE, Brazil.
  • 4 Universidade Federal da Paraíba (UFPB), Departamento de Química e Física (DQF), 58397-000, Areia, PB, Brazil.
  • 5 Universidade Federal de Pernambuco (UFPE), Departamento de Ciências Farmacêuticas (DCFAR), 50670-901, Recife, PE, Brazil.
  • 6 Universidade de Pernambuco (UPE), Faculdade de Ciências, Educação e Tecnologia de Garanhuns (FACETEG), 55290-000, Garanhuns, PE, Brazil.
  • 7 Universidade Estadual da Paraíba (UEPB), Departamento de Farmácia, 58429-500, Campina Grande, PB, Brazil.
  • 8 Universidade Estadual de Campinas (Unicamp), Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), 13083-970, Campinas, SP, Brazil.
  • 9 Universidade Estadual de Campinas (Unicamp), Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), 13083-970, Campinas, SP, Brazil; Universidade Estadual de Campinas (Unicamp), Faculdade de Ciências Farmacêuticas (FCF), 13083-970, Campinas, SP, Brazil.
  • 10 Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos (DANTI), 50670-901, Recife, PE, Brazil. Electronic address: nenalima.mariadocarmo@gmail.com.
PMID: 28505535 DOI: 10.1016/j.ejmech.2017.05.023
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.

Keywords

Anticancer therapy; Cellular death; DNA interaction; Medicinal chemistry; Topoisomerase inhibition.

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