Synthesis of thiophene-thiosemicarbazone derivatives and evaluation of their in vitro and in vivo antitumor activities

  • Eur J Med Chem. 2015 Nov 2:104:148-56. doi: 10.1016/j.ejmech.2015.09.036.
Jamerson Ferreira de Oliveira  1 ,  Anekécia Lauro da Silva  1 ,  Débora Barbosa Vendramini-Costa  2 ,  Cezar Augusto da Cruz Amorim  1 ,  Júlia Furtado Campos  3 ,  Amélia Galdino Ribeiro  1 ,  Ricardo Olímpio de Moura  4 ,  Jorge Luiz Neves  5 ,  Ana Lúcia Tasca Gois Ruiz  2 ,  João Ernesto de Carvalho  2 ,  Maria do Carmo Alves de Lima  6
Affiliations
  • 1. Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil.
  • 2. Universidade Estadual de Campinas (Unicamp), Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), 13083-970 Campinas, SP, Brazil.
  • 3. Instituto Nacional de Tecnologia Nordeste/MCT, Centro de Tecnologias Estratégicas do Nordeste, 50740-540 Recife, PE, Brazil.
  • 4. Universidade Estadual da Paraíba (UEPB), Departamento de Farmácia, 58429-500 Paraíba, PB, Brazil.
  • 5. Universidade Federal de Pernambuco (UFPE), Departamento de Química Fundamental, 50670-901 Recife, PE, Brazil.
  • 6. Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil. Electronic address: [email protected].
PMID: 26454648 DOI: 10.1016/j.ejmech.2015.09.036
Abstract

A series of thiophene-2-thiosemicarbazones derivatives (5-14) was synthesized, characterized and evaluated for their antitumor activity. They were tested in vitro against human tumor cell lines through the colorimetric method. The results revealed that compounds 7 and 9 were the most effective in inhibiting 50% of the cell growth after 48 h of treatment. As compound 7 showed a potent antiproliferative profile, it has been chosen for further studies in 786-0 cell line by flow cytometry. Treatments with compound 7 (50 μM) induced early phosphatidylserine exposure after 18 h of exposure and this process progressed phosphatidylserine exposure with loss of cell membrane integrity after 24 h of treatment, suggesting a time-dependent cell death process. Regarding the cell cycle profile, no changes were observed after treatment with compound 7 (25 μM), suggesting a mechanism of cell death independent on the cell cycle. The in vivo studies show that compound 7 possess low acute toxicity, being the doses of 30-300 mgKg(-1) chosen for studies in Ehrlich solid tumor model in mice. All doses were able to inhibit tumor development being the lowest one the most effective. Our findings highlight thiophene-2-thiosemicarbazones as a promising class of compounds for further studies concerning new Anticancer therapies.

Keywords
Antitumor; Cytotoxicity; Medicinal chemistry; Thiophene; Thiosemicarbazone.