title: Synthesis of thiophene-thiosemicarbazone derivatives and evaluation of their in vitro and in vivo antitumor activities.
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.
authors.affiliation: Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil.
authors.forename: Jamerson Ferreira
authors.initials: JF
authors.lastname: de Oliveira
authors.affiliation: Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil.
authors.forename: Anekécia Lauro
authors.initials: AL
authors.lastname: da Silva
authors.affiliation: Universidade Estadual de Campinas (Unicamp), Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), 13083-970 Campinas, SP, Brazil.
authors.forename: Débora Barbosa
authors.initials: DB
authors.lastname: Vendramini-Costa
authors.affiliation: Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil.
authors.forename: Cezar Augusto
authors.initials: CA
authors.lastname: da Cruz Amorim
authors.affiliation: Instituto Nacional de Tecnologia Nordeste/MCT, Centro de Tecnologias Estratégicas do Nordeste, 50740-540 Recife, PE, Brazil.
authors.forename: Júlia Furtado
authors.initials: JF
authors.lastname: Campos
authors.affiliation: Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil.
authors.forename: Amélia Galdino
authors.initials: AG
authors.lastname: Ribeiro
authors.affiliation: Universidade Estadual da Paraíba (UEPB), Departamento de Farmácia, 58429-500 Paraíba, PB, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Olímpio de Moura
authors.affiliation: Universidade Federal de Pernambuco (UFPE), Departamento de Química Fundamental, 50670-901 Recife, PE, Brazil.
authors.forename: Jorge Luiz
authors.initials: JL
authors.lastname: Neves
authors.affiliation: Universidade Estadual de Campinas (Unicamp), Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), 13083-970 Campinas, SP, Brazil.
authors.forename: Ana Lúcia Tasca Gois
authors.initials: AL
authors.lastname: Ruiz
authors.affiliation: Universidade Estadual de Campinas (Unicamp), Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), 13083-970 Campinas, SP, Brazil.
authors.forename: João
authors.initials: J
authors.lastname: Ernesto de Carvalho
authors.affiliation: Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil. Electronic address: nenalima.mariadocarmo@gmail.com.
authors.forename: Maria do Carmo
authors.initials: Mdo C
authors.lastname: Alves de Lima
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D013876:Thiophenes; D013882:Thiosemicarbazones
keywords: Antitumor; Cytotoxicity; Medicinal chemistry; Thiophene; Thiosemicarbazone