title: Synthesis, DNA Binding, and Antiproliferative Activity of Novel Acridine-Thiosemicarbazone Derivatives.
abstract: In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide derivatives (3a-h) were synthesized, their antiproliferative activities were evaluated, and DNA binding properties were performed with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives. The calculated binding constants ranged from 1.74 × 10(4) to 1.0 × 10(6) M(-1) and quenching constants from -0.2 × 10(4) to 2.18 × 10(4) M(-1) indicating high affinity to ctDNA base pairs. The most efficient compound in binding to ctDNA in vitro was (Z)-2-(acridin-9-ylmethylene)-N- (4-chlorophenyl) hydrazinecarbothioamide (3f), while the most active compound in antiproliferative assay was (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide (3a). There was no correlation between DNA-binding and in vitro antiproliferative activity, but the results suggest that DNA binding can be involved in the biological activity mechanism. This study may guide the choice of the size and shape of the intercalating part of the ligand and the strategic selection of substituents that increase DNA-binding or antiproliferative properties.
authors.affiliation: Laboratório de Imunopatologia Keizo Asami (LIKA) and Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil. sinara.monica@gmail.com.|Faculdade de Ciências, Educação e Tecnologia de Garanhuns (FACETEG), Universidade de Pernambuco (UPE), Garanhuns 55290-000, PE, Brazil. sinara.monica@gmail.com.
authors.forename: Sinara Mônica Vitalino
authors.initials: SM
authors.lastname: de Almeida
authors.affiliation: Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil. elizabeth.almeidalafayette@gmail.com.
authors.forename: Elizabeth Almeida
authors.initials: EA
authors.lastname: Lafayette
authors.affiliation: Laboratório de Imunopatologia Keizo Asami (LIKA) and Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil. lucia-patricia@hotmail.com.
authors.forename: Lúcia Patrícia Bezerra Gomes
authors.initials: LP
authors.lastname: da Silva
authors.affiliation: Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil. cezar.amoriim@gmail.com.
authors.forename: Cézar Augusto da Cruz
authors.initials: CA
authors.lastname: Amorim
authors.affiliation: Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil. tiagobento2006@gmail.com.
authors.forename: Tiago Bento
authors.initials: TB
authors.lastname: de Oliveira
authors.affiliation: Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (DFT/CPQBA), Universidade Estadual de Campinas (UNICAMP), Campinas 13083-970, SP, Brazil. aa_ruiz@hotmail.com.
authors.forename: Ana Lucia Tasca Gois
authors.initials: AL
authors.lastname: Ruiz
authors.affiliation: Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (DFT/CPQBA), Universidade Estadual de Campinas (UNICAMP), Campinas 13083-970, SP, Brazil. carvalho@cpqba.unicamp.br.|Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-859, SP, Brazil. carvalho@cpqba.unicamp.br.
authors.forename: João Ernesto
authors.initials: JE
authors.lastname: de Carvalho
authors.affiliation: Departamento de Farmácia, Laboratório de Síntese e Vetorização de Moléculas, Universidade Estadual da Paraíba (UEPB), Campus Campina Grande 58429-500, PB, Brazil. ricardo.olimpiodemoura@gmail.com.
authors.forename: Ricardo Olímpio
authors.initials: RO
authors.lastname: de Moura
authors.affiliation: Laboratório de Imunopatologia Keizo Asami (LIKA) and Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil. ebeltrao@hotmail.com.
authors.forename: Eduardo Isidoro Carneiro
authors.initials: EI
authors.lastname: Beltrão
authors.affiliation: Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil. nenalima.mariadocarmo@gmail.com.
authors.forename: Maria do Carmo Alves
authors.initials: Mdo C
authors.lastname: de Lima
authors.affiliation: Laboratório de Imunopatologia Keizo Asami (LIKA) and Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil. lbcj@hotlink.com.br.
authors.forename: Luiz Bezerra
authors.initials: LB
authors.lastname: de Carvalho Júnior
mesh_terms: D000166:Acridines / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D004247:DNA / Q000737:chemistry; D061986:MCF-7 Cells; D013882:Thiosemicarbazones / Q000737:chemistry*
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D013882:Thiosemicarbazones; D004247:DNA; C427203:calf thymus DNA
keywords: DNA binding; acridine; antiproliferative; thiosemicarbazone