title: New spiro-acridines: DNA interaction, antiproliferative activity and inhibition of human DNA topoisomerases.
abstract: Two new spiro-acridines were synthesized by introducing cyano-N-acylhydrazone between the acridine and phenyl rings followed by spontaneous cyclization. The final compounds (E)-1'-(benzylideneamino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-01) and (E)-1'-((4-methoxybenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-02) were evaluated for their interactions with calf thymus DNA, antiproliferative and human topoisomerase I and IIα inhibitory activities. Both compounds presented ability to bind DNA. The binding constant determined by UV-vis spectroscopy was found to be 104M-1. Antiproliferative assay demonstrated that AMTAC-01 and AMTAC-02 were most active against prostate and melanoma tumor cell lines, respectively. The compound did not present Topo I inhibitory activity. However, both derivatives displayed topoisomerase IIα inhibitory activity comparable to amsacrine, and AMTAC-02 was more potent than AMTAC-01 with methoxy substituent group on phenyl ring. This study demonstrates that the new derivatives are promising molecules with topoisomerase IIα inhibitory and antiproliferative activities.
authors.affiliation: Laboratório de Imunopatologia Keizo Asami (LIKA) and Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil; Faculdade de Ciências, Educação e Tecnologia de Garanhuns (FACETEG), Universidade de Pernambuco (UPE), Garanhuns 55290-000, PE, Brazil. Electronic address: sinara.monica@gmail.com.
authors.forename: Sinara Mônica Vitalino de
authors.initials: SM
authors.lastname: Almeida
authors.affiliation: Laboratório de Química e Inovação Terapêutica (LQIT) - Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil.
authors.forename: Elizabeth Almeida
authors.initials: EA
authors.lastname: Lafayette
authors.affiliation: Laboratório de Química e Inovação Terapêutica (LQIT) - Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil.
authors.forename: Willams Leal
authors.initials: WL
authors.lastname: Silva
authors.affiliation: Departamento de Biologia Molecular, Centro de Ciências Exatas e da Natureza, Universidade Federal da Paraíba, João Pessoa, Paraíba 58059-900, Brazil.
authors.forename: Vanessa de
authors.initials: V
authors.lastname: Lima Serafim
authors.affiliation: Universidade Federal de Pernambuco (UFPE), Departamento de Química Fundamental, 50670-901 Recife, PE, Brazil.
authors.forename: Thais Meira
authors.initials: TM
authors.lastname: Menezes
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: Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Universidade Estadual de Campinas, 13083-970 Campinas, SP, Brazil.
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, Universidade Estadual de Campinas, 13083-970 Campinas, SP, Brazil.
authors.forename: João Ernesto de
authors.initials: JE
authors.lastname: Carvalho
authors.affiliation: Universidade Estadual da Paraíba (UEPB), Campus Campina Grande 58429-500, PB, Brazil.
authors.forename: Ricardo Olímpio de
authors.initials: RO
authors.lastname: Moura
authors.affiliation: Laboratório de Imunopatologia Keizo Asami (LIKA) and Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil.
authors.forename: Eduardo Isidoro Carneiro
authors.initials: EI
authors.lastname: Beltrão
authors.affiliation: Laboratório de Imunopatologia Keizo Asami (LIKA) and Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil.
authors.forename: Luiz Bezerra de
authors.initials: LB
authors.lastname: Carvalho Júnior
authors.affiliation: Laboratório de Química e Inovação Terapêutica (LQIT) - Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil.
authors.forename: Maria do Carmo Alves de
authors.initials: MD
authors.lastname: Lima
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D026942:DNA Topoisomerases / Q000378:metabolism*; D006801:Humans; D066244:Proton Magnetic Resonance Spectroscopy; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*
chemical_list: D000166:Acridines; D013141:Spiro Compounds; D059003:Topoisomerase Inhibitors; D004247:DNA; C427203:calf thymus DNA; D026942:DNA Topoisomerases
keywords: DNA-binding; Spiro-acridine; Topoisomerase