title: Docking, synthesis and antiproliferative activity of N-acylhydrazone derivatives designed as combretastatin A4 analogues.
abstract: Cancer is the second most common cause of death in the USA. Among the known classes of anticancer agents, the microtubule-targeted antimitotic drugs are considered to be one of the most important. They are usually classified into microtubule-destabilizing (e.g., Vinca alkaloids) and microtubule-stabilizing (e.g., paclitaxel) agents. Combretastatin A4 (CA-4), which is a natural stilbene isolated from Combretum caffrum, is a microtubule-destabilizing agent that binds to the colchicine domain on β-tubulin and exhibits a lower toxicity profile than paclitaxel or the Vinca alkaloids. In this paper, we describe the docking study, synthesis, antiproliferative activity and selectivity index of the N-acylhydrazone derivatives (5a-r) designed as CA-4 analogues. The essential structural requirements for molecular recognition by the colchicine binding site of β-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values ≤18 µM and ≥4 nM) were identified. Among these active compounds, LASSBio-1586 (5b) emerged as a simple antitumor drug candidate, which is capable of inhibiting microtubule polymerization and possesses a broad in vitro and in vivo antiproliferative profile, as well as a better selectivity index than the prototype CA-4, indicating improved selective cytotoxicity toward cancer cells.
authors.affiliation: Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR). Universidade Federal do Rio de Janeiro, Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio) Rio de Janeiro, Brasil; Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.
authors.forename: Daniel Nascimento
authors.initials: DN
authors.lastname: do Amaral
authors.affiliation: Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, Brasil.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Cavalcanti
authors.affiliation: Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, Brasil.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Bezerra
authors.affiliation: Departamento de Ciências Biológicas, Campus Senador Helvídio Nunes de Barros, Universidade Federal do Piauí, Picos, Brasil.
authors.forename: Paulo Michel P
authors.initials: PM
authors.lastname: Ferreira
authors.affiliation: Instituto de Física, Universidade Federal de Goiás, Goiânia, Brazil.
authors.forename: Rosane de Paula
authors.initials: Rde P
authors.lastname: Castro
authors.affiliation: Instituto de Física, Universidade Federal de Goiás, Goiânia, Brazil.
authors.forename: José Ricardo
authors.initials: JR
authors.lastname: Sabino
authors.affiliation: Faculdade de Medicina, Departamento de Radiologia, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Camila Maria Longo
authors.initials: CM
authors.lastname: Machado
authors.affiliation: Faculdade de Medicina, Departamento de Radiologia, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.affiliation: Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, Brasil.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pessoa
authors.affiliation: Departamento de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, Brasil.
authors.forename: Carlos M R
authors.initials: CM
authors.lastname: Sant'Anna
authors.affiliation: Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR). Universidade Federal do Rio de Janeiro, Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio) Rio de Janeiro, Brasil; Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.affiliation: Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR). Universidade Federal do Rio de Janeiro, Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio) Rio de Janeiro, Brasil; Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.
authors.forename: Lídia Moreira
authors.initials: LM
authors.lastname: Lima
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D015195:Drug Design; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008870:Microtubules / Q000378:metabolism; D062105:Molecular Docking Simulation; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D013267:Stilbenes; D014404:Tubulin; C058728:fosbretabulin; D003078:Colchicine; D005472:Fluorouracil