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Design, Synthesis and Evaluation of 2,4-Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors.
Herrera-Vázquez, Frida S; Matadamas-Martínez, Félix; Aguayo-Ortiz, Rodrigo; Dominguez, Laura; Ramírez-Apan, Teresa; Yépez-Mulia, Lilián; Hernández-Luis, Francisco.
Afiliação
  • Herrera-Vázquez FS; Departamento de Farmacia, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
  • Matadamas-Martínez F; Departamento de Farmacia, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
  • Aguayo-Ortiz R; Unidad Médica de Alta Especialidad-Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, 06720, Mexico.
  • Dominguez L; Departamento de Fisicoquímica, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
  • Ramírez-Apan T; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Yépez-Mulia L; Departamento de Fisicoquímica, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
  • Hernández-Luis F; Instituto de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
ChemMedChem ; 15(19): 1802-1812, 2020 10 05.
Article em En | MEDLINE | ID: mdl-32686342
Microtubules are highly dynamic polymers composed of α- and ß-tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to ß-tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well-known tubulin-depolymerizing agents that have close binding sites in the ß-tubulin. In this study, we designed and synthesized a set of nine 2,4-diaminoquinazoline derivatives that could occupy both NZ and COL binding sites. The synthesized compounds were evaluated for their antiproliferative activities against five cancer cell lines (PC-3, HCT-15, MCF-7, MDA-MB-231, and SK-LU-1), a noncancerous one (COS-7), and peripheral blood mononuclear cells (PBMC). The effect of compounds 4 e and 4 i on tubulin organization and polymerization was analyzed on the SK-LU-1 cell line by indirect immunofluorescence, western blotting, and tubulin polymerization assays. Our results demonstrated that both compounds exert their antiproliferative activity by inhibiting tubulin polymerization. Finally, a possible binding pose of 4 i in the NZ/COL binding site was determined by using molecular docking and molecular dynamics (MD) approaches. To our knowledge, this is the first report of non-N-substituted 2,4-diaminoquinazoline derivatives with the ability to inhibit tubulin polymerization.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quinazolinas / Tubulina (Proteína) / Desenho de Fármacos / Moduladores de Tubulina / Antineoplásicos Limite: Humans Idioma: En Revista: ChemMedChem Assunto da revista: FARMACOLOGIA / QUIMICA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: México País de publicação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quinazolinas / Tubulina (Proteína) / Desenho de Fármacos / Moduladores de Tubulina / Antineoplásicos Limite: Humans Idioma: En Revista: ChemMedChem Assunto da revista: FARMACOLOGIA / QUIMICA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: México País de publicação: Alemanha