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Structure-Based Optimization of Carbendazim-Derived Tubulin Polymerization Inhibitors through Alchemical Free Energy Calculations.
Cano-González, Lucia; Espinosa-Mendoza, Johan D; Matadamas-Martínez, Félix; Romero-Velásquez, Ariana; Flores-Ramos, Miguel; Colorado-Pablo, Luis Fernando; Cerbón-Cervantes, Marco Antonio; Castillo, Rafael; González-Sánchez, Ignacio; Yépez-Mulia, Lilián; Hernández-Campos, Alicia; Aguayo-Ortiz, Rodrigo.
Afiliação
  • Cano-González L; Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
  • Espinosa-Mendoza JD; Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
  • Matadamas-Martínez F; Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico.
  • Romero-Velásquez A; Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
  • Flores-Ramos M; Escuela Nacional de Estudios Superiores, Unidad Mérida, Universidad Nacional Autónoma de México, Yucatán 97357, Mexico.
  • Colorado-Pablo LF; Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
  • Cerbón-Cervantes MA; Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
  • Castillo R; Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
  • González-Sánchez I; Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
  • Yépez-Mulia L; Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico.
  • Hernández-Campos A; Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
  • Aguayo-Ortiz R; Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
J Chem Inf Model ; 63(22): 7228-7238, 2023 Nov 27.
Article em En | MEDLINE | ID: mdl-37947759
Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis in human cancer cells by inhibiting tubulin polymerization. Crystallographic structures of α/ß-tubulin multimers complexed with nocodazole and mebendazole, two carbendazim derivatives with potent anticancer activity, highlighted the possibility of designing compounds that occupy both benzimidazole- and colchicine-binding sites. In addition, previous studies have demonstrated that the incorporation of a phenoxy group at position 5/6 of carbendazim increases the antiproliferative activity in cancer cell lines. Despite the significant progress made in identifying new tubulin-targeting anticancer compounds, further modifications are needed to enhance their potency and safety. In this study, we explored the impact of modifying the phenoxy substitution pattern on antiproliferative activity. Alchemical free energy calculations were used to predict the binding free energy difference upon ligand modification and define the most viable path for structure optimization. Based on these calculations, seven compounds were synthesized and evaluated against lung and colon cancer cell lines. Our results showed that compound 5a, which incorporates an α-naphthyloxy substitution, exhibits the highest antiproliferative activity against both cancer lines (SK-LU-1 and SW620, IC50 < 100 nM) and induces morphological changes in the cells associated with mitotic arrest and mitotic catastrophe. Nevertheless, the tubulin polymerization assay showed that 5a has a lower inhibitory potency than nocodazole. Molecular dynamics simulations suggested that this low antitubulin activity could be associated with the loss of the key H-bond interaction with V236. This study provides insights into the design of novel carbendazim derivatives with anticancer activity.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Moduladores de Tubulina / Antineoplásicos Limite: Humans Idioma: En Revista: J Chem Inf Model Assunto da revista: INFORMATICA MEDICA / QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: México País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Moduladores de Tubulina / Antineoplásicos Limite: Humans Idioma: En Revista: J Chem Inf Model Assunto da revista: INFORMATICA MEDICA / QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: México País de publicação: Estados Unidos