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Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)
ISSN (Print): 1871-5206
ISSN (Online): 1875-5992
Epub Full Text Article
DOI: 10.2174/1871520614666140127113218      Price:  $95









Three Amino Acid Derivatives of Valproic Acid: Design, Synthesis, Theoretical and Experimental Evaluation as Anticancer Agents

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Author(s): Gabriela R. Luna-Palencia, Federico Martínez-Ramos, Ismael Vásquez-Moctezuma, Manuel Jonathan Fragoso-Vázquez, Jessica Elena Mendieta-Wejebe, Itzia I. Padilla-Martínez, Yudibeth Sixto-López, David Méndez-Luna, José Trujillo-Ferrara, Marco Antonio Meraz-Ríos, Yadira Fonseca-Sabater and José Correa-Basurto
Abstract:
Valproic acid (VPA) is extensively used as an anticonvulsive agent and as a treatment for other neurological disorders. It has been shown that VPA exerts an anti-proliferative effect on several types of cancer cells by inhibiting the activity of histone deacetylases (HDACs), which are involved in replication and differentiation processes. However, VPA has some disadvantages, among which are poor water solubility and hepatotoxicity. Therefore, the aim of the present study was to design and synthesize three derivatives of VPA to improve its physicochemical properties and anti-proliferative effects. For this purpose, the amino acids aspartic acid, glutamic acid and proline were added to the molecular structure of VPA. Docking and molecular dynamics simulations were used to determine the mode of recognition of these three derivatives by different conformations of HDAC8. This receptor was used as the specific target because of its high affinity for this type of substrate. The results demonstrate that, compared to VPA, the test compounds bind to different sites on the enzyme and that hydrogen bonds and hydrophobic interactions play key roles in this difference. The IC50 values of the VPA derivatives, experimentally determined using HeLa cells, were in the mM range. This result indicates that the derivatives have greater anti-proliferative effects than the parent compound. Hence, these results suggest that these amino acid derivatives may represent a good alternative for anticancer treatment
Keywords:
Amino acids, anticancer agents, histone deacetylase 8, theoretical/experimental studies, valproic acid derivatives
Affiliation:
Molecular Modeling and Drug Design Laboratory, Biophysics and Biocatalysis Lab, Biochemistry Lab, Sección de Estudios de Posgrado e Investigación y Departamento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Distrito Federal 11340, México