Three Amino Acid Derivatives of Valproic Acid: Design, Synthesis, Theoretical and Experimental Evaluation as Anticancer Agents
Gabriela R. Luna-Palencia, Federico Martinez-Ramos, Ismael Vasquez-Moctezuma, Manuel Jonathan Fragoso-Vazquez, Jessica Elena Mendieta-Wejebe, Itzia I. Padilla-Martínez, Yudibeth Sixto-Lopez, David Mendez-Luna, Jose Trujillo-Ferrara, Marco A. Meraz-Rios, Yadira Fonseca-Sabater and Jose Correa-Basurto
Affiliation: Molecular Modeling and Drug Design Laboratory, Biophysics and Biocatalysis Lab, Biochemistry Lab, Seccion de Estudios de Posgrado e Investigacion y Departamento de Bioquimica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron, Distrito Federal 11340, Mexico.
Keywords: Amino acids, anticancer agents, histone deacetylase 8, theoretical/experimental studies, valproic acid derivatives.
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 antiproliferative
effects than the parent compound. Hence, these results suggest that these amino acid derivatives may represent a good
alternative for anticancer treatment.
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