Three amino acid derivatives of valproic acid: design, synthesis, theoretical and experimental evaluation as anticancer agents.
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.
Gabriela R
GR
Luna-Palencia
Federico
F
Martinez-Ramos
Ismael
I
Vasquez-Moctezuma
Manuel Jonathan
MJ
Fragoso-Vazquez
Jessica Elena
JE
Mendieta-Wejebe
Itzia I
II
Padilla-Martínez
Yudibeth
Y
Sixto-Lopez
David
D
Mendez-Luna
Jose
J
Trujillo-Ferrara
Marco A
MA
Meraz-Rios
Yadira
Y
Fonseca-Sabater
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. jcorreab@ipn.mx.
Jose
J
Correa-Basurto
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D001224:Aspartic Acid; D018698:Glutamic Acid; D014635:Valproic Acid; D011392:Proline; C409470:HDAC8 protein, human; D006655:Histone Deacetylases