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.

o-Alkylselenenylated benzoic acid accesses several sites in serum albumin according to fluorescence studies, Raman spectroscopy and theoretical simulations.

In the circulatory system, serum albumin (SA) is an important transporter of the majority of molecules with biological activity. We focused the current study on the anti-inflammatory compound, o-alkylselenenylated benzoic acid (ALKSEBEA), to determine its ability to access SA. Herein, we employed experimental procedures (fluorescence studies, Raman spectroscopy) and docking study on SA obtained from the Protein Data Bank and key conformers obtained from molecular dynamics simulations. The results show that ALKSEBEA accesses SA using a cooperative behavior according to fluorescence studies. In addition, the Raman results indicate that the ligand binding affects the backbone constituents. These results were confirmed by docking simulations tested on several SA conformers, which showed that ALKSEBEA bound on several sites on SA via π-π or π-cation interactions and that the ligand reaches other binding sites, where aromatic and basic residues as well as the backbone residues are involved.