TY - JOUR
T1 - Three amino acid derivatives of valproic acid
T2 - Design, synthesis, theoretical and experimental evaluation as anticancer agents
AU - Luna-Palencia, Gabriela R.
AU - Martínez-Ramos, Federico
AU - Vásquez-Moctezuma, Ismael
AU - Fragoso-Vázquez, Manuel Jonathan
AU - Mendieta-Wejebe, Jessica Elena
AU - Padilla-Martínez, Itzia I.
AU - Sixto-López, Yudibeth
AU - Méndez-Luna, David
AU - Trujillo-Ferrara, José
AU - Meraz-Ríos, Marco A.
AU - Fonseca-Sabater, Yadira
AU - Correa-Basurto, José
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Amino acids
KW - Anticancer agents
KW - Histone deacetylase 8
KW - Theoretical/experimental studies
KW - Valproic acid derivatives
UR - http://www.scopus.com/inward/record.url?scp=84905648407&partnerID=8YFLogxK
U2 - 10.2174/1871520614666140127113218
DO - 10.2174/1871520614666140127113218
M3 - Artículo
SN - 1871-5206
VL - 14
SP - 984
EP - 993
JO - Anti-Cancer Agents in Medicinal Chemistry
JF - Anti-Cancer Agents in Medicinal Chemistry
IS - 7
ER -