Three amino acid derivatives of valproic acid: Design, synthesis, theoretical and experimental evaluation as anticancer agents

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 A. Meraz-Ríos, Yadira Fonseca-Sabater, José Correa-Basurto

Research output: Contribution to journalArticle

3 Citations (Scopus)

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. © 2014 Bentham Science Publishers.
Original languageAmerican English
Pages (from-to)984-993
Number of pages884
JournalAnti-Cancer Agents in Medicinal Chemistry
DOIs
StatePublished - 1 Jan 2014

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Valproic Acid
Antineoplastic Agents
Amino Acids
Histone Deacetylases
Molecular Dynamics Simulation
Nervous System Diseases
Molecular Structure
Hydrophobic and Hydrophilic Interactions
HeLa Cells
Proline
Aspartic Acid
Anticonvulsants
Solubility
Inhibitory Concentration 50
Glutamic Acid
Hydrogen
Water
Enzymes
Neoplasms

Cite this

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title = "Three amino acid derivatives of valproic acid: Design, synthesis, theoretical and experimental evaluation as anticancer agents",
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. {\circledC} 2014 Bentham Science Publishers.",
author = "Luna-Palencia, {Gabriela R.} and Federico Mart{\'i}nez-Ramos and Ismael V{\'a}squez-Moctezuma and Fragoso-V{\'a}zquez, {Manuel Jonathan} and Mendieta-Wejebe, {Jessica Elena} and Padilla-Mart{\'i}nez, {Itzia I.} and Yudibeth Sixto-L{\'o}pez and David M{\'e}ndez-Luna and Jos{\'e} Trujillo-Ferrara and Meraz-R{\'i}os, {Marco A.} and Yadira Fonseca-Sabater and Jos{\'e} Correa-Basurto",
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Three amino acid derivatives of valproic acid: Design, synthesis, theoretical and experimental evaluation as anticancer agents. / Luna-Palencia, Gabriela R.; Martínez-Ramos, Federico; Vásquez-Moctezuma, Ismael; Fragoso-Vázquez, Manuel Jonathan; Mendieta-Wejebe, Jessica Elena; Padilla-Martínez, Itzia I.; Sixto-López, Yudibeth; Méndez-Luna, David; Trujillo-Ferrara, José; Meraz-Ríos, Marco A.; Fonseca-Sabater, Yadira; Correa-Basurto, José.

In: Anti-Cancer Agents in Medicinal Chemistry, 01.01.2014, p. 984-993.

Research output: Contribution to journalArticle

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T1 - Three amino acid derivatives of valproic acid: 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 - 2014/1/1

Y1 - 2014/1/1

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. © 2014 Bentham Science Publishers.

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