TY - JOUR
T1 - N-(2-hydroxyphenyl)-2-propylpentanamide, a valproic acid aryl derivative designed in silico with improved anti-proliferative activity in HeLa, rhabdomyosarcoma and breast cancer cells
AU - Prestegui-Martel, Berenice
AU - Bermúdez-Lugo, Jorge Antonio
AU - Chávez-Blanco, Alma
AU - Dueñas-González, Alfonso
AU - García-Sánchez, José Rubén
AU - Pérez-González, Oscar Alberto
AU - Padilla-Martínez, Itzia Irene
AU - Fragoso-Vázquez, Manuel Jonathan
AU - Mendieta-Wejebe, Jessica Elena
AU - Correa-Basurto, Ana María
AU - Méndez-Luna, David
AU - Trujillo-Ferrara, José
AU - Correa-Basurto, José
N1 - Publisher Copyright:
© 2016 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2016/11/3
Y1 - 2016/11/3
N2 - Epigenetic alterations are associated with cancer and their targeting is a promising approach for treatment of this disease. Among current epigenetic drugs, histone deacetylase (HDAC) inhibitors induce changes in gene expression that can lead to cell death in tumors. Valproic acid (VPA) is a HDAC inhibitor that has antitumor activity at mM range. However, it is known that VPA is a hepatotoxic drug. Therefore, the aim of this study was to design a set of VPA derivatives adding the arylamine core of the suberoylanilide hydroxamic acid (SAHA) with different substituents at its carboxyl group. These derivatives were submitted to docking simulations to select the most promising compound. The compound 2 (N-(2-hydroxyphenyl)-2-propylpentanamide) was the best candidate to be synthesized and evaluated in vitro as an anti-cancer agent against HeLa, rhabdomyosarcoma and breast cancer cell lines. Compound 2 showed a better IC50 (μM range) than VPA (mM range) on these cancer cells. And also, 2 was particularly effective on triple negative breast cancer cells. In conclusion, 2 is an example of drugs designed in silico that show biological properties against human cancer difficult to treat as triple negative breast cancer.
AB - Epigenetic alterations are associated with cancer and their targeting is a promising approach for treatment of this disease. Among current epigenetic drugs, histone deacetylase (HDAC) inhibitors induce changes in gene expression that can lead to cell death in tumors. Valproic acid (VPA) is a HDAC inhibitor that has antitumor activity at mM range. However, it is known that VPA is a hepatotoxic drug. Therefore, the aim of this study was to design a set of VPA derivatives adding the arylamine core of the suberoylanilide hydroxamic acid (SAHA) with different substituents at its carboxyl group. These derivatives were submitted to docking simulations to select the most promising compound. The compound 2 (N-(2-hydroxyphenyl)-2-propylpentanamide) was the best candidate to be synthesized and evaluated in vitro as an anti-cancer agent against HeLa, rhabdomyosarcoma and breast cancer cell lines. Compound 2 showed a better IC50 (μM range) than VPA (mM range) on these cancer cells. And also, 2 was particularly effective on triple negative breast cancer cells. In conclusion, 2 is an example of drugs designed in silico that show biological properties against human cancer difficult to treat as triple negative breast cancer.
KW - Flexible docking
KW - X-ray structure
KW - histone deacetylase inhibitors
KW - molecular modeling
KW - valproic acid
UR - http://www.scopus.com/inward/record.url?scp=84980316080&partnerID=8YFLogxK
U2 - 10.1080/14756366.2016.1210138
DO - 10.1080/14756366.2016.1210138
M3 - Artículo
C2 - 27483122
SN - 1475-6366
VL - 31
SP - 140
EP - 149
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
ER -