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

作者：Prestegui Martel Berenice; Antonio Bermudez Lugo Jorge; Chavez Blanco Alma; Duenas Gonzalez Alfonso; Ruben Garcia Sanchez Jose; Alberto Perez Gonzalez Oscar; Irene Padilla Martinez Itzia; Jonathan Fragoso Vazquez Manuel; Elena Mendieta Wejebe Jessica; Maria Correa Basurto Ana; Mendez Luna David; Trujillo Ferrara Jose; Correa Basurto Jose^*

来源：Journal of Enzyme Inhibition and Medicinal Chemistry, 2016, 31(sup3): 140-149.

DOI：10.1080/14756366.2016.1210138

• Flexible docking
• histone deacetylase inhibitors
• molecular modeling
• valproic acid
• X-ray structure

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 (M 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.

• 出版日期2016-12