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.

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 compound2(N-(2-hydroxyphenyl)-2-propylpentanamide) was the best candidate to be synthesized and evaluatedin vitroas an anti-cancer agent against HeLa, rhabdomyosarcoma and breast cancer cell lines. Compound2showed a better IC50(μM range) than VPA (mM range) on these cancer cells. And also,2was particularly effective on triple negative breast cancer cells. In conclusion,2is an example of drugs designedin silicothat show biological properties against human cancer difficult to treat as triple negative breast cancer. [ABSTRACT FROM PUBLISHER]