Design And Optimization Of Novel Hydroxamate-Based Histone Deacetylase Inhibitors Of Triazole Substituted Aromatic Amides Bearing Potent Activities Against Solid Tumors

Molecular targeted therapy is one of the hottest topics in the field of cancer treatment, which is believed to be more effective to cancer cells and less harmful to normal cells compared with traditional chemical treatments. Among the known molecular targets, Histone deacetylases (HDACs), which are overexpressed in wide varieties of cancers and play significant roles in the progression and development of cancer, are thought to be one of the promising targets for the treatment of cancers.Up to date, four HDACs inhibitors (HDACis) have been approved by the U.S. FDA for the treatment of some kinds of hematologic malignancies. However, the effects of HDACis used as monotherapies against solid tumors has been disappointing. Our initial work led to the discovery of YF-454A, which showed good anti-proliferative and anti-metastatic activities in several tumors cell lines, but suffered poor physicochemical properties. In the next research process, we focused on improving the druggability of our lead compound.It was reported that 1,2,3-triazoles are attractive connecting units with unique structure and properties in the sense that they can bind biomolecular targets and improve the solubility, TPSA as well as many other properties. After introducing 1,2,3-triazole unit to our scaffold structure, we have synthesized a group of novel HDACis. Indeed, some of these HDACis have better physicochemical properties than YF-454A. Then we tested all these compounds in vitro anti-proliferative and anti-metastatic assays. Ultimately, one compound 8a with good in vitro activities have been tested in vivo animal models showed prominent anti-solid tumor activities, which also validated our original design idea.