Synthesis and biological evaluation of 6-phenylpurine linked hydroxamates as novel histone deacetylase inhibitors

A series of 6-phenylpurine based hydroxamates have been designed, synthesized and evaluated. Compound 3b and its analogs are potent histone deacetylase (HDAC) but weak PI3K/mTOR inhibitors. These compounds demonstrated broad anti-cancer activities against 38 cancer cell lines with leukemia, lymphoma, and the majority of liver cancer cell lines exhibiting the most sensitivity towards these compounds. Compound 3b demonstrated modulation of HDAC targets in vitro in a dose-dependent manner. It has good in vitro ADME profile that translated into a greatly improved pharmacokinetic profile. 3b also demonstrated modulation of HDACs in tumors in a PC-3 xenograft model. It was further evaluated in combination therapies in vitro. It exhibited additive or synergistic growth inhibition effect in HepG2 cells when combined with a number of approved drugs such as sorafenib, sunitinib, and erlotinib. Hence, 3b has the potential to be combined with the above to treat advanced liver cancer. As such, current data warrant further evaluation, optimization, and subsequent in vivo validation of the potential combination therapies.