Histone deacetylase 6 inhibitors with blood-brain barrier penetration as a potential strategy for CNS-Disorders therapy.

Histone deacetylase 6 inhibitors (HDAC6is) have been applied to certain cancer diseases and more recently to central nervous system (CNS) disorders including Rett syndrome, Alzheimer's and Parkinson's diseases, and major depressive disorder. Brain penetrance is the major challenge for the development of HDAC6is as potential therapeutics for CNS disorders due in part to the polarity of hydroxamate ZBG. Hence, only a handful of brain-penetrant HDAC6is have been reported and a few display appropriate in vitro and in vivo activities in models of neurological diseases in last decades. This review summarizes the contemporary research being done on HADC6is with brain penetration both the biological pathways involved and the structural modification attempts.

Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities.

A series of quinazolinyl-containing benzamide derivatives were designed, synthesized and evaluated for their in vitro histone deacetylase 1 (HDAC1) inhibitory activities. Compounds 11a surpassed the known class I selective HDAC inhibitor MS-275 in both HDAC1 enzymatic inhibitory activity and cellular anti-proliferative activity against a selected set of cancer cell types (Hut78, K562, Hep3B and HCT116 cells) with no observed effects on human normal cells. In particular, compound 11a inhibited HDAC1 over the other tested HDACs isoforms (HDAC2, HDAC6 and HDAC8) with acceptable safety profiles. Moreover, compound 11a displayed favorable oral pharmacokinetic properties and showed significant antitumor activity in the A549 tumor xenograft model in vivo.