Design, synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups

Abstract

A series of hydroxamic acid-based HDACIs with 4-aminoquinazolinyl moieties as capping groups was profiled. Most compounds showed more potent HDACs inhibition activity than clinically used drug SAHA. Among them, compounds 5f and 5h selectively inhibited HDAC 1,2 over HDAC8, and showed strong activity in several cellular assays, not possessing significant toxicity to primary human cells and hERG inhibition. Strikingly, 5f possessed acceptable pharmacokinetic characteristics and exhibited significant antitumor activity in an A549 xenograft model study at well tolerated doses.

Keywords: 4-aminoquinazolinyl; Antiproliferative activity; Histone deacetylases; Selectivity; Synthesis.