2. Academic Validation
  3. Design, synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups

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

  • Bioorg Med Chem Lett. 2017 Nov 1;27(21):4885-4888. doi: 10.1016/j.bmcl.2017.09.036.
Qingwei Zhang 1,  Yang Li 2,  Baoyin Zhang 2,  Bingliu Lu 2,  Jianqi Li 3
Affiliations

Affiliations

  • 1 Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, PR China. Electronic address: sipiqingwei@163.com.
  • 2 Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, PR China.
  • 3 Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, PR China. Electronic address: lijianqb@126.com.
PMID: 28947154 DOI: 10.1016/j.bmcl.2017.09.036
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.

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