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

Authors
  • Zhang, Qingwei1
  • Li, Yang2
  • Zhang, Baoyin2
  • Lu, Bingliu2
  • Li, Jianqi3
  • 1 Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, PR China. Electronic address: [email protected] , (China)
  • 2 Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, PR China. , (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: [email protected] , (China)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Nov 01, 2017
Volume
27
Issue
21
Pages
4885–4888
Identifiers
DOI: 10.1016/j.bmcl.2017.09.036
PMID: 28947154
Source
Medline
Keywords
License
Unknown

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.

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