TY - JOUR
T1 - Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities
AU - Zhang, Zixue
AU - Zhang, Qingwei
AU - Zhang, Hao
AU - Jiao, Minru
AU - Guo, Zheng
AU - Peng, Xinyan
AU - Fu, Lei
AU - Li, Jianqi
N1 - Funding Information:
This work was financially supported by the National Science and Technology Major Project (No. 2018ZX09711002-002-009), the National Natural Science Foundation of China (No. 81703358) and Science and Technology Commission of Shanghai Municipality (Nos. 18QB1404200, 17431903900, 21S11908000).
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Anti-proliferative activity
KW - Histone deacetylases
KW - Quinazolinyl
KW - Selectivity
KW - Tumor growth inhibition
UR - http://www.scopus.com/inward/record.url?scp=85116863265&partnerID=8YFLogxK
U2 - 10.1016/j.bioorg.2021.105407
DO - 10.1016/j.bioorg.2021.105407
M3 - Article
C2 - 34653945
AN - SCOPUS:85116863265
SN - 0045-2068
VL - 117
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 105407
ER -