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

Zixue Zhang; Qingwei Zhang; Hao Zhang; Minru Jiao; Zheng Guo; Xinyan Peng; Lei Fu; Jianqi Li

doi:10.1016/j.bioorg.2021.105407

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

Zixue Zhang
, Qingwei Zhang^*
, Hao Zhang
, Minru Jiao
, Zheng Guo
, Xinyan Peng
, Lei Fu
, Jianqi Li

^*Corresponding author for this work

Shanghai Jiao Tong University
China State Institute of Pharmaceutical Industry
Fudan University

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

Abstract

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.

Original language	English
Article number	105407
Journal	Bioorganic Chemistry
Volume	117
DOIs	https://doi.org/10.1016/j.bioorg.2021.105407
Publication status	Published - Dec 2021

Keywords

Anti-proliferative activity
Histone deacetylases
Quinazolinyl
Selectivity
Tumor growth inhibition

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10.1016/j.bioorg.2021.105407

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@article{b23344943d8041709fd3dfdc706571d6,

title = "Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities",

abstract = "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.",

keywords = "Anti-proliferative activity, Histone deacetylases, Quinazolinyl, Selectivity, Tumor growth inhibition",

author = "Zixue Zhang and Qingwei Zhang and Hao Zhang and Minru Jiao and Zheng Guo and Xinyan Peng and Lei Fu and Jianqi Li",

note = "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: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = dec,

doi = "10.1016/j.bioorg.2021.105407",

language = "English",

volume = "117",

journal = "Bioorganic Chemistry",

issn = "0045-2068",

}

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 - https://www.scopus.com/pages/publications/85116863265

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 -

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

Abstract

Keywords

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