Design, synthesis and biological evaluation of quinoline derivatives as HDAC class I inhibitors

Chen Chen, Xuben Hou, Guohua Wang, Wenyan Pan, Xinying Yang, Yingkai Zhang, Hao Fang

Research output: Contribution to journalArticle

Abstract

Inhibition of histone deacetylase (HDAC) has been regarded as a potential therapeutic approach for treatment of multiple diseases including cancer. Based on pharmacophore model of HDAC inhibitors, a series of quinoline-based N-hydroxycinnamamides and N-hydroxybenzamides were designed and synthesized as potent HDAC inhibitors. All target compounds were evaluated for their in vitro HDAC inhibitory activities and anti-proliferative activities and the best compound 4a surpass Vorinostat in both enzymatic inhibitory activity and cellular anti-proliferative activity. In terms of HDAC isoforms selectivity, compounds 4a exhibited preferable inhibition for class I HDACs, especially for HDAC8, the IC50 value (442 nM) was much lower than that of Vorinostat (7468 nM). Subsequently, we performed class I & IIa HDACs whole cell enzyme assay to evaluate inhibitory activity in whole cell context. Compounds 4a and 4e displayed much better cellular activity for class I HDACs than that for class IIa HDACs, which indicated that 4a and 4e might be potent class I HDAC inhibitors. Meanwhile, flow cytometry analysis showed that compound 4a and 4e can promote cell apoptosis in vitro.

Original languageEnglish (US)
Pages (from-to)11-23
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume133
DOIs
StatePublished - Jun 16 2017

Fingerprint

Histone Deacetylase Inhibitors
Histone Deacetylases
Derivatives
Flow cytometry
Enzyme Assays
Inhibitory Concentration 50
Assays
Flow Cytometry
Protein Isoforms
Apoptosis
Enzymes
quinoline
Neoplasms
vorinostat
Therapeutics

Keywords

  • Anti-proliferative
  • Class I celluar activity
  • Class I HDACs
  • Hydroxamic acid
  • Pro-apoptosis activity
  • Quinoline

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Design, synthesis and biological evaluation of quinoline derivatives as HDAC class I inhibitors. / Chen, Chen; Hou, Xuben; Wang, Guohua; Pan, Wenyan; Yang, Xinying; Zhang, Yingkai; Fang, Hao.

In: European Journal of Medicinal Chemistry, Vol. 133, 16.06.2017, p. 11-23.

Research output: Contribution to journalArticle

Chen, Chen ; Hou, Xuben ; Wang, Guohua ; Pan, Wenyan ; Yang, Xinying ; Zhang, Yingkai ; Fang, Hao. / Design, synthesis and biological evaluation of quinoline derivatives as HDAC class I inhibitors. In: European Journal of Medicinal Chemistry. 2017 ; Vol. 133. pp. 11-23.
@article{dd20defbdc52449fac6cd0cee6330e52,
title = "Design, synthesis and biological evaluation of quinoline derivatives as HDAC class I inhibitors",
abstract = "Inhibition of histone deacetylase (HDAC) has been regarded as a potential therapeutic approach for treatment of multiple diseases including cancer. Based on pharmacophore model of HDAC inhibitors, a series of quinoline-based N-hydroxycinnamamides and N-hydroxybenzamides were designed and synthesized as potent HDAC inhibitors. All target compounds were evaluated for their in vitro HDAC inhibitory activities and anti-proliferative activities and the best compound 4a surpass Vorinostat in both enzymatic inhibitory activity and cellular anti-proliferative activity. In terms of HDAC isoforms selectivity, compounds 4a exhibited preferable inhibition for class I HDACs, especially for HDAC8, the IC50 value (442 nM) was much lower than that of Vorinostat (7468 nM). Subsequently, we performed class I & IIa HDACs whole cell enzyme assay to evaluate inhibitory activity in whole cell context. Compounds 4a and 4e displayed much better cellular activity for class I HDACs than that for class IIa HDACs, which indicated that 4a and 4e might be potent class I HDAC inhibitors. Meanwhile, flow cytometry analysis showed that compound 4a and 4e can promote cell apoptosis in vitro.",
keywords = "Anti-proliferative, Class I celluar activity, Class I HDACs, Hydroxamic acid, Pro-apoptosis activity, Quinoline",
author = "Chen Chen and Xuben Hou and Guohua Wang and Wenyan Pan and Xinying Yang and Yingkai Zhang and Hao Fang",
year = "2017",
month = "6",
day = "16",
doi = "10.1016/j.ejmech.2017.03.064",
language = "English (US)",
volume = "133",
pages = "11--23",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Design, synthesis and biological evaluation of quinoline derivatives as HDAC class I inhibitors

AU - Chen, Chen

AU - Hou, Xuben

AU - Wang, Guohua

AU - Pan, Wenyan

AU - Yang, Xinying

AU - Zhang, Yingkai

AU - Fang, Hao

PY - 2017/6/16

Y1 - 2017/6/16

N2 - Inhibition of histone deacetylase (HDAC) has been regarded as a potential therapeutic approach for treatment of multiple diseases including cancer. Based on pharmacophore model of HDAC inhibitors, a series of quinoline-based N-hydroxycinnamamides and N-hydroxybenzamides were designed and synthesized as potent HDAC inhibitors. All target compounds were evaluated for their in vitro HDAC inhibitory activities and anti-proliferative activities and the best compound 4a surpass Vorinostat in both enzymatic inhibitory activity and cellular anti-proliferative activity. In terms of HDAC isoforms selectivity, compounds 4a exhibited preferable inhibition for class I HDACs, especially for HDAC8, the IC50 value (442 nM) was much lower than that of Vorinostat (7468 nM). Subsequently, we performed class I & IIa HDACs whole cell enzyme assay to evaluate inhibitory activity in whole cell context. Compounds 4a and 4e displayed much better cellular activity for class I HDACs than that for class IIa HDACs, which indicated that 4a and 4e might be potent class I HDAC inhibitors. Meanwhile, flow cytometry analysis showed that compound 4a and 4e can promote cell apoptosis in vitro.

AB - Inhibition of histone deacetylase (HDAC) has been regarded as a potential therapeutic approach for treatment of multiple diseases including cancer. Based on pharmacophore model of HDAC inhibitors, a series of quinoline-based N-hydroxycinnamamides and N-hydroxybenzamides were designed and synthesized as potent HDAC inhibitors. All target compounds were evaluated for their in vitro HDAC inhibitory activities and anti-proliferative activities and the best compound 4a surpass Vorinostat in both enzymatic inhibitory activity and cellular anti-proliferative activity. In terms of HDAC isoforms selectivity, compounds 4a exhibited preferable inhibition for class I HDACs, especially for HDAC8, the IC50 value (442 nM) was much lower than that of Vorinostat (7468 nM). Subsequently, we performed class I & IIa HDACs whole cell enzyme assay to evaluate inhibitory activity in whole cell context. Compounds 4a and 4e displayed much better cellular activity for class I HDACs than that for class IIa HDACs, which indicated that 4a and 4e might be potent class I HDAC inhibitors. Meanwhile, flow cytometry analysis showed that compound 4a and 4e can promote cell apoptosis in vitro.

KW - Anti-proliferative

KW - Class I celluar activity

KW - Class I HDACs

KW - Hydroxamic acid

KW - Pro-apoptosis activity

KW - Quinoline

UR - http://www.scopus.com/inward/record.url?scp=85016494821&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016494821&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2017.03.064

DO - 10.1016/j.ejmech.2017.03.064

M3 - Article

C2 - 28371677

AN - SCOPUS:85016494821

VL - 133

SP - 11

EP - 23

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -