2. Academic Validation
  3. Design, synthesis and anticancer potential of NSC-319745 hydroxamic acid derivatives as DNMT and HDAC inhibitors

Design, synthesis and anticancer potential of NSC-319745 hydroxamic acid derivatives as DNMT and HDAC inhibitors

  • Eur J Med Chem. 2017 Jul 7:134:281-292. doi: 10.1016/j.ejmech.2017.04.017.
Zigao Yuan 1,  Qinsheng Sun 2,  Dan Li 1,  Shuangshuang Miao 3,  Shaopeng Chen 3,  Lu Song 1,  Chunmei Gao 4,  Yuzong Chen 5,  Chunyan Tan 6,  Yuyang Jiang 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 2 Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 3 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 4 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: chunmeigao@sz.tsinghua.edu.cn.
  • 5 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Bioinformatics and Drug Design Group, Department of Pharmacy, Centre for Computational Science and Engineering, National University of Singapore, 117543, Singapore.
  • 6 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 7 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
PMID: 28419930 DOI: 10.1016/j.ejmech.2017.04.017
Abstract

DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) are important epigenetic targets during Anticancer drug development. Recent study indicates that DNMT inhibitors and HDAC inhibitors display synergistic effects in certain cancers, therefore, development of molecules targeting both DNMT and HDAC is of therapeutic advantage against these cancers. Based on the structure of DNMT inhibitor NSC-319745 and the pharmacophore characteristics of HDAC inhibitors, a series of hydroxamic acid derivatives of NSC-319745 were designed and synthesized as DNMT and HDAC multifunctional inhibitors. Most compounds displayed potential DNMT inhibitory potency and potent HDAC inhibitory activity, especially compound 15a showed much better DNMT1 inhibitory potency than NSC-319745, and inhibited HDAC1, HDAC6 with IC50 values of 57, 17 nM, respectively. Furthermore, the synthesized compounds exhibited significant cytotoxicity against human Cancer cells K562 and U937. Further mechanistic studies demonstrated that 15a treatment in U937 increased histones H3K9 and H4K8 acetylation, prompted P16 CpG islands demethylation and upregulated P16 expression, regulated apoptosis-related protein expression on the cellular level and induced remarkable U937 Apoptosis. Moreover, genotoxicity of representative compounds was evaluated. In summary, our study provided a practical drug design strategy targeting multiple Enzymes, and 15a represents a novel and promising lead compound for the development of novel epigenetic inhibitors as antitumor agents.

Keywords

Antitumor bioactivity; DNMT; Drug design; Epigenetic targets; HDAC; Multi-target.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z