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Citation: Qinsheng Sun, Qiuzi Dai, Cunlong Zhang, Yan Chen, Lei Zhao, Zigao Yuan, Yuyang Jiang. Design, synthesis and antitumor evaluations of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual inhibitors[J]. Chinese Chemical Letters, ;2021, 32(8): 2479-2483. doi: 10.1016/j.cclet.2021.02.004 shu

Design, synthesis and antitumor evaluations of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual inhibitors

Qinsheng Sun ^{a, b, c} ,
Qiuzi Dai ^b ,
Cunlong Zhang ^d ,
Yan Chen ^{a, b, c} ,
Lei Zhao ^b ,
Zigao Yuan ^{b, c, d, *} ,
Yuyang Jiang ^{b, c, e, *}

a.
School of Life Science, Tsinghua University, Beijing 100084, China
b.
National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
c.
Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518055, China
d.
National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518110, China
e.
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China

^*

yzg12@tsinghua.org.cn

jiangyy@sz.tsinghua.edu.cn

Received Date: 21 December 2020
Revised Date: 13 January 2021
Accepted Date: 2 February 2021
Available Online: 4 February 2021

Figures(5)

DNA methyltransferase (DNMT) and histone deacetylase (HDAC) are well recognized epigenetic targets for discovery of antitumor agents. In this study, we designed and synthesized a series of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual inhibitors. MTT assays and enzymatic inhibitory activity tests indicated that compound 204 exhibited potent DNMT1 and HDAC1/6 inhibitory potency simultaneously in enzymatic levels and at cellular levels, inducing hypomethylation of p16 and hyperacetylation of histones H3K9 and H4K8. Besides, 204 remarkably inhibited proliferation against cancer cells U937 by prompting G0/G1 cell cycle arrest. Molecular docking models explained the functional mechanism of 204 inhibiting DNMT1 and HDAC. Preliminary studies on metabolic profiles revealed that 204 showed desirable stability in liver microsomes. Our study suggested that 204 inhibiting DNMT and HDAC concurrently can be a potential lead compound for epigenetic cancer therapy.
- Epigenetic,
- DNMT,
- HDAC,
- Multitarget,
- Antitumor bioactivity
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