Cycloalkane analogues of sinefungin as EHMT1/2 inhibitors

Qing Liu; Xiaoqing Cai; Dehua Yang; Yi Chen; Yafang Wang; Liming Shao; Ming-Wei Wang

doi:10.1016/j.bmc.2017.06.032

Cycloalkane analogues of sinefungin as EHMT1/2 inhibitors

Bioorg Med Chem. 2017 Sep 1;25(17):4579-4594. doi: 10.1016/j.bmc.2017.06.032. Epub 2017 Jun 21.

Authors

Qing Liu¹, Xiaoqing Cai², Dehua Yang², Yi Chen³, Yafang Wang³, Liming Shao⁴, Ming-Wei Wang⁵

Affiliations

¹ School of Pharmacy, Fudan University, Shanghai 201203, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; The National Center for Drug Screening, Shanghai 201203, China.
² The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; The National Center for Drug Screening, Shanghai 201203, China.
³ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: limingshao@fudan.edu.cn.
⁵ School of Pharmacy, Fudan University, Shanghai 201203, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; The National Center for Drug Screening, Shanghai 201203, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: mwwang@simm.ac.cn.

PMID: 28739157
DOI: 10.1016/j.bmc.2017.06.032

Abstract

A series of cycloalkyl substituted analogues of the natural product sinefungin lacking the amino-acid moiety was designed and synthesized. Two stereoisomers (6-R and 6-S) were separated and their bioactivities examined against EHMT1/2. Of which, compound 14d showed an inhibitory activity against EHMT1/2 (88.9%, IC₅₀=21.8μM for EHMT1 and 77.6%, IC₅₀=39.6μM for EHMT2, respectively) similar to that of sinefungin (100.0%, IC₅₀=28.4μM for EHMT1 and 79.5%, IC₅₀=30.1μM for EHMT2, respectively). Further studies against other methyltransferases such as PRMT1 showed no activity except that 12d displayed about 20% inhibition.

Keywords: Cycloalkyl substituted analogue; Methyltransferase inhibitor; Natural product; Sinefungin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / chemistry
Adenosine / metabolism
Adenosine / toxicity
Alkanes / chemistry
Cell Line, Tumor
Cell Proliferation / drug effects
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / toxicity
Histocompatibility Antigens / metabolism
Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
Histone-Lysine N-Methyltransferase / metabolism
Humans
Inhibitory Concentration 50
Structure-Activity Relationship

Substances

9-(5',6',7'-deoxy-6'-amine-7'-cyclopropylheptafuranoside-1')adenine
Alkanes
Enzyme Inhibitors
Histocompatibility Antigens
EHMT1 protein, human
EHMT2 protein, human
Histone-Lysine N-Methyltransferase
Adenosine
sinefungin