Discovery, synthesis and biological evaluation of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) as novel sphingomyelin synthase 1 inhibitors

Ya-Li Li; Xiang-Yu Qi; Hui Jiang; Xiao-Dong Deng; Yan-Ping Dong; Ting-Bo Ding; Lu Zhou; Peng Men; Yong Chu; Ren-Xiao Wang; Xian-Cheng Jiang; De-Yong Ye

doi:10.1016/j.bmc.2015.07.060

Discovery, synthesis and biological evaluation of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) as novel sphingomyelin synthase 1 inhibitors

Bioorg Med Chem. 2015 Sep 15;23(18):6173-84. doi: 10.1016/j.bmc.2015.07.060. Epub 2015 Jul 30.

Authors

Ya-Li Li¹, Xiang-Yu Qi¹, Hui Jiang², Xiao-Dong Deng¹, Yan-Ping Dong³, Ting-Bo Ding¹, Lu Zhou¹, Peng Men¹, Yong Chu¹, Ren-Xiao Wang⁴, Xian-Cheng Jiang⁵, De-Yong Ye⁶

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826, Zhangheng Rd., Shanghai 201203, China.
² State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
³ Department of Food and Pharmaceutical Engineering, Suihua University, Suihua 152061, China.
⁴ State Key Lab of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China. Electronic address: wangrx@mail.sioc.ac.cn.
⁵ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826, Zhangheng Rd., Shanghai 201203, China; State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA. Electronic address: xjiang@downstate.edu.
⁶ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826, Zhangheng Rd., Shanghai 201203, China. Electronic address: dyye@shmu.edu.cn.

PMID: 26314925
DOI: 10.1016/j.bmc.2015.07.060

Abstract

Sphingomyelin synthase (SMS) has been proved to be a potential drug target for the treatment of atherosclerosis. However, few SMS inhibitors have been reported. In this paper, structure-based virtual screening was performed on hSMS1. SAPA 1a was discovered as a novel SMS1 inhibitor with an IC50 value of 5.2 μM in enzymatic assay. A series of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) were synthesized and their biological activities toward SMS1 were evaluated. Among them, SAPA 1j was found to be the most potent SMS1 inhibitor with an IC50 value of 2.1 μM in in vitro assay. The molecular docking studies suggested the interaction modes of SMS1 inhibitors and PC with the active site of SMS1. Site-directed mutagenesis validated the involvement of residues Arg342 and Tyr338 in enzymatic sphingomyelin production. The discovery of SAPA derivatives as a novel class of SMS1 inhibitors would advance the development of more effective SMS1 inhibitors.

Keywords: Inhibitor; Molecular docking; Point mutagenesis; Sphingomyelin synthase; Structure-based virtual screening.

Publication types

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

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry*
Acetamides / metabolism
Binding Sites
Catalytic Domain
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
HeLa Cells
Humans
Membrane Proteins / antagonists & inhibitors*
Membrane Proteins / genetics
Membrane Proteins / metabolism
Molecular Docking Simulation
Mutagenesis, Site-Directed
Nerve Tissue Proteins / antagonists & inhibitors*
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Structure-Activity Relationship
Transferases (Other Substituted Phosphate Groups) / antagonists & inhibitors*
Transferases (Other Substituted Phosphate Groups) / genetics
Transferases (Other Substituted Phosphate Groups) / metabolism

Substances

Acetamides
Enzyme Inhibitors
Membrane Proteins
Nerve Tissue Proteins
SGMS1 protein, human
Transferases (Other Substituted Phosphate Groups)