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

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.
Ya-Li Li 1,  Xiang-Yu Qi 1,  Hui Jiang 2,  Xiao-Dong Deng 1,  Yan-Ping Dong 3,  Ting-Bo Ding 1,  Lu Zhou 1,  Peng Men 1,  Yong Chu 1,  Ren-Xiao Wang 4,  Xian-Cheng Jiang 5,  De-Yong Ye 6
Affiliations

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.

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