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

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.

• Authors: 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
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 18 Pg. 6173-84 (Sep 15 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 26314925 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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