Synthesis and biological evaluation of unique stereodimers of sinomenine analogues as potential inhibitors of NO production

Bioorg Med Chem. 2011 May 15;19(10):3096-104. doi: 10.1016/j.bmc.2011.04.006. Epub 2011 Apr 7.

Abstract

Inhibition of the excessive NO production has been recognized as a potential means for the treatment of rheumatoid arthritis (RA). In order to discover more potent inhibitors and explore the preliminary structure activity relationship, a series of unique stereodimers of sinomenine analogues were designed and synthesized. Their inhibitory activity on NO production and cytotoxicity were evaluated using LPS-activated murine macrophages RAW264.7 assay and MTT method, respectively. Among these compounds, 1a, 2, 2a, 2b, and 4 showed potent inhibitory activity on NO production without obvious cytotoxicity. Furthermore, 2, 2a, and 2b significantly suppressed mRNA expression of iNOS. Interestingly, (S)-dimers displayed a better bioactivity than (R)-dimers. These compounds may sever as lead candidates in the development of novel therapeutic drugs for RA treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Dimerization
  • Gene Expression / drug effects
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Morphinans / chemical synthesis
  • Morphinans / chemistry*
  • Morphinans / pharmacology*
  • Nitric Oxide / antagonists & inhibitors*
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / genetics
  • RNA, Messenger / genetics
  • Stereoisomerism

Substances

  • Morphinans
  • RNA, Messenger
  • Nitric Oxide
  • sinomenine
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse