Synthesis and phospholipase C inhibitory activity of D609 diastereomers

Lipids. 2002 Apr;37(4):401-6. doi: 10.1007/s1145-002-0908-0.

Abstract

The potassium xanthate D609 is widely accepted as a selective inhibitor of PC-specific phospholipase C (PC-PLC). The tricyclo[5.2.1.(02,6)]decane skeleton present in D609 can lead to four diastereomeric pairs, but the diastereoselectivity of PC-PLC inhibition has never been reported. In this article, the synthesis of racemic D609 diastereomers and that of other xanthates, as well as their inhibitory effect on PC-PLC is reported. All xanthates obtained were competitive inhibitors of PC-PLC from Bacillus cereus (PLCBc). No significant differences were found in the activity of D609 diastereomers (Ki 13-17 microM), suggesting the absence of a diastereochemical control of the enzyme by xanthate inhibitors. This result was confirmed after obtaining other potassium xanthates differing from D609 in the aliphatic chain. Among them, the potassium O-n-decenylxanthate was the most active inhibitor of PLCBc (Ki 10 microM). These data indicate that the essential structural requirements for PLCBc in vitro inhibition by xanthates are the presence of a Zn-chelating dithiocarbonate head and a sufficiently hydrophobic aliphatic moiety.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bridged-Ring Compounds / chemical synthesis
  • Bridged-Ring Compounds / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Norbornanes
  • Spectrum Analysis
  • Stereoisomerism
  • Thiocarbamates
  • Thiones / chemical synthesis
  • Thiones / pharmacology*
  • Type C Phospholipases / antagonists & inhibitors*

Substances

  • Bridged-Ring Compounds
  • Enzyme Inhibitors
  • Norbornanes
  • Thiocarbamates
  • Thiones
  • tricyclodecane-9-yl-xanthogenate
  • Type C Phospholipases