Synthesis and phospholipase C inhibitory activity of D609 diastereomers.
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.
González-Roura
Albert
A
Department of Biological Organic Chemistry, IIQAB-CSIC, Barcelona, Spain.
Casas
Josefina
J
Llebaria
Amadeu
A
D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D009636:Norbornanes; D013057:Spectrum Analysis; D013237:Stereoisomerism; D013859:Thiocarbamates; D013871:Thiones / Q000138:chemical synthesis / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors*
D001952:Bridged-Ring Compounds; D004791:Enzyme Inhibitors; D009636:Norbornanes; D013859:Thiocarbamates; D013871:Thiones; C046498:tricyclodecane-9-yl-xanthogenate; D010738:Type C Phospholipases