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.
Shaping up for inhibition: Identification of three‐dimensional structural similarities (see picture) between the active sites of zinc dinuclear aminopeptidases and trinuclear phospholipase C hydrolytic enzymes that are not related by sequence or tertiary structure led to the discovery of phospholipase C inhibition by α‐aminohydroxamic acids, a typical family of aminopeptidase inhibitors.
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