Microorganisms were screened for the ability to modify the squalene synthase inhibitor squalestatin
1.
Biotransformation of
1 by two actinomycetes, SI5106 and SI5138, yielded three products hydroxylated on the 4, 6-dimethyl-oct-2-enoyl side chain either at the 6 position (
5) or 7 position (
4 two diastereoisomers), and lacking the acetyl ester from the C-1 side chain. Many strains were found to hydrolyse the 4, 6-dimethyl-oct-2-enoyl or acetyl esters to yield squalestatins
2 or
3.
The 3-methyl ester (
6) of
1 was obtained using
Fusarium sp. F13945. This fungus also produced a farnesoic acid derivative, possibly in response to inhibition of its squalene synthase by
1. The biotransformation products of
1 all retained potent squalene synthase inhibitory activity.
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