Novel Squalestatins Produced by Biotransformation

Abstract

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.