Novel squalestatins produced by biotransformation.
Microorganisms were screened for the ability to modify the squalene synthase inhibitor squalestatin 1. Biotransformation of 1 by two actinomycetes, S15106 and S15138, 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.
Middleton
R F
RF
Department of Natural Products, Glaxo Research & Development Ltd., Stevenage, Hertfordshire, United Kingdom.
Foster
G
G
Cannell
R J
RJ
Sidebottom
P J
PJ
Taylor
N L
NL
Noble
D
D
Todd
M
M
Dawson
M J
MJ
Lawrence
G C
GC
D000192:Actinomycetales / Q000378:metabolism*; D001711:Biotransformation; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D005670:Fusarium / Q000378:metabolism; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D013302:Streptomyces / Q000378:metabolism; D014233:Tricarboxylic Acids / Q000737:chemistry / Q000378:metabolism*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D014233:Tricarboxylic Acids; C075117:squalestatin 1; C093905:squalestatin 2; C093906:squalestatin 3; D013186:Farnesyl-Diphosphate Farnesyltransferase