title: 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, 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.
authors.affiliation: Department of Natural Products, Glaxo Research & Development Ltd., Stevenage, Hertfordshire, United Kingdom.
authors.forename: R F
authors.initials: RF
authors.lastname: Middleton
authors.forename: G
authors.initials: G
authors.lastname: Foster
authors.forename: R J
authors.initials: RJ
authors.lastname: Cannell
authors.forename: P J
authors.initials: PJ
authors.lastname: Sidebottom
authors.forename: N L
authors.initials: NL
authors.lastname: Taylor
authors.forename: D
authors.initials: D
authors.lastname: Noble
authors.forename: M
authors.initials: M
authors.lastname: Todd
authors.forename: M J
authors.initials: MJ
authors.lastname: Dawson
authors.forename: G C
authors.initials: GC
authors.lastname: Lawrence
mesh_terms: 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*
chemical_list: 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