Diastereomeric ecdysteroids with a cyclic hemiacetal in the side chain produced by cytochrome P450 in hormonally resistant insect cells.
A microsomal cytochrome P450 from a cell line of the insect Chironomus tentans has been shown to hydroxylate the steroid hormone 20-hydroxyecdysone at C(26) to yield 20,26-dihydroxyecdysone, P1, which is further metabolized to P2 and P3. Based on (1)H NMR studies, acetonide formation and quantum chemical calculations, P2 and P3 represent novel slowly interconvertible geometrical isomers, occurring at a 3:1 ratio, presumably arising from hemiacetal formation between the 26-aldehyde group and the 22R-hydroxyl group to build a tetrahydropyran ring in the side chain. The stereochemistry at C(26) was S in P2 (trans-diol) and R in P3 (cis-diol), respectively. Both metabolites showed S configuration at C(25). With Chironomus cells, P2/P3 was inactive as both a hormonal agonist and antagonist, whereas 20,26-dihydroxyecdysone (P1) showed weak agonist activity. Thus, cytochrome P450-mediated inactivation of 20-hydroxyecdysone may be responsible for the hormonal insensitivity observed in some subclones of this cell line.
Kayser
Hartmut
H
Syngenta Crop Protection AG, Research and Technology, WRO-1060.4.04, CH-4002 Basel, Switzerland. harmut.kayser@syngenta.com
Ertl
Peter
P
Eilinger
Philipp
P
Spindler-Barth
Margret
M
Winkler
Tammo
T
D000080:Acetals / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001681:Biological Assay; D002460:Cell Line; D002683:Chironomidae; D002851:Chromatography, High Pressure Liquid; D002999:Clone Cells; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004351:Drug Resistance; D026461:Ecdysteroids / Q000096:biosynthesis* / Q000737:chemistry* / Q000494:pharmacology; D004441:Ecdysterone / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
D000080:Acetals; D026461:Ecdysteroids; D004441:Ecdysterone; D003577:Cytochrome P-450 Enzyme System