Synthesis and biological activities of turkesterone 11alpha-acyl derivatives.
Turkesterone is a phytoecdysteroid possessing an 11alpha-hydroxyl group. It is an analogue of the insect steroid hormone 20-hydroxyecdysone. Previous ecdysteroid QSAR and molecular modelling studies predicted that the cavity of the ligand binding domain of the ecdysteroid receptor would possess space in the vicinity of C-11/C-12 of the ecdysteroid. We report the regioselective synthesis of a series of turkesterone 11alpha-acyl derivatives in order to explore this possibility. The structures of the analogues have been unambiguously determined by spectroscopic means (NMR and low-resolution mass spectrometry). Purity was verified by HPLC. Biological activities have been determined in Drosophila melanogaster B(II) cell-based bioassay for ecdysteroid agonists and in an in vitro radioligand-displacement assay using bacterially-expressed D. melanogaster EcR/USP receptor proteins. The 11alpha-acyl derivatives do retain a significant amount of biological activity relative to the parent ecdysteroid. Further, although activity initially drops with the extension of the acyl chain length (C2 to C4), it then increases (C6 to C10), before decreasing again (C14 and C20). The implications of these findings for the interaction of ecdysteroids with the ecdysteroid receptor and potential applications in the generation of affinity-labelled and fluorescently-tagged ecdysteroids are discussed.
Dinan
Laurence
L
Department of Biological Sciences. University of Exeter, Hatherly Laboratories, Prince of Wales Road, Exeter, Devon, EX4 4PS, UK. L.N.Dinan@exeter.ac.uk
Bourne
Pauline
P
Whiting
Pensri
P
Tsitsekli
Ada
A
Saatov
Ziyadilla
Z
Dhadialla
Tarlochan S
TS
Hormann
Robert E
RE
Lafont
René
R
Coll
Josep
J
D000818:Animals; D002460:Cell Line; D004331:Drosophila melanogaster; D026461:Ecdysteroids / Q000819:agonists*; D004441:Ecdysterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007301:Insect Hormones / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D011485:Protein Binding; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D026461:Ecdysteroids; D007301:Insect Hormones; D011987:Receptors, Steroid; C055469:ecdysone receptor; D004441:Ecdysterone; C017787:turkesterone