Conformationally restricted hybrid analogues of the hormone 1 alpha,25-dihydroxyvitamin D(3): design, synthesis, and biological evaluation.
Four new conformationally restricted hybrid analogues of the hormone 1 alpha-25-dihydroxyvitamin D(3) (1,25D3) have been synthesized in a convergent manner by combining enantiomerically pure C,D-ring ketones (-)-15 and (-)-17 with racemic 1-hydroxymethyl A-ring phosphine oxide (+/-)-18. Parent hybrid analogue 6, which combines the calcemia-inactivating 1 beta-hydroxymethyl A-ring modification with the antiproliferation- activating 20-epi-22-oxa-25-hydroxydiethyl C,D-ring side chain modification, is comparable in potency to 1,25D3 at the low nM level in inhibiting proliferation in a wide assortment of malignant cell lines in vitro with extremely low calcemic activity in vivo. Surprisingly, both conformationally restricted analogues of 6 (8b and 9b), which incorporate rigidifying units at their 25-hydroxyl side chain termini, retained the desirable antiproliferative, transcriptional, and calcemic activities of the parent compound.
White
M C
MC
Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA. white@ascat.harvard.edu
Burke
M D
MD
Peleg
S
S
Brem
H
H
Posner
G H
GH
D000818:Animals; D002117:Calcitriol / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation
D002117:Calcitriol