New vitamin D3 derivatives with unexpected antiproliferative activity: 1-(hydroxymethyl)-25-hydroxyvitamin D3 homologs.
Surprisingly, both of the synthetic 1-(hydroxymethyl)-25-hydroxyvitamin D3 diastereomers (-)-2 and (+)-3 retained the antiproliferative activity of natural calcitriol in murine keratinocytes. Preliminary studies indicated, however, that both of these synthetic diastereomers were less than 0.1% as effective as calcitriol for binding to the 1,25-(OH)2-D3 receptor and that they were less than 0.1% as potent as calcitriol for calbindin-D28K induction in organ-cultured embryonic chick duodenum. 1-(Hydroxymethyl)-25-hydroxyvitamin D3 homologs (-)-2 and (+)-3 were synthesized in a convergent manner by combining enantiomerically pure C,D-ring ketone 12 with highly enantiomerically enriched A-ring phosphine oxides (-)-11a and (+)-11b. These A-ring chirons were prepared starting from thermal [2 + 4] cycloaddition of 3-bromo-2-pyrone and acrolein.
Posner
G H
GH
Department of Chemistry, School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland 21218.
Nelson
T D
TD
Guyton
K Z
KZ
Kensler
T W
TW
D000818:Animals; D001667:Binding, Competitive; D064092:Calbindin 1; D064026:Calbindins; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002642:Chick Embryo; D004386:Duodenum / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009924:Organ Culture Techniques; D009955:Ornithine Decarboxylase / Q000378:metabolism; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C576499:Calb1 protein, mouse; D064092:Calbindin 1; D064026:Calbindins; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D064030:S100 Calcium Binding Protein G; C076210:1 alpha-(hydroxymethyl)-25-hydroxyvitamin D3; C076211:1-hydroxymethyl-3-norhydroxy-3,25-dihydroxyvitamin D3; D009955:Ornithine Decarboxylase; D002117:Calcitriol; D013755:Tetradecanoylphorbol Acetate