New highly calcemic 1 alpha,25-dihydroxy-19-norvitamin D(3) compounds with modified side chain: 26,27-dihomo- and 26,27-dimethylene analogs in 20S-series.
New highly potent 2-substituted (20S)-1 alpha,25-dihydroxy-19-norvitamin D(3) analogs with elongated side chain were prepared by Wittig-Horner coupling of A-ring phosphine oxide with the corresponding protected (20S)-25-hydroxy Grundmann's ketones. Biologic evaluation in vitro and in vivo of the synthesized compounds was accomplished. All the synthesized vitamins possessing a 25-hydroxylated saturated side chain were slightly less active (3-5X) than 1 alpha,25-dihydroxyvitamin D(3) in binding to the porcine intestinal vitamin D receptor and significantly more potent (12-150X) in causing differentiation of HL-60 cells. In vivo, 2-methylene-26,27-dihomo and 2 alpha-methyl-26,27-dimethylene analogs were at least 10 times more active, and 2 alpha-methyl-26,27-dihomo compound at least 5 times more active than the vitamin D hormone both in stimulating intestinal calcium transport and bone calcium mobilization (serum calcium increase). It was also established that a 260 pmol dose of the corresponding 2 beta-methyl analogs had a similar effect on intestinal calcium transport and a much more pronounced effect on bone calcium mobilization as the same dose of 1 alpha,25-dihydroxyvitamin D(3).
Sicinski
Rafal R
RR
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Prahl
Jean M
JM
Smith
Connie M
CM
DeLuca
Hector F
HF
D000818:Animals; D001692:Biological Transport; D001842:Bone and Bones / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000097:blood* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D006900:Hydroxylation; D007413:Intestinal Mucosa / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D018167:Receptors, Calcitriol / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013552:Swine; D014808:Vitamin D Deficiency / Q000378:metabolism
D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium