Synthesis and biological activity of 1 alpha, 25-dihydroxy-18-norvitamin D3 and 1 alpha, 25-dihydroxy-18,19-dinorvitamin D3.
1 alpha, 25-dihydroxy-18-norvitamin D3 and 1 alpha, 25-dihydroxy-18,19-dinorvitamin D3 were prepared via Wittig-Horner coupling of 25-hydroxy-18-nor Grundmann type ketone with the corresponding A-ring phosphine oxides. Configuration at C-13 in the 18-nor Grundmann type alcohol (C,D-ring synthon), obtained by oxidative degradation of vitamin D3, was determined by 1H NMR spectroscopy and molecular mechanics calculations. Additional proof of the assigned trans-C/D-junction of the key intermediate 18-nor Grundmann type ketone follows from its chiroptical properties (circular dichroism data) and further chemical transformations. 1 alpha, 25-Dihydroxy-18-norvitamin D3 was found more potent than 1 alpha, 25-dihydroxyvitamin D3 in binding to the porcine intestinal vitamin D receptor (5-10x), in differentiation of HL-60 cells (5-10x), and in inhibition of HL-60 proliferation. 1 alpha, 25-Dihydroxy-18, 19-dinorvitamin D3 appeared equally active as 1 alpha, 25-dihydroxyvitamin D3 in these activities. In vivo, 1 alpha, 25-dihydroxy-18-norvitamin D3 was only slightly less active than 1 alpha, 25-dihydroxyvitamin D3 in intestinal calcium transport and bone calcium mobilization, while 1 alpha, 25-dihydroxy-18,19-dinorvitamin D3 showed activities 10 times lower. These studies imply that deletion of C-18 does not impair activity of analogs of 1 alpha, 25-dihydroxyvitamin D3.
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison 53706, USA.
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Sicinski
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Perlman
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Prahl
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Smith
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DeLuca
D000818:Animals; D001693:Biological Transport, Active; D001842:Bone and Bones / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D018922:HL-60 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C102046:1,25-dihydroxy-18,19-dinorvitamin D3; C102045:1,25-dihydroxy-18-norvitamin D3; D002117:Calcitriol; D002118:Calcium