24-homologated 1,25-dihydroxyvitamin D3 compounds: separation of calcium and cell differentiation activities.
A series of 24-homologated 1,25-dihydroxyvitamin D3 compounds have been chemically synthesized and studied with regard to their activity in inducing differentiation of human promyelocyte HL-60 cells to monocytes and in calcium mobilizing activity in vitamin D deficient rats. Homologation of 1,25-dihydroxyvitamin D3 or its delta 22 analogue by one or two carbons increases by 10-fold and three-carbon homologation reduces by half the activity in causing differentiation of HL-60. On the other hand, homologation causes a substantial decrease in in vivo calcium mobilization activity. The addition of each carbon at the 24-position decreases binding to the HL-60 receptor or rat intestinal receptor by 5-10-fold so that binding affinity of the trihomo compound for the receptors is 130 times less that of 1,25-dihydroxyvitamin D3. Thus, binding affinity for the receptor cannot account for the preferential activity of the 24-homologated compounds in inducing cell differentiation.
Perlman
K
K
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin, Madison 53706.
Kutner
A
A
Prahl
J
J
Smith
C
C
Inaba
M
M
Schnoes
H K
HK
DeLuca
H F
HF
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007942:Leukemia, Experimental / Q000473:pathology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D002117:Calcitriol; D002118:Calcium