Analogs of the hormonal form of vitamin D and their possible use in leukemia.
We have concluded a large analog study that suggests that specific analogs of 1,25-(OH)2D3 can be prepared that have markedly enhanced activity in promoting differentiation of HL-60 promyelocytes to benign monocytes. We have observed that lengthening the side chain of 1,25-(OH)2D3 increases activity in HL-60 by 1 order of magnitude when the side chain is increased in length by 1 carbon. At the same time, the biological activity of these compounds in serum calcium elevation is either unchanged or diminished. Thus, lengthening the side chain may well provide a preferentially active form of vitamin D on the promyelocytes. Shortening the side chain has resulted a 10-fold loss of activity in HL-60 for each carbon removed. Furthermore, elimination of the 26- and 27-carbons decreases biological activity by 100-fold. If, however, the hydroxyl is left off the side chain and small hydrocarbon side chains of ethyl or isopropyl are substituted, very high activity in HL-60 is achieved without activity in mobilizing calcium in vivo. We, therefore, have compounds in hand which illustrate at least in vitro specific activity in HL-60.
DeLuca
H F
HF
Department of Biochemistry, University of Wisconsin-Madison 53706.
Ostrem
V K
VK
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology
D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D002117:Calcitriol; D002118:Calcium