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.