Syntheses and differentiating action of vitamin D endoperoxides. Singlet oxygen adducts of vitamin D derivatives in human myeloid leukemia cells (HL-60)

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Abstract
Singlet oxygen adducts of various vitamin D derivatives, 6,19-dihydro-6,19-epidoxyvitamin D (vitamin D endoperoxides, 2 and 2''), were chemically synthesized, and their biological activity in inducing differentiation of a human myeloid leukemia cell line (HL-60 cells) was examined. The potency of the endoperoxidases derived from vitamin D derivatives possessing the 1.alpha.-hydroxyl group such as 1.alpha.,25-dihydroxyvitamin D3 endoperoxides (2b and 2b'') was markedly (10-2) diminished relative to the respective parent vitamin D compounds. In contrast, 25-hydroxyvitamin D3 endoperoxides [25-(OH)D3 endoperoxides, 2a and 2a''] and their analogues fluorinated at the 24- or 26- and 27-positions were 2.5-10 times more potent than 25-hydroxyvitamin D3 (1a) in spite of the absence of the conjugated triene structure typical of vitamin D compounds. The potency of these vitamin D endoperoxides (2 and 2''), especially those lacking the 1.alpha.-hydroxyl group, in inducing differentiation of HL-60 cells was not correlated with their activity in binding to the cytosol receptor for 1.alpha.,25-dihydroxyvitamin D3 (1b). The binding efficiency to the receptor was relatively lower than the differentiating activity. To examine the action of vitamin D endoperoxides, carbon analogues of 25-(OH)D3 endoperoxides, two C-6 epimers of 25-hydroxy-6,19-dihydro-6,19-ethanovitamin D3 (6 and 6''), were synthesized. The carbon analogues (6 and 6'') had no potential to induce differentiation of HL-60 cells. These results suggest that vitamin D endoperoxides (2 and 2'') express their biological activity probably after being converted to some other compounds.