Syntheses and differentiating action of vitamin D endoperoxides. Singlet oxygen adducts of vitamin D derivatives in human myeloid leukemia cells (HL-60).
Singlet oxygen adducts of various vitamin D derivatives, 6,19-dihydro-6,19-epidioxyvitamin 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 endoperoxides 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.
Yamada
S
S
Yamamoto
K
K
Naito
H
H
Suzuki
T
T
Ohmori
M
M
Takayama
H
H
Shiina
Y
Y
Miyaura
C
C
Tanaka
H
H
Abe
E
E
D001667:Binding, Competitive; D002112:Calcifediol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D002762:Cholecalciferol / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology* / Q000503:physiopathology; D010084:Oxidation-Reduction; D010100:Oxygen; D010587:Phagocytosis / Q000187:drug effects; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism; D026082:Singlet Oxygen; D013329:Structure-Activity Relationship
D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D026082:Singlet Oxygen; D002762:Cholecalciferol; C046473:25-hydroxy-6,19-dihydro-6,19-ethanovitamin D3; D002112:Calcifediol; D010100:Oxygen