Synthetic analogues of vitamin D3 with an oxygen atom in the side chain skeleton. A trial of the development of vitamin D compounds which exhibit potent differentiation-inducing activity without inducing hypercalcemia.
Four analogues of vitamin D3 with an oxygen atom in the side chain skeleton were synthesized to determine whether their differentiation-inducing activity could be separated structurally from their activity to induce hypercalcemia. The order of the in vitro potency to reduce nitroblue tetrazolium in human myeloid leukemia cells (HL-60) was 22-oxa-1 alpha, 25-(OH)2D3 greater than 1 alpha, 25-(OH)2D3 greater than 20-oxa-1 alpha, 25-(OH)2D3 not equal to 22-oxa-1 alpha-(OH)D3 greater than 1 alpha-(OH)D3 greater than 20-oxa-1 alpha-(OH)D3. 22-Oxa-1 alpha, 25-(OH)2D3 was also about 10-times more potent than 1 alpha, 25-(OH)2D3 in suppressing proliferation and inducing differentiation of mouse myelomonocytic leukemia cells (WEHI-3), but the former was much weaker than the latter in inducing the release of 45Ca from prelabeled fetal mouse calvaria. These results suggest that the differentiation-inducing activity of vitamin D compounds can be separated structurally from their activity to induce hypercalcemia.
Abe
J
J
Research Laboratories, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
Morikawa
M
M
Miyamoto
K
K
Kaiho
S
S
Fukushima
M
M
Miyaura
C
C
Abe
E
E
Suda
T
T
Nishii
Y
Y
D000818:Animals; D001862:Bone Resorption / Q000187:drug effects*; D001842:Bone and Bones / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002762:Cholecalciferol / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D013329:Structure-Activity Relationship
D002762:Cholecalciferol; D002118:Calcium