189894-15-3Relevant articles and documents
Synthesis and biological activities of the two C(23) epimers of 1α,23,25-trihydroxy-24-oxo-19-nor-vitamin D3: Novel analogs of 1α,23(S),25-trihydroxy-24-oxo-vitamin D3, a natural metabolite of 1α,25- dihydroxyvitamin D3
Lee, Nancy E.,Williard, Paul G.,Brown, Alex J.,Campbell, Moray J.,Koeffler, H. Phillip,Peleg, Sara,Rao, D. Sunita,Reddy, G. Satyanarayana
, p. 252 - 265 (2007/10/03)
In a previous report, we indicated that 1α,23(S),25-trihydroxy-24- oxovitamin D3 [1α,23(S),25(OH)3-24-oxo-D3], a natural metabolite of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is almost equipotent to 1α,25(OH)2D3 in suppressing parathyroid hormone (PTH) secretion (Lee et al., 1997. Biochemistry 36, 9429-9437). Also, 1α,23(S),25(OH)3-24-oxo-D3 has been shown to possess only weak in vivo calcemic actions. Thus, vitamin D3 analogs structurally related to 1α,23(S),25(OH)3-24-oxo-D3 may have therapeutic value. Furthermore, biologic activity studies of various synthetic analogs of 1α,25(OH)2D3 showed that the removal of carbon-19 (C- 19) reduces the calcemic activity of 1α,25(OH)2D3. Therefore, in an attempt to produce vitamin D3 analogs with a better therapeutic index, we synthesized C(23) epimers of 1α,23,25(OH)3-24-oxo-19-nor-vitamin D3 [1α,23,25(OH)3-24-oxo-19-nor-D3]. The two epimers were compared to 1α,25(OH)2-19-nor-D3 and 1α,25(OH)2D3 in their ability to generate biologic activities in several in vitro assay systems. In the assay measuring the suppression of parathyroid hormone (PTH) secretion in bovine parathyroid cells, 1α,23(S),25(OH)3-24-oxo-19-nor-D3 was as potent as 1α,25(OH)2-19- nor-D3 but was less potent than 1α,25(OH)2D3. In the same assay 1α,23(R),25(OH)3-24-oxo-19-nor-D3 exhibited greater potency than 1α,23(S),25(OH)3-24-oxo-19-nor-D3. In the assays measuring the ability of vitamin D compounds to inhibit clonal growth and to induce differentiation of human promyelocytic leukemia (HL-60) cells, 1α,23(S),25(OH)3-24-oxo-19-nor- D3 was less potent than 1α,25(OH)2-19-nor-D3 but was equipotent to 1α,25(OH)2D3. More importantly, in the same assays, 1α,23(R),25(OH)3-24- oxo-19-nor-D3 was more potent than 1α,23(S),25(OH)3-24-oxo-19-nor-D3 and was equipotent to 1α,25(OH)2-19-nor-D3. Also, the vitamin D receptor- mediated transcriptional activity of 1α,23(R),25(OH)3-24-oxo-19-nor-D3 was almost equal to that of 1α,25(OH)2-19-nor-D3, but higher than that of 1α,23(S),25(OH)3-24-oxo-19-nor-D3. This finding explains in part the greater in vitro biologic activities of 1α,23(R),25(OH)3-24-oxo-19-nor-D3. In summary, our results indicate that 1α,23(R),25(OH)3-24-oxo-19-nor-D3 and to a lesser extent 1α,23(S),25(OH)3-24-oxo-19-nor-D3 are potent 19-nor vitamin D3 analogs, which suppress PTH secretion in bovine parathyroid cells and strongly inhibit clonal growth and induce differentiation of HL-60 cells in vitro. (C) 2000 Elsevier Science Inc.
