期刊
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
卷 110, 期 3-5, 页码 269-277出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2007.11.007
关键词
vitamin D receptor antagonist; 1 alpha,25-dihydroxyvitamin D(3)-26,23-lactam analogues; HL-60 cell differentiation; osteoclast formation; gene expression
资金
- NIAMS NIH HHS [P01 AR049363-05, P01 AR049363, P01 AR 049363] Funding Source: Medline
(23S,25S)-N-Benzyl-1 alpha,25-dihydroxyvitamin D(3)-26,23-lactam ((23S,25S)-N-benzyl-1 alpha,25-(OH)(2)D(3)-26,23-lactam, (23S,25S)-DLAM-1P) antagonizes nuclear vitamin D receptor (VDR)-mediated differentiation of human promyelocytic leukemia (HL-60) cells [Y. Kato, Y. Nakano, H. Sano, A. Tanatani, H. Kobayashi, R. Shimazawa, H. Koshino, Y. Hashimoto, K. Nagasawa, Synthesis of 1 alpha,25-dihydroxy vitamin D(3)-26,23-lactams (DLAMs), a novel series of 1 alpha,25-dihydroxy vitamin D(3) antagonist, Bioorg. Med. Chem. Lett. 14 (2004) 2579-2583]. To enhance its VDR antagonistic actions, we synthesized multiple analogues of 1 alpha,25-(OH)(2)D(3)-26,23-lactam. Among these analogues, (23S,25S)-N-phenetyl-1 alpha,25-(OH)(2)D(3)-26,23-lactam, ((23S,25S)-DLAM-2P) had the strongest VDR binding affinity, which was 3 times higher than that of (23S,25S)-DLAM-1P. The 1 alpha,25-(OH)(2)D(3)-26,23-lactam analogues never induced HL-60 cell differentiation even at 10(-6) M, but (23S,25S)-DLAM-1P and (23S,25S)-DLAM-2P significantly and dose-dependently inhibited HL-60 differentiation induced by 10(-8) M 1 alpha,25-dihydroxyvitamin D(3) (1 alpha,25-(OH)(2)D(3)). These compounds also inhibited human and mouse cultures of osteoclast formation by marrow cells treated with 1 alpha,25-(CH)(2)D(3)- Moreover, the 1 alpha,25-(OH)(2)D(3)-26,23-lactam analogues minimally induced 25-hydroxyvitamin D(3)-24-hydroxylase gene expression in HL-60 cells and human and mouse osteoblastic cells, but 10(-6) M (23S,25S)-DLAM-1P or (23S,25S)-DLAM-2P significantly blocked 24-hydroxylase gene expression induced by 10(-8) M 1 alpha,25-(OH)(2)D(3). (23S,25S)-DIAM-2P was 5-12 times more potent as a vitamin D antagonist than (23S,25S)-DLAM-1P in HL-60 cells, human and mouse bone marrow cultures. These results demonstrate that (23S,25S)-DLAM-1P and (23S,25S)-DLAM-2P antagonize HL-60 cell differentiation and osteoclast formation by human and mouse osteoclast precursors induced by 1 alpha,25-(OH)(2)D(3) through blocking VDR-mediated gene transcription. In contrast, (23S)-25-deoxy-1 alpha-thydroxyvitamin D(3)-26,23-lactone, which only blocks human VDR, these vitamin D antagonists can block VDR in human cells and rodent cells. (C) 2008 Elsevier Ltd. All rights reserved.
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