Document Detail

1alpha,25-Dihydroxyvitamin D(3)-26,23-lactam analogues function as vitamin D receptor antagonists in human and rodent cells.
MedLine Citation:
PMID:  18501591     Owner:  NLM     Status:  MEDLINE    
(23S,25S)-N-Benzyl-1alpha,25-dihydroxyvitamin D(3)-26,23-lactam ((23S,25S)-N-benzyl-1alpha,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 1alpha,25-dihydroxy vitamin D(3)-26,23-lactams (DLAMs), a novel series of 1alpha,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 1alpha,25-(OH)(2)D(3)-26,23-lactam. Among these analogues, (23S,25S)-N-phenetyl-1alpha,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 1alpha,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 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)). These compounds also inhibited human and mouse cultures of osteoclast formation by marrow cells treated with 1alpha,25-(OH)(2)D(3). Moreover, the 1alpha,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 1alpha,25-(OH)(2)D(3). (23S,25S)-DLAM-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 1alpha,25-(OH)(2)D(3) through blocking VDR-mediated gene transcription. In contrast, (23S)-25-deoxy-1alpha-hydroxyvitamin D(3)-26,23-lactone, which only blocks human VDR, these vitamin D antagonists can block VDR in human cells and rodent cells.
Seiichi Ishizuka; Noriyoshi Kurihara; Yuko Hiruma; Daishiro Miura; Jun-ichi Namekawa; Azusa Tamura; Yuko Kato-Nakamura; Yusuke Nakano; Kazuya Takenouchi; Yuichi Hashimoto; Kazuo Nagasawa; G David Roodman
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-04-22
Journal Detail:
Title:  The Journal of steroid biochemistry and molecular biology     Volume:  110     ISSN:  0960-0760     ISO Abbreviation:  J. Steroid Biochem. Mol. Biol.     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-06-16     Completed Date:  2008-10-01     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  9015483     Medline TA:  J Steroid Biochem Mol Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  269-77     Citation Subset:  IM    
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MeSH Terms
Calcitriol / analogs & derivatives*,  pharmacology
Cell Differentiation / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Gene Expression Regulation / drug effects
Genes, Reporter / drug effects
HL-60 Cells
Lactams / chemistry,  pharmacology*
Models, Biological
Osteoclasts / drug effects,  metabolism,  physiology
Receptors, Calcitriol / antagonists & inhibitors*
Steroid Hydroxylases / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Lactams; 0/Receptors, Calcitriol; 0/TEI 9647; EC 1.14.-/Steroid Hydroxylases; EC D 24-hydroxylase; FXC9231JVH/Calcitriol

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