1α,25-Dihydroxyvitamin D3-26,23-lactam analogues function as vitamin D receptor antagonists in human 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

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

(23S,25S)-N-Benzyl-1α,25-dihydroxyvitamin D3-26,23-lactam ((23S,25S)-N-benzyl-1α,25-(OH)2D3-26,23-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 1α,25-dihydroxy vitamin D3-26,23-lactams (DLAMs), a novel series of 1α,25-dihydroxy vitamin D3 antagonist, Bioorg. Med. Chem. Lett. 14 (2004) 2579-2583]. To enhance its VDR antagonistic actions, we synthesized multiple analogues of 1α,25-(OH)2D3-26,23-lactam. Among these analogues, (23S,25S)-N-phenetyl-1α,25-(OH)2D3-26,23-lactam, ((23S,25S)-DLAM-2P) had the strongest VDR binding affinity, which was 3 times higher than that of (23S,25S)-DLAM-1P. The 1α,25-(OH)2D3-26,23-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 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3). These compounds also inhibited human and mouse cultures of osteoclast formation by marrow cells treated with 1α,25-(OH)2D3. Moreover, the 1α,25-(OH)2D3-26,23-lactam analogues minimally induced 25-hydroxyvitamin D3-24-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 1α,25-(OH)2D3. (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 1α,25-(OH)2D3 through blocking VDR-mediated gene transcription. In contrast, (23S)-25-deoxy-1α-hydroxyvitamin D3-26,23-lactone, which only blocks human VDR, these vitamin D antagonists can block VDR in human cells and rodent cells.

Original languageEnglish (US)
Pages (from-to)269-277
Number of pages9
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume110
Issue number3-5
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

Keywords

  • 1α,25-Dihydroxyvitamin D-26,23-lactam analogues
  • Gene expression
  • HL-60 cell differentiation
  • Osteoclast formation
  • Vitamin D receptor antagonist

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Ishizuka, S., Kurihara, N., Hiruma, Y., Miura, D., Namekawa, J. I., Tamura, A., Kato-Nakamura, Y., Nakano, Y., Takenouchi, K., Hashimoto, Y., Nagasawa, K., & Roodman, G. D. (2008). 1α,25-Dihydroxyvitamin D3-26,23-lactam analogues function as vitamin D receptor antagonists in human and rodent cells. Journal of Steroid Biochemistry and Molecular Biology, 110(3-5), 269-277. https://doi.org/10.1016/j.jsbmb.2007.11.007