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 Citations (Scopus)

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 2008
Externally publishedYes

Fingerprint

Lactams
Calcitriol Receptors
Calcitriol
Rodentia
HL-60 Cells
Osteoclasts
Mixed Function Oxygenases
Gene expression
Vitamin D
Cell Differentiation
Bone Marrow
Cells
Gene Expression
Calcifediol

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

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

Cite this

1α,25-Dihydroxyvitamin D3-26,23-lactam analogues function as vitamin D receptor antagonists in human and rodent cells. / Ishizuka, Seiichi; Kurihara, Noriyoshi; Hiruma, Yuko; Miura, Daishiro; Namekawa, Jun ichi; Tamura, Azusa; Kato-Nakamura, Yuko; Nakano, Yusuke; Takenouchi, Kazuya; Hashimoto, Yuichi; Nagasawa, Kazuo; Roodman, G. David.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 110, No. 3-5, 06.2008, p. 269-277.

Research output: Contribution to journalArticle

Ishizuka, S, Kurihara, N, Hiruma, Y, Miura, D, Namekawa, JI, Tamura, A, Kato-Nakamura, Y, Nakano, Y, Takenouchi, K, Hashimoto, Y, Nagasawa, K & Roodman, GD 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, vol. 110, no. 3-5, pp. 269-277. https://doi.org/10.1016/j.jsbmb.2007.11.007
Ishizuka, Seiichi ; Kurihara, Noriyoshi ; Hiruma, Yuko ; Miura, Daishiro ; Namekawa, Jun ichi ; Tamura, Azusa ; Kato-Nakamura, Yuko ; Nakano, Yusuke ; Takenouchi, Kazuya ; Hashimoto, Yuichi ; Nagasawa, Kazuo ; Roodman, G. David. / 1α,25-Dihydroxyvitamin D3-26,23-lactam analogues function as vitamin D receptor antagonists in human and rodent cells. In: Journal of Steroid Biochemistry and Molecular Biology. 2008 ; Vol. 110, No. 3-5. pp. 269-277.
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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.",
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author = "Seiichi Ishizuka and Noriyoshi Kurihara and Yuko Hiruma and Daishiro Miura and Namekawa, {Jun ichi} and Azusa Tamura and Yuko Kato-Nakamura and Yusuke Nakano and Kazuya Takenouchi and Yuichi Hashimoto and Kazuo Nagasawa and Roodman, {G. David}",
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TY - JOUR

T1 - 1α,25-Dihydroxyvitamin D3-26,23-lactam analogues function as vitamin D receptor antagonists in human and rodent cells

AU - Ishizuka, Seiichi

AU - Kurihara, Noriyoshi

AU - Hiruma, Yuko

AU - Miura, Daishiro

AU - Namekawa, Jun ichi

AU - Tamura, Azusa

AU - Kato-Nakamura, Yuko

AU - Nakano, Yusuke

AU - Takenouchi, Kazuya

AU - Hashimoto, Yuichi

AU - Nagasawa, Kazuo

AU - Roodman, G. David

PY - 2008/6

Y1 - 2008/6

N2 - (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.

AB - (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.

KW - 1α,25-Dihydroxyvitamin D-26,23-lactam analogues

KW - Gene expression

KW - HL-60 cell differentiation

KW - Osteoclast formation

KW - Vitamin D receptor antagonist

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