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

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• 作者：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 Roo
• 关键词：Vitamin D receptor antagonist ; 1 ; //www.sciencedirect.com/scidirimg/entities/204e.gif"" alt=""greek small letter alpha"" title=""greek small letter alpha"" border=""0""> ; 25-Dihydroxyvitamin D₃-26 ; 23-lactam analogues ; HL-60 cell differenti
• 刊名：The Journal of Steroid Biochemistry and Molecular Biology
• 出版年：2008
• 出版时间：June 2008
• 年：2008
• 卷：110
• 期：3-5
• 页码：269-277
• 全文大小：1021 K

文摘

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