Syntheses of 25-Adamantyl-25-alkyl-2-methylidene-1α,25-dihydroxyvitamin D 3 Derivatives with Structure–Function Studies of Antagonistic and Agonistic Active Vitamin D Analogs.

Autor: Maekawa, Kazuki, Ishizawa, Michiyasu, Ikawa, Takashi, Sajiki, Hironao, Matsumoto, Taro, Tokiwa, Hiroaki, Makishima, Makoto, Yamada, Sachiko
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Zdroj: Biomolecules (2218-273X); Jul2023, Vol. 13 Issue 7, p1082, 22p
Abstrakt: The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a major regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). We have previously synthesized vitamin D derivatives with large adamantane (AD) rings at position 24, 25, or 26 of the side chain to study VDR agonist and/or antagonist properties. One of them—ADTK1, with an AD ring and 23,24-triple bond—shows a high VDR affinity and cell-selective VDR activity. In this study, we synthesized novel vitamin D derivatives (ADKM1-6) with an alkyl group substituted at position 25 of ADTK1 to develop more cell-selective VDR ligands. ADKM2, ADKM4, and ADKM6 had VDR transcriptional activity comparable to 1,25(OH)2D3 and ADTK1, although their VDR affinities were weaker. Interestingly, ADKM2 has selective VDR activity in kidney- and skin-derived cells—a unique phenotype that differs from ADTK1. Furthermore, ADKM2, ADKM4, and ADKM6 induced osteoblast differentiation in human dedifferentiated fat cells more effectively than ADTK1. The development of vitamin D derivatives with bulky modifications such as AD at position 24, 25, or 26 of the side chain is useful for increased stability and tissue selectivity in VDR-targeting therapy. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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