Fujii Shinya, Kano Atsushi, Songkram Chalermkiat, Masuno Hiroyuki, Taoda Yoshiyuki, Kawachi Emiko, Hirano Tomoya, Tanatani Aya, Kagechika Hiroyuki
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan; Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Bioorg Med Chem. 2014 Feb 15;22(4):1227-35. doi: 10.1016/j.bmc.2014.01.015. Epub 2014 Jan 21.
1α,25-Dihydroxyvitamin D3 [1α,25(OH)₂D₃: 1] is a specific modulator of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are therapeutic candidates for multiple clinical applications. We recently developed non-secosteroidal VDR agonists bearing a p-carborane cage (a carbon-containing boron cluster) as a hydrophobic core structure. These carborane derivatives are structurally quite different from classical secosteroidal vitamin D analogs. Here, we report systematic synthesis and activity evaluation of carborane-based non-secosteroidal vitamin D analogs. The structure-activity relationships of carborane derivatives are different from those of secosteroidal vitamin D derivatives, and in particular, the length and the substituent position of the dihydroxylated side chain are rather flexible in carborane derivatives. The structure-activity relationships presented here should be helpful in development of non-secosteroidal vitamin D analogs for clinical applications.
1α,25-二羟基维生素D3 [1α,25(OH)₂D₃: 1] 是核维生素D受体 (VDR) 的特异性调节剂，新型维生素D类似物是多种临床应用的治疗候选药物。我们最近开发了带有对碳硼烷笼（一种含碳硼簇）作为疏水核心结构的非甾体VDR激动剂。这些碳硼烷衍生物在结构上与经典的甾体维生素D类似物有很大不同。在此，我们报告基于碳硼烷的非甾体维生素D类似物的系统合成和活性评估。碳硼烷衍生物的构效关系与甾体维生素D衍生物不同，特别是在碳硼烷衍生物中，二羟基化侧链的长度和取代基位置相当灵活。这里呈现的构效关系应有助于开发用于临床应用的非甾体维生素D类似物。
