Yamamoto Keiko, Inaba Yuka, Yoshimoto Nobuko, Choi Mihwa, DeLuca Hector F, Yamada Sachiko
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Tokyo 101-0062, Japan.
J Med Chem. 2007 Mar 8;50(5):932-9. doi: 10.1021/jm060889f. Epub 2007 Feb 14.
We previously reported that 22R-methyl-20-epi-1,25-(OH)2D3 (3) possesses strong binding affinity for the vitamin D receptor (VDR) and shows superagonistic biological activities. To examine the effect of the length of an alkyl substituent at C(22) and to extend our compound library, we successfully synthesized 22R-ethyl-20-epi-1,25-(OH)2D3 (4) and 22R-butyl-20-epi-1,25-(OH)2D3 (5). Surprisingly, 22-ethyl analogue 4 showed stronger VDR binding affinity and transactivation potency than the superagonist of methyl analogue 3, but its calcemic activity in vivo was weaker than that of both the methyl analogue 3 and the natural hormone (1), while 22-butyl analogue 5 showed activities comparable to those of the hormone (1). A study of the docking of these new analogues to the VDR-LBD and alanine scanning mutational analysis demonstrated that 22-methyl and 22-ethyl substituents enhance the favorable hydrophobic interactions with residues lining the ligand binding pocket of the VDR, and that 22-butyl analogue 5 binds to the VDR by an induced fit mechanism.
我们之前报道过，22R-甲基-20-表-1,25-(OH)₂D₃（3）对维生素D受体（VDR）具有很强的结合亲和力，并表现出超激动剂的生物活性。为了研究C(22)位烷基取代基长度的影响并扩展我们的化合物库，我们成功合成了22R-乙基-20-表-1,25-(OH)₂D₃（4）和22R-丁基-20-表-1,25-(OH)₂D₃（5）。令人惊讶的是，22-乙基类似物4显示出比甲基类似物3的超激动剂更强的VDR结合亲和力和反式激活能力，但其体内的血钙活性比甲基类似物3和天然激素（1）都弱，而22-丁基类似物5显示出与激素（1）相当的活性。对这些新类似物与VDR-LBD的对接研究和丙氨酸扫描突变分析表明，22-甲基和22-乙基取代基增强了与VDR配体结合口袋内衬残基的有利疏水相互作用，并且22-丁基类似物5通过诱导契合机制与VDR结合。
