De novo design and synthesis of aromatic vitamain D analogs having rigid three-dimensional structure and differential activity

1)以人维甲酸受体g(HRARg)的维生素D受体配体结合域(VDR-LBD)的晶体结构为基础，建立了VDR-LBD的三维结构同源模型。将天然配体1，25-(OH)2D3对接在VDR-LBD上，确定了面向配体结合袋(LBP)并与配体相互作用的氨基酸残基。模型结构通过与配体相互作用的关键氨基酸的丙氨酸扫描突变分析得到证实。模型结构和配体对接方式与同时公布的VDR-LBD缺失突变体(VDR D 165-215)的晶体结构基本相同。2)在VDR模型的基础上，设计合成了10个CD-和A-环体系中具有芳香环的非甾体维生素D类似物。用Suzuki方法成功地偶联了芳香族CD环和A环。目前正在对这些化合物的生物活性进行检测。还合成了含氟的A环类似物。以D-葡萄糖为起始原料，建立了19-去甲基维生素D衍生物A环合成子的立体选择性合成新方法。

1) Three-dimensional structure of vitamnin D receptor ligand-binding domain (VDR-LBD) was homology modeled based on the crystal structure of LBD of human retinoic acid receptor g (hRAR g). The natural ligand, 1,25-(OH) 2D3, was docked in the VDR-LBD and amino acid residues facing ligand binding pocket (LBP) and interacting with the ligand were identified. The model structure was substantiated by alanine scanning mutation analysis of the putative key amino acids interacting with ligand The model structure and ligand-docking manner were essentially the same as the crystal structure of VDR-LBD deletion mutant (VDR D 165-215) which was disclosed simultaneously.2) Based out the VDR model, some ten non-steroid vitamnin D analogs having aromatic rings for the CD-and A-ring systems were designed and synthesized. The aromatic CD-and A-rings were successfully coupled by using Suzuki method. Biological activities of these compounds are now under examination. Fluorinated A-ring analogs were also synthesized. Also new stereoselective synthetic method for A-ring synthon of 19-norvitamin D derivatives was established starting from D-glucose.