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

1)根据人维甲酸受体g（hRAR g）配体结合域（VDR-LBD）的晶体结构，对VDR-LBD的三维结构进行了同源模建。将天然配体1，25-（OH）2D 3对接到VDR-LBD中，并鉴定了面向配体结合口袋（LBP）并与配体相互作用的氨基酸残基。通过对与配体相互作用的关键氨基酸进行丙氨酸扫描突变分析，证实了该模型的结构，模型结构和配体对接方式与VDR-LBD缺失突变体的晶体结构基本相同（VDR D 165-215），其被错误地公开。2）基于VDR模型，设计并合成了约10种具有CD-和A-环系统的芳环的非甾体维生素D类似物。用Suzuki方法成功地偶联了芳香族的CD环和A环。这些化合物的生物活性正在研究中。还合成了氟化的A-环类似物。建立了以D-葡萄糖为原料立体选择性合成19-去甲维生素D衍生物A环合成子的新方法。

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.