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

具有刚性三维结构和差异活性的芳香族维生素D类似物的从头设计与合成

• 批准号: 11694253
• 负责人: YAMADA Sachiko
• 金额: $ 3.78万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11694253/
• 关键词: Vitamin D; Nuclear receptor; Homology modeling; Analogs; Non-steroid vitamin D; Differential action; Structure-function relationship; Three-dimensional structure; 遺伝子転写

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.

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。

项目成果

Yamada S, Yamamoto K: "New vitamin D analogs and structure-function relationship"Bio Clinica. 13. 1161-1167 (1994)

Yamada S、Yamamoto K：“新的维生素 D 类似物和结构-功能关系”Bio Clinica。

Choi M, Yamamoto K, Masuno H, Yamada S, et al.: "Three-dimensional structure-function relationship of vitamin D and Vitamin D receptor model"Vitamin D Endocrine System (Proceedings of the XIth Workshop on VitamiN D). 243-246 (2000)

Choi M，Yamamoto K，Masuno H，Yamada S，等：“维生素D和维生素D受体模型的三维结构-功能关系”维生素D内分泌系统（第十一届维生素D研讨会论文集）。

山田幸子(松本俊夫 他 編): "選択的エストロゲン受容体モジュレーター:SERM"医療ジャーナル. 215 (2001)

Sachiko Yamada（由 Toshio Matsumoto 等人编辑）：“选择性雌激素受体调节剂：SERM”医学杂志 215 (2001)。

崔美花(Norman AW 他 編): "Vitamin D Endocrine System (3D Structure of VDR ligand binding domain and structure-function relationship of vitamin D, 1 ; Alanine scanning mutation analysis of amino-acid residues lining ligand binding pocket and assignment of the r

Mika Choi（Norman AW 等编辑）：“维生素 D 内分泌系统（VDR 配体结合域的 3D 结构和维生素 D 的结构功能关系，1；配体结合袋内衬氨基酸残基的丙氨酸扫描突变分析和r 的赋值

清水正人: "Synthesis of(10Z)-and(10E)-19-Fluoro-1α,25-dihydroxyvitamin D_3 : Compounds to Probe Vitamin D Conformation in Receptor Complex by ^<19>F-NMR"Chem.Pharm.Bull.. 48. 1484-1493 (2000)

Masato Shimizu：“(10Z)-和(10E)-19-氟-1α,25-二羟基维生素D_3的合成：通过^ 19 F-NMR探测受体复合物中维生素D构象的化合物”Chem.Pharm.Bull。 . 48. 1484-1493 (2000)