5 0 0 0 ビタミンDの消化管炎症に対する関りと新規炎症性腸疾患治療戦略
近年、血中ビタミンD(VD)濃度が炎症性腸疾患(IBD)症状の悪性化リスクと強く関連することが報告されている。本研究ではVDとIBDとの関係性を、動物モデルを使用して広く解析し、VDをIBDの治療や予防に活用することを目的とする。具体的には、①腸炎モデルにVDを投与し、VDの IBDに対する治療効果や医薬品応用への可能性を検討する、②VD欠乏モデルの消化管病態を解析し、IBD病態とVDとの関りを理解する、という二つの視点から研究を遂行する。 上記の研究を通して、食事やサプリメントによるVD摂取をIBDの治療や予防に繋げ ることを最終目標に本研究を推進する。
1 0 0 0 OA Seco-ステロイド骨格の構造展開と核内受容体を介する生物活性
- 著者
- 橘高 敦史
- 出版者
- 公益社団法人 日本薬学会
- 雑誌
- YAKUGAKU ZASSHI (ISSN:00316903)
- 巻号頁・発行日
- vol.128, no.9, pp.1235-1250, 2008 (Released:2008-09-01)
- 参考文献数
- 76
- 被引用文献数
- 7 7
1α,25-Dihydroxyvitamin D3 (1) regulates a variety of biological actions through vitamin D receptor (VDR), including calcium and phosphorus homeostasis, bone remodeling, cellular proliferation and differentiation and many other functions. To enhance its potency and to study the structure/function relationship, we synthesized a series of analogs of 1 with a modification at the C-2α position. Introducing 2α-methyl, 2α-(3-hydroxypropyl), or 2α-(3-hydroxypropoxy) group increased its binding affinity for the VDR 2- to 4-fold compared to 1. The crystal structures of the VDR bound to these analogs provide a molecular explanation for the interaction between the 2α-substituents and water molecules exist in the VDR-ligand binding domain. Based on the accumulated knowledge in VDR agonists, we synthesized 2-substituted analogs of ‘double side chain’ (gemini), 19-norvitamin D3 (MART-10), TEI-9647 (VDR antagonist), 1-alkylated vitamin D3, 14-epi-previtamin D3 etc. Gemini analogs showed potent HL-60 cell differentiation activity (13-38 times compared to 1), and MART-10 exhibited remarkable antiproliferative activity on PZ-HPV-7 cells even at 10-10 M. (24S)-2α-(3-Hydroxypropoxy)-24-propyl-TEI-9647 showed potent VDR antagonism, and its IC50 value was 7.4 pM against 10 nM of 1. 1α-Methyl-2α-(3-hydroxypropyl)-25-hydroxyvitamin D3 improved the binding affinity for the mutant VDR(Arg274Leu), which causes hereditary vitamin D resistant rickets. 1α,25-Dihydroxy-2α-methyl-14-epi-previtamin D3 showed moderate osteocalcin transcriptional activity on HOS cells. We theorize that modification at A-ring alone and in combination with functionalization of the other parts of the vitamin D molecule would provide important new information on the mechanism of vitamin D actions that could lead to the development of new therapeutic regimes for the treatment of various diseases.