松醇及pseudoguaianolide衍生物之製備

Preparation of aminopinitol and pseudoguaianolide derivatives

王韻婷(Yun-Ting Wang)

指導教授 ： 李水盛

國立臺灣大學/醫學院/藥學研究所/碩士(2010年)

https://doi.org/10.6342/NTU.2010.10662

摘要

21世紀，隨著環境及生活習性的改變，「三高」成了現代人的文明病，其中的高血糖則是和糖尿病 (Diabetes Mellitus) 息息相關，已成為世界各地廣泛盛行的一種慢性病，使用藥物治療對於糖尿病達到理想血糖控制是必要的，雖然目前市面上已有多種口服降血糖用藥可供選擇，但都有其相對的禁忌及副作用，因此新藥的開發仍有相當需求。
α-glucosidase inhibitor (AGH) 藥物的作用機轉為抑制在小腸刷狀緣上的甲型葡萄糖水解酶，進而減少碳水化合物的代謝，而減少葡萄糖之產生與吸收，可改善飯後高血糖的情形。根據文獻報導，松醇 (D-pinitol) 具有擬胰島素作用而可增加細胞對葡萄糖的吸收，本實驗設計，即希望以松醇為起始物進行結構修飾，得到類似Miglitol或是Voglibose架構之化合物並測試其活性，首先將松醇第四位置之羥基經四步反應轉換為胺基，接著在氮上進行不同的醯烷化反應，所得產物大致可分成三個系列，(1) 直接性的烷基化 (化合物23~26) (2) 醯化反應 (化合物27~30) (3) 還原性胺化反應 (化合物 31~34)，將所得化合物進行甲型葡萄糖水解酶活性測試，結果抑制活性皆不佳，將進行後續相關之glucose transporter assay。
本實驗之另一部分為利用化學反應方法改善分離之不便，由鵝不食草中分離出的主要成分之主架構為倍半萜環酯類 (sesquiterpene lactones) 中的pseudoguaianolide，被認為具有細胞毒殺性，而在支鏈上有不同的碳數取代，也因結構的極性相似度高造成分離上的繁瑣及困難，利用水解方式切除酯鍵保留原主架構，以供後續相關的衍生化產物之製備。

關鍵字

糖尿病 ； 甲型葡萄糖水解酶抑制劑 ； 松醇 ； 倍半萜環酯類 ； 細胞毒殺性 ； 含胺松醇衍生物

並列摘要

The prevalence of type 2 diabetes continues to grow worldwide. The use of drug therapy to help people who suffer this disease to control their blood glucose is necessary. Despite the availability of several classes of anti-diabetic drugs, maintaining sufficient long-term glycaemic control remains a common challenge, and side effects have also become an increasingly important issue. Therefore, the development of new anti-diabetic drug is urgent.
The mechanism of α-glucosidase inhibitor (AGH) is targeting on the enzymes in the small intestine brush border, which are responsible for breakdown of oligosaccharides and disaccharides into monosaccharides suitable for absorption. They can delay the digestion of carbohydrates and therefore retard glucose entry into the systemic circulation, and then lower postprandial glucose levels to achieve therapeutic control of diabetes. Recent research has found D-pinitol may have profound insulin-like properties and is proven to be an excellent aid in improving glucose metabolism.
In this study, D-pinitol was used as starting material to prepare azapinitols, like Miglitol or Voglibose, whose activity were assayed. Through four step reactions, was converted hydroxyl group at C-4 in pinitol to an amine group. Subsequent, N-acylation and N-alkylation yielded three series of products: (1) acylation (compound 23~26) (2) reductive amination (compound 27~30) (3) direct alkylation (compound 31~34). Collect all of the synthesize compounds to test the α-glucosidase assay.
The second part of this thesis attempted to solve the separation problem of pseudoguaianolide present in Centipeda minima by chemical method. The structures of this series of compounds only different in the carbon numbers on the ester side chain. The greatly similar polarity causes difficulty for further purification. Thus, we tried to use hydrolyze the various ester side chain to form the same product containing 6-hydroxy group for further structure modification.

並列關鍵字

Diabetes mellitus ； α-glucosidase inhibitor ； D-Pinitol ； Sesquiterpene lactones ； pseudoguaianolide ； cytotoxicity ； amino-pinitol derivatives

參考文獻

4. 行政院衛生署2005-2008國民營養健康狀況變遷調查

61. 謝伯鴻, 國立台灣大學醫學院藥學研究所碩士論文:苯丙醯黃酮屬裡糖苷類化合物之製備作抑制甲型葡萄糖水解酶之研究. 2008, July

47. Herr, C. H.; Whitmore, F. C.; Schiessler, R. W., The wolff-kishner reaction at atmospheric pressure. Journal of the American Chemical Society 1945, 67, 2061-2063.

54. Comprehensive Organic Functional Group Transformation 2, 2nd p30, Katritazk, A., Taylor, R., USA (1995)

1. http://www.diabetes.org/ (American Diabetes Association)