(I) Polygalatenosides A , B及其衍生物之合成與活性研究; (II) 類茴香黴素小分子之設計、合成與活性研究

(I) Synthesis and Bioevaluation of Polygalatenosides A , B and Derivatives; (II) Design, Synthesis and Bioevaluation of Anisomycin-Based Small Molecules

黃志銘

指導教授 ： 劉瑞雄 ； 鄭偉杰

國立清華大學/理學院/化學系/博士(2009年)

https://doi.org/10.6843/NTHU.2009.00776

摘要

Abstract
In this thesis, a convergent and straightforward synthetic route for preparation of polygalatenosides A, B, and a series of their derivatives was developed. I also explored the norepinephrine transporter (NET) and serotonin transporter (SERT) inhibition of polygalatenoside derivatives. In the meantime, the anisomycin-like derivatives were also synthesized and examined for inhibition of Saccharomyces cereuisiae, Candida albicans, and human breast cancer cell (MCF7).
In part 1 of this thesis, a small compound library of new polygalatenoside derivatives were synthesized. The first total synthesis of polygalatenosides A and B was performed, and absolute D-configuration of galactoside moeity in A and B was also confirmed for the first time. The biological analysis showed that 3a and 5b did not show the significant inhibition of SERT.
In part 2, seven new anisomycin-like derivatives were synthesized. Our successful synthetic strategy ultilized the structural transformation from amino acid through β-lactam and pyrrolidinone to the amino pyrrolidines. The biological analysis showed the 87d and 87g have little inhibition of MCF7.

關鍵字

茴香黴素 ； 呲咯烷酮 ； 吡咯烷 ； 青黴素

並列摘要

中文摘要 於本篇論文中，本人發展一個集中與直接的路徑來製備polygalatenosides A 與B 及其一系列的衍生物。另外，本人亦探討polygalatenoside 衍生物對於正 腎上腺素及血清素輸送者的抑制效果。同樣地，本人也合成了類茴香黴素的衍生 物並且測試其對啤酒酵母、白色念珠菌與人類乳癌細胞之抑制。 在本論文的第一部分，本人合成新polygalatenoside衍生物的小型化合物資料 庫。對於polygalatenosides A與B來說，我們不但完成了首次的全合成，而且在其 半乳糖的結構部分也證實為D組態。在生物活性分析的數據顯示出，化合物3a與 5b對血清素輸送者具有小規模的抑制效果。 在第二部分中，本人合成了七個類茴香黴素的衍生物。在我們的成功合成策 略裡，利用了幾種結構之間的轉換，包括胺基酸、β-內醯胺、呲咯烷酮與胺基吡 咯烷等。 在生物活性分析的數據顯示出，化合物87d與87g對人類乳癌細胞具有 小規模的抑制效果。

並列關鍵字

anisomycin ； pyrrolidinone ； pyrrolidine ； beta lactam

參考文獻

4. (a) Chung, I. W.; Moore, N. A.; Oh, W. K.; O’ Neill, M. F.; Ahn, J. S.; Park, J. B.; Kang, U. G.; Kim, Y. S. Pharmacol. Biochem. Behav. 2002, 71, 191; (b) Chen, Y. L.; Hsieh, C. L.; Wu, P. H. B.; Lin, J. G. J. Ethnopharmacol. 2004, 95, 47; (c) Park, C. H.; Choi, S. H.; Seo, J. H.; Koo, J. W.; Seo, H. S.; Kim, H. S.; Jeong, S. J.; Suh, Y. H. J. Neurosci. Res. 2002, 70, 484; (d) Jia, H.; Jiang, Y.; Ruan, Y.; Zhang, Y.; Ma, X.; Zhang, J.; Beyreuther, K.; Tu, P.; Zhang, D. Neurosci. Lett. 2004, 367, 123; (e) Lee, H. J.; Ban, J. Y.; Koh, S. B. Am. J. Chin. Med. 2004, 32, 599; (f) Shin, K. Y.; Lee, J.-Y.; Won, B. Y.; Jung, H. Y.; Chang, K.-A.; Koppula, S.; Suh, Y.-H. Neurosci. Lett. 2005, 465, 157; (g) Shin, K. Y.; Won, B. Y.; Heo, C.; Kim, H. J.; Jang, D.-P.; Park, C. H.; Kim, S.; Kim, H.-S.; Kim, Y.-B.; Lee, H. G.; Lee, S. H.; Cho, Z.-H.; Suh, Y.-H. J. Neurosci. Res. 2009, 87, 260.

5. (a) Jiang, Y.; Tu, P. Chem. Pharm. Bull. 2005, 53, 1164; (b) Jiang, Y.; Tu, P. F. Phytochemistry 2002, 60, 813; (c) Miyase, T.; Iwata, Y.; Ueno, A. Chem. Pharm. Bull. 1991, 39, 3082; (d) Jiang, Y.; Tu, P. J. Asian Nat. Prod. Res. 2003, 5, 279; (e) Ikeya, Y.; Sugama, K.; Okada, M.; Mitsuhashi, H. Chem. Pharm. Bull. 1991, 39, 2600; (f) Jiang, Y.; Zhang, W.; Tu, P.; Xu, X. J. Nat. Prod. 2005, 68, 875.

12. Murali, R.; Nagarajan, M. Carbohydr. Res. 1996, 280, 351.

15. Mong, K.-K. T.; Wong, C.-H. Angew. Chem. Int. Ed. 2002, 41, 4087.

23. Hansen, H. C.; Magmusson, G. Carbohydr. Res. 1999, 322, 166.