Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
Bioorg Med Chem. 2010 Jun 1;18(11):3790-4. doi: 10.1016/j.bmc.2010.04.048. Epub 2010 Apr 21.
Chromatographic separation of the extract from roots of Adenophora triphylla resulted in the isolation of two pyrrolidines, six piperidines, and two piperidine glycosides. The structures of new iminosugars were elucidated by spectroscopic methods as 2,5-dideoxy-2,5-imino-d-altritol (DIA) (2), beta-1-C-butenyl-1-deoxygalactonojirimycin (8), 2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (9), and 6-O-beta-d-glucopyranosyl-2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (10). beta-1-C-Butyl-1-deoxygalactonojirimycin (7) and compound 8 were found to be better inhibitors of alpha-galactosidase than N-butyl-1-deoxygalactonojirimycin. The present work elucidated that DIA was a powerful competitive inhibitor of human lysosome alpha-galactosidase A (alpha-Gal A) with a K(i) value of 0.5muM. Furthermore, DIA improved the thermostability of alpha-Gal A in vitro and increased intracellular alpha-Gal A activity by 9.6-fold in Fabry R301Q lymphoblasts after incubation for 3days. These experimental results suggested that DIA would act as a specific pharmacological chaperone to promote the smooth escape from the endoplasmic reticulum (ER) quality control system and to accelerate transport and maturation of the mutant enzyme.
从三叶沙参根的提取物中通过色谱分离得到了两个吡咯烷、六个哌啶和两个哌啶糖苷。通过光谱方法阐明了新的亚氨基糖的结构为 2,5-二脱氧-2,5-亚氨基-d-阿糖醇（DIA）（2）、β-1-C-丁烯基-1-脱氧半乳糖基基二氢吡咯烷（8）、2,3-二脱氧-β-1-C-乙基-1-脱氧半乳糖基二氢吡咯烷（9）和 6-O-β-d-吡喃葡萄糖基-2,3-二脱氧-β-1-C-乙基-1-脱氧半乳糖基二氢吡咯烷（10）。发现β-1-C-丁基-1-脱氧半乳糖基二氢吡咯烷（7）和化合物 8 是比 N-丁基-1-脱氧半乳糖基二氢吡咯烷更好的α-半乳糖苷酶抑制剂。本工作阐明了 DIA 是一种有效的人溶酶体α-半乳糖苷酶 A（α-Gal A）竞争性抑制剂，K(i)值为 0.5μM。此外，DIA 提高了α-Gal A 在体外的热稳定性，并在孵育 3 天后使 Fabry R301Q 淋巴母细胞内的α-Gal A 活性增加了 9.6 倍。这些实验结果表明，DIA 将作为一种特异性的药理学伴侣，促进突变酶从内质网（ER）质量控制系统中顺利逃逸，并加速其转运和成熟。
