Development of potent and selective glycosidase inhibitors

• Main Authors: Ting-Chien Lin, 林鼎堅
• Other Authors: Chun-Hung Lin
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/ya2uk2

博士 === 國立臺灣大學 === 化學研究所 === 106 === Glucuronidation is a major drug-metabolizing reaction in humans. Glucuronidated metabolites are hydrolyzed by intestinal bacterial β-glucuronidase (GUS) and release their toxic aglycones in intestines, resulting in intestinal damage. Diarrhea is a common dose-limiting toxicity caused by symbiotic bacterial GUS that reactivate cancer chemotherapeutic CPT-11 in the gut. Selective inhibition of bacterial GUS without killing microbiota alleviates these side effects. Although uronic isofagomine is a strong GUS inhibitor, while suffers from lack of selectivity. The derivatives of uronic isofagomine we designed and synthesized inhibit bacterial GUSs broadly. The human/E. coli GUS selectivity ratio reaches 23378. The selectivity was based on amino acids of aglycone binding site that alkyl chains of inhibitors interact with. Different from human GUS, bacterial GUSs possess more hydrophobic amino acids in aglycone binding site. The derivatives of uronic isofagomine shows effective against GUS in living E. coli cells and did not kill the bacteria. We further validated the ability of inhibitors to disrupt GUS activities in gut by mouse model.