Access Type
Open Access Dissertation
Date of Award
January 2020
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Nutrition and Food Science
First Advisor
Kequan Zhou
Abstract
Irinotecan is a derived compound from the plant alkaloid camptothecin (CPT). It specifically inhibits eukaryotic DNA enzyme topoisomerase I. Irinotecan was approved by the FDA as the second-line therapy for metastatic colon or rectal cancer in 1996. However, one of its leading side effects is diarrhea. It has been reported that up to 88% of treated patients were suffering from diarrhea and 31% of cases with grade 3 or 4 diarrhea. Irinotecan is metabolized into SN-38G in the liver, then SN-38G is excreted to the intestinal tract and deconjugated back to SN-38 by bacterial β-glucuronidase. The free SN-38 in the gut leads to the delayed diarrhea by damaging the intestinal mucosa. Therefore, selectively inhibiting bacterial β-glucuronidase has been an attractive strategy to alleviate irinotecan-induced delayed diarrhea. We preliminarily screened over 80 extracts and found that an extract of noni (Morinda citrifolia) fruits showed potent inhibitory activity on gut bacterial β-glucuronidase. In this study, four bacterial β-glucuronidase inhibitors were obtained following bioactive assay-guided isolation, including two sesquineolignans, (7S,8S,7'R,8'R)-isoamericanol B (1) and americanol B (2), and two dineolignans, moricitrin A (3) and B (4). Compounds 2-4 are new, and the absolute configuration of compound 1 was determined for the first time. Their chemical structures were elucidated through HRESIMS and NMR spectra, and their absolute configurations were established via the comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. These compounds showed potent inhibition against gut bacterial β-glucuronidase with IC50 values in the range 0.62-6.91 µM. The inhibition presented specificity for β-glucuronidase as all the compounds showed no or weak effects on digestive enzymes such as α-amylase, α-glucosidase and lipase, suggesting that their gastrointestinal side effects could be minimized. These specific inhibitors as naturally occurring dietary compounds may be developed as promising candidates to alleviate irinotecan-induced diarrhea.
Recommended Citation
Yang, Fei, "Development Of Specific Natural Bacterial Beta-Glucuronidase Inhibitors For Reducing Irinotecan-Associated Diarrhea" (2020). Wayne State University Dissertations. 2515.
https://digitalcommons.wayne.edu/oa_dissertations/2515