Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 22, Pages 9222-9238Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00963
Keywords
-
Categories
Funding
- Ministry of Science and Technology, Taipei, Taiwan [MOST 103-2320-B-037-011-MY3, MOST 105-2320-B-037-007, MOST 105-2320-B-037-011, MOST 106-2320-B-037-015, MOST 106-2320-B-041-001, MOST 106-2632-B-037-003]
- Taiwan Ministry of Health and Welfare [MOHW 106-TDU-B-212-144007]
- Health and Welfare Surcharge of Tobacco Products
- Grant of Biosignature in Colorectal Cancers, Academia Sinica, Taiwan
- Program for Translational Innovation of Biopharmaceutical Development-Technology Supporting Platform Axis
- Kaohsiung Medical University [KMU-DT106003, KMU-TP104E16, KMU-TP104E42, KMU-TP104H07, KMU-TP104H08, KMU-TP105C00, KMU-TP105E17, KMU-TP105E33, KMU-TP105H07, KMU-TP105H08]
- KMU-KMUH Co-Project of Key Research from Kaohsiung Medical University [KMU-DK106002, KMU-DK107001]
Ask authors/readers for more resources
The direct inhibition of bacterial,beta-glucuronidase (beta G) activity is expected to reduce the reactivation of glucuronide-conjugated drugs in the intestine, thereby reducing drug toxicity. In this study, we report on the effects of pyrazolo [4,3-c] quinolines acting as a new class of bacterial beta G-specific inhibitors in a pH-dependent manner. Refinement of this chemotype for establishing structure-activity relationship resulted in the identification of potential leads. Notably, the oral administration of 3-amino-4-(4-fluorophenylamino)-1H-pyrazolo[4,3-c]quinoline (42) combined with chemotherapeutic CPT-11 treatment prevented CPT-11-induced serious diarrhea while maintaining the antitumor efficacy in tumor-bearing mice. Importantly, the inhibitory effects of 42 to E. coli beta G was reduced as the pH decreased due to the various surface charges of the active pocket of the enzyme, which may make their combination more favorable at neutral pH. These results demonstrate novel insights into the potent bacterial beta G-specific inhibitor that would allow this inhibitor to be used for the purpose of reducing drug toxicity.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available