4 years ago

Specific Inhibition of Bacterial β-Glucuronidase by Pyrazolo[4,3-c]quinoline Derivatives via a pH-Dependent Manner To Suppress Chemotherapy-Induced Intestinal Toxicity

Specific Inhibition of Bacterial β-Glucuronidase by Pyrazolo[4,3-c]quinoline Derivatives via a pH-Dependent Manner To Suppress Chemotherapy-Induced Intestinal Toxicity
Yeh-Long Chen, Chih-Hua Tseng, Kai-Wen Cheng, Jaw-Yuan Wang, Ta-Chun Cheng, Yu-Chung Chuang, Cherng-Chyi Tzeng, Yun-Chi Lu, Yu-Lin Leu, Chia-Ning Yang, Tian-Lu Cheng
The direct inhibition of bacterial β-glucuronidase (βG) 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 βG-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 βG 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 βG-specific inhibitor that would allow this inhibitor to be used for the purpose of reducing drug toxicity.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00963

DOI: 10.1021/acs.jmedchem.7b00963

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