Journal of Medicinal Chemistry, volume 60, issue 22, pages 9222-9238

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

Cheng Kai-wen 1
Tseng Chin-Kai 2, 3, 4, 5
Yang Chang Biau 6
Tzeng Cherng-Chyi 4, 7
Cheng Ta-Chun 8
Leu Yu-Lin 9
Chuang Yu-Chung 6
Wang Jaw Yuan 10, 11
Lu Yun Chi 12
CHEN Yeh-Long 5, 7
Cheng Tian-Lu 1, 8, 12, 13, 14
6
 
Department of Life Sciences, National University of Kaohsiung, Kaohsiung 811, Taiwan
9
 
Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City 717, Tainan
Publication typeJournal Article
Publication date2017-11-09
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor7.3
ISSN00222623, 15204804
Drug Discovery
Molecular Medicine
Abstract
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.

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GOST Copy
Cheng K. et al. Specific Inhibition of Bacterial β-Glucuronidase by Pyrazolo[4,3-c]quinoline Derivatives via a pH-Dependent Manner To Suppress Chemotherapy-Induced Intestinal Toxicity // Journal of Medicinal Chemistry. 2017. Vol. 60. No. 22. pp. 9222-9238.
GOST all authors (up to 50) Copy
Cheng K., Tseng C., Yang C. B., Tzeng C., Cheng T., Leu Y., Chuang Y., Wang J. Y., Lu Y. C., CHEN Y., Cheng T. Specific Inhibition of Bacterial β-Glucuronidase by Pyrazolo[4,3-c]quinoline Derivatives via a pH-Dependent Manner To Suppress Chemotherapy-Induced Intestinal Toxicity // Journal of Medicinal Chemistry. 2017. Vol. 60. No. 22. pp. 9222-9238.
RIS |
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RIS Copy
TY - JOUR
DO - 10.1021/acs.jmedchem.7b00963
UR - https://doi.org/10.1021%2Facs.jmedchem.7b00963
TI - Specific Inhibition of Bacterial β-Glucuronidase by Pyrazolo[4,3-c]quinoline Derivatives via a pH-Dependent Manner To Suppress Chemotherapy-Induced Intestinal Toxicity
T2 - Journal of Medicinal Chemistry
AU - Cheng, Kai-wen
AU - Tzeng, Cherng-Chyi
AU - Cheng, Ta-Chun
AU - Leu, Yu-Lin
AU - Chuang, Yu-Chung
AU - CHEN, Yeh-Long
AU - Yang, Chang Biau
AU - Cheng, Tian-Lu
AU - Tseng, Chin-Kai
AU - Wang, Jaw Yuan
AU - Lu, Yun Chi
PY - 2017
DA - 2017/11/09 00:00:00
PB - American Chemical Society (ACS)
SP - 9222-9238
IS - 22
VL - 60
SN - 0022-2623
SN - 1520-4804
ER -
BibTex |
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BibTex Copy
@article{2017_Cheng
author = {Kai-wen Cheng and Cherng-Chyi Tzeng and Ta-Chun Cheng and Yu-Lin Leu and Yu-Chung Chuang and Yeh-Long CHEN and Chang Biau Yang and Tian-Lu Cheng and Chin-Kai Tseng and Jaw Yuan Wang and Yun Chi Lu},
title = {Specific Inhibition of Bacterial β-Glucuronidase by Pyrazolo[4,3-c]quinoline Derivatives via a pH-Dependent Manner To Suppress Chemotherapy-Induced Intestinal Toxicity},
journal = {Journal of Medicinal Chemistry},
year = {2017},
volume = {60},
publisher = {American Chemical Society (ACS)},
month = {nov},
url = {https://doi.org/10.1021%2Facs.jmedchem.7b00963},
number = {22},
pages = {9222--9238},
doi = {10.1021/acs.jmedchem.7b00963}
}
MLA
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MLA Copy
Cheng, Kai-wen, et al. “Specific Inhibition of Bacterial β-Glucuronidase by Pyrazolo[4,3-c]quinoline Derivatives via a pH-Dependent Manner To Suppress Chemotherapy-Induced Intestinal Toxicity.” Journal of Medicinal Chemistry, vol. 60, no. 22, Nov. 2017, pp. 9222-9238. https://doi.org/10.1021%2Facs.jmedchem.7b00963.
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