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

doi:10.1021/acs.jmedchem.7b00963

Chia Nan University of Pharmacy & Science Institutional Repository > 藥理學院 > 藥學系(所) > 期刊論文 > Item 310902800/31704

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標題:	Specific Inhibition of Bacterial beta-Glucuronidase by Pyrazolo[4,3-c]quinoline Derivatives via a pH-Dependent Manner To Suppress Chemotherapy-Induced Intestinal Toxicity
作者:	Cheng, Kai-Wen Tseng, Chih-Hua Yang, Chia-Ning Tzeng, Cherng-Chyi Cheng, Ta-Chun Leu, Yu-Lin Chuang, Yu-Chung Wang, Jaw-Yuan Lu, Yun-Chi Chen, Yeh-Long Cheng, Tian-Lu
貢獻者:	Natl Sun Yat Sen Univ, Inst Biomed Sci Kaohsiung Med Univ, Sch Pharm Kaohsiung Med Univ, Dept Fragrance & Cosmet Sci Kaohsiung Med Univ, Res Ctr Nat Prod & Drug Dev Kaohsiung Med Univ, Ctr Infect Dis & Canc Res Natl Univ Kaohsiung, Dept Life Sci Kaohsiung Med Univ, Dept Med & Appl Chem Kaohsiung Med Univ, Ctr Biomarkers & Biotech Drugs Chia Nan Univ Pharm & Sci, Dept Pharm Kaohsiung Med Univ, Coll Med, Grad Inst Clin Med Kaohsiung Med Univ,Kaohsiung Med Univ Hosp, Dept Surg, Div Gastroenterol & Gen Surg Kaohsiung Med Univ, Coll Med, Grad Inst Med Kaohsiung Med Univ, Dept Biomed & Environm Biol Kaohsiung Med Univ,Kaohsiung Med Univ Hosp, Dept Med Res
關鍵字:	Irinotecan Hydrochloride Cpt-11 Cancer Drug Toxicity Induced Diarrhea Mechanical Calculations Colon Carcinogenesis Antitumor Agent Rats Microflora Electrostatics Simulations
日期:	2017-11-23
上傳時間:	2018-11-30 15:53:34 (UTC+8)
出版者:	Amer Chemical Soc
摘要:	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.
關聯:	Journal of Medicinal Chemistry, v.60, n.22, pp.9222-9238
显示于类别:	[藥學系(所)] 期刊論文

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