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    Please use this identifier to cite or link to this item: http://ir.cnu.edu.tw/handle/310902800/31704


    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
    Appears in Collections:[藥學系(所)] 期刊論文

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