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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 |
| 顯示於類別: | [藥學系(所)] 期刊論文
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