肝臟葡萄醣醛酸化是人體主要的解毒代謝路徑，有毒物質(如化療藥物、致癌劑)藉由和葡萄醣醛酸鍵結而降低毒性。然而，當此類葡萄醣醛酸代謝物經由膽汁進入到腸道後，會被腸道菌所表現的葡萄醣醛酸酶水解而恢復其毒性，因此破壞腸道細胞造成腸道毒性，長久累積將誘發腸道腫瘤生成及病變。因此，開發腸道菌葡萄醣醛酸酶專一性抑制劑降低其活性，將可以避免有毒物質在腸道內的再活化及釋放，進而保護腸道避免化學誘發損傷。在本研究中，我們篩選出哌唑[4,3-c]喹啉衍生物(化合物42)，其可作為大腸桿菌葡萄醣醛酸酶專一性抑制劑，有效降低小鼠腸道中腸道菌葡萄醣醛酸酶活性。將化合物42合併化療藥CPT-11治療，可有效降低CPT-11誘發小鼠嚴重腹瀉，並且不影響CPT-11抗癌療效。此外，以化合物42餵食腸道多發性腺瘤小鼠可有效降低致癌劑DMH誘發腸道瘜肉生成。因此，化合物42具有相當之潛力作為化療佐劑及化學預防劑用於預防化學誘發腸道毒性並且預防大腸癌生成。

Hepatic glucuronidation is a major route for detoxification. Drugs and carcinogens are conjugated with glucuronic acid to be inactive. However, the inactive glucuronides are reactivated back to active toxins by bacterial β-glucuronidase (βG) in the intestine, thus inducing severe intestinal toxicity and promoting colon carcinogenesis. Therefore, inhibition of bacterial βG activity by a specific βG inhibitor has potential to protect the intestine from drug- or carcinogen-induced damage. Here, we report the characterization of 3-amino-4-(4-fluorophenylamino)-1H-pyrazolo[4,3-c]quinoline (compound 42), a new E. coli βG (eβG)-specific inhibitor that acts in novel a pH-dependent manner. Notably, the oral administration of compound 42 combined with chemotherapeutic CPT-11 treatment prevented CPT-11-induced serious diarrhea while maintaining the antitumor efficacy in tumor-bearing mice. Moreover, administration with compound 42 also reduced the formation of intestinal tumor polyps in carcinogenic 1,2-dimethylhydrazine (DMH)-treated mice. Together, these results indicate that compound 42 effectively prevents drug-induced diarrhea and carcinogen-induced tumorigenesis in the intestine, and thus has potential for use as a chemotherapy adjuvant and a chemoprevention agent to prevent chemical-induced intestinal toxicity and the development of colorectal cancer.

Table of Contents
誌謝 i
中文摘要 ii
Abstract iii
List of Figures vi
List of Tables vii
Abbreviations viii
Introduction 1
Chapter 1
Screening and characterization of a specific and potent bacterial βG inhibitor 4
1.1 Introduction 4
1.2 Results 5
1.2.1 Screening for eβG-specific inhibitors 5
1.2.2 Inhibition of eβG enzyme activity by pyrazolo[4,3-c]quinolines 11
1.2.3 Inhibition of endogenous eβG activity and toxicity in E. coli 17
1.2.4 Microbial βG activity inhibition in mice intestine 19
1.2.5 Molecular docking of compound 42 to βG enzymes 21
1.2.6 pH-dependent inhibition of eβG by compound 42 24
1.3 Materials and Methods 26
1.3.1 Compounds 26
1.3.2 βG enzyme activity assay 26
1.3.3 Synthesized compounds 27
1.3.4 E. coli βG activity assay 34
1.3.5 E. coli cell viability 35
1.3.6 Image of bacterial βG activity in mice intestine 35
1.3.7 Mice fecal βG activity assay 36
1.3.8 Molecular docking 37
1.3.9 Molecular dynamics simulations 37
1.3.10 Binding free energy calculations 39
1.3.11 pH-dependent βG activity assay 41
1.3.12 Electrostatic potential surface 41
1.4 Discussion 41
Chapter 2
Specific inhibition of bacterial βG activity to suppress chemotherapy-induced diarrhea 45
2.1 Introduction 45
2.2 Results 47
2.2.1 Pharmacokinetics studies of compound 42 47
2.2.2 Suppression of CPT-11-induced intestinal damage by compound 42 51
2.2.3 Effects of compound 42 on CPT-11 treatment in tumor-bearing mice 53
2.3 Materials and Methods 55
2.3.1 Pharmacokinetic study of compound 42 in rats 55
2.3.2 Mice model of CPT-11-induced intestinal damage 55
2.3.3 CPT-11 therapeutic efficacy and diarrhea in tumor-bearing mice 56
2.4 Discussion 57
Chapter 3
Bacterial βG-specific inhibitor as a chemopreventive agent for carcinogen-induced intestinal tumorigenesis 61
3.1 Introduction 61
3.2 Results 64
3.2.1 Microbial βG activity inhibition in the intestine of APCmin/+ mice 64
3.2.2 Chemoprevention efficacy of compound 42 in intestinal tumorigenesis 67
3.2.3 Histopathogical changes in the intestine of APCmin/+ mice 70
3.3 Materials and Methods 73
3.3.1 Carcinogen-induced tumorigenesis models 73
3.3.2 Bacterial βG activity analysis 73
3.3.3 Histological analysis 74
3.4 Discussion 75
Conclusion 79
References 83
Appendices 92
Appendix I: Publications 92
Appendix II: Patents 98
Appendix III: Achievement 99

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