合成具有醣基之咪唑[4,3-c]喹林生物作為細菌beta葡萄醣醛酸酶的專一性抑制劑

Synthesis of substituted glycosyl-pyrazolo[4,3-c]quinoline derivatives as bacterial beta glucuronidase specific inhibitors

傅偉宸(Wei-Chen Fu)

指導教授 ： 曾志華

高雄醫學大學/藥學院/藥學系博士班/碩士(2015年)

摘要

Irinotecan(Camptosar)(CPT-11) 為化療三大用藥之一，唯其副作用具有噁心、嘔吐，大部分患者會有此症狀，於注射後 1 天內或 24 小時之後產生，故研究方針是針對於CPT-11在肝中經由CE轉化成SN-38此一具有藥物活性之成分，再經由UGT轉化成SN-38G進入胃腸道，但在進入腸道後SN38-G會經由大腸桿菌E-coli　beta葡萄糖醛酸酶又轉化回SN-38，而SN-38會對腸道造成刺激致使出現嘔吐及腹瀉的副作用。
　　目前在實驗室中得知的E-coli　beta葡萄糖醛酸酶抑制活性劑中，氮4-二苯基-1氫-咪唑並[4,3-c]喹淋-3,4-二胺擁有不錯的抑制性，而且對人類的beta葡萄糖醛酸酶是幾乎沒有毒性的。因此，在延續性的研究發展中，我們針對於藥物結構再接上新的醣基做水解酶的標靶探尋，希望可以找到一個對於E-coli　beta 葡萄糖醛酸酶更好的抑制活性，或者利用醣類的水溶性，在醣類被水解酶給水解還原出標靶藥物前，都能夠經由醣基獲得較高的溶解度，在人體腸道中能水解釋放出來，達到一個很好的藥物傳遞效果。
　　本研究計畫是用三種醣類（葡萄糖，木醣，半乳糖）接上標靶藥物做方向性的探尋，製做其衍生物及其含有保護基的結構。

關鍵字

醣基 ； 大腸桿菌 ； 結腸癌

並列摘要

Irinotecan (Camptosar, Pfizer) is a drug for the treatment of cancer. It’s main use in colon cancer, in particular, in combination with 5-fluorouracil. Irinotecan received accelerated approval by FDA in 1996 and full approval in 1998. Now we usually called it CPT-11. However, it has significant side effects such as diarrhea and extreme suppression of the immune system. The dose-limiting side effect of the common colon cancer chemotherapeutic Irinotecan is severe diarrhea caused by symbiotic bacterial beta-glucuronidases (beta G) that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial -glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme.
Irinotecan causes severe diarrhea generated by its complex activation and subsequent metabolism. SN-38 produced by carboxylesterases is glucuronidated in the liver by uridine diphosphate (UDP)–glucuronosyltransferase enzymes to form inactive SN-38G. Once in the intestines,　SN-38G serves as a substrate for bacterial  -glucuronidase enzymes in the commensal microbiota that remove the glucuronide group as a carbon source, producing reactivated SN-38, that caused the diarrhea.
Contain 1H-Pyrazolo[4,3-c]quinolin- 3-amine derivatives were found to possess potent E. coli G (eG) inhibitory activity without inhibition of human G. This thesis is aimed to further improve potency and selectivity of three sugar (glucose, galactose, xylose), Our results indicated that a number of sugar-bearing 1H-Pyrazolo[4,3-c]quinolin- 3-amine derivative exhibited more potent eG inhibitory activity than their respective aglycan counterparts.

並列關鍵字

glycoside ； ecoli ； colon

參考文獻

1. Kong, R.; Liu, T.; Zhu, X.; Ahmad, S.; Williams, A. L.; Phan, A. T.; Zhao, H.; Scott, J. E.; Yeh, L. A.; Wong, S. T., Old drug new use--amoxapine and its metabolites as potent bacterial beta-glucuronidase inhibitors for alleviating cancer drug toxicity. Clin Cancer Res. 2014, 20, 3521-30.

2. Pommier, Y., Topoisomerase I inhibitors: camptothecins and beyond. Nature reviews. Cancer 2006, 6, 789-802.

3. Wall, M. E.; Wani, M. C.; Natschke, S. M.; Nicholas, A. W., Plant antitumor agents. 22. Isolation of 11-hydroxycamptothecin from Camptotheca acuminata Decne: total synthesis and biological activity. J. Med. Chem. 1986, 29, 1553-5.

4. Blandizzi, C.; De Paolis, B.; Colucci, R.; Di Paolo, A.; Danesi, R.; Del Tacca, M., Acetylcholinesterase blockade does not account for the adverse cardiovascular effects of the antitumor drug irinotecan: a preclinical study. Toxicol. Appl. Pharm 2001, 177, 149-56.

5. Hofheinz, R. D.; Kubicka, S.; Wollert, J.; Arnold, D.; Hochhaus, A., Gefitinib in combination with 5-fluorouracil (5-FU)/folinic acid and irinotecan in patients with 5-FU/oxaliplatin- refractory colorectal cancer: a phase I/II study of the Arbeitsgemeinschaft fur Internistische Onkologie (AIO). Onkologie 2006, 29, 563-7.