臺灣博碩士論文加值系統

日本血吸蟲麩胺基硫轉換酶(簡稱SjGST)，目前是治療日本血吸蟲病的一個主要的用藥抑制目標。此酵素在蟲體內不只是負責代謝外來的毒素，而且對於血吸蟲的抗藥性也佔了很大的影響。了解SjGST催化不同受質的情形，可以進而推測蟲體內利用榖胱甘肽(glutathione, GSH)來代謝受質的代謝機制，並利於新藥的開發研究。從24個親電性化合物中，我們篩選出5個SjGST的受質(化合物7、8、16、20和23)並經由SjGST的催化合成，得到榖胱甘肽共軛物(簡稱GSR，化合物25、26、27、28、29、42和43)。這些GSR的立體結構判斷，可利用核磁共振技術 (1H-, 13C-NMR, COSY, HMQC, HMBC)以及質譜來確定其產物的結構。SjGST催化不同的受質時，會有不同的速率差異(速率大小：化合物16＞23＞20＞7)。且化合物 5、6、12、14、15、13和21是可以進行化學自發反應來產生其相對應的產物GSR(化合物 35、36、37、38、39、40和41)，我們首次發現，化學自發反應產生的GSR會是SjGST的抑制劑，其抑制濃度均可達到μM左右，其中抑制效果比較好的化合物為36，其的IC50小於10μM，而39 的IC50為4.53 μM。

SjGST (Schistosoma japonicum Glutathione S-transferase), an attractive drug target against schistosomiasis, not only mediates detoxification in xenobiotic process but also implicates in the development of drug resistance. Knowledge of SjGST catalysis toward various substrates will reveal glutathione-dependent metabolism in parasite and disclose the development of new drugs. 5 out of 24 compounds (7、8、16、20 and 23) demonstrate exclusively SjGST-dependent catalysis of detoxification to afford glutathione conjugates (25、26、27、28、29、42 and 43). Metabolic products of glutathione conjugates were prepared through the strategy of enzymatic synthesis in preparative scale and characterized by 1H-, 13C-NMR, COSY, HMQC, HMBC and mass spectroscopy. Compounds 5、6、12、14、15、13 and 21 were able to produce glutathione conjugates (35、36、37、38、39、40 and 41) via chemical reactions. Interestingly，we discovered that the glutathione conjugates derived from chemical reactions displayed significant inhibitory properties toward SjGST. For example, compounds 36 and 39 have a value of IC50 ＜10μM.

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