經化學修飾之斑螫素衍生物對於人類肝癌細胞作用之研究

斑螫素與去甲基斑螫素與其相關結構衍生物之抗癌功效有一部分的原因已被發現是經由抑制癌細胞的磷酸化蛋白所達成。而原本具有抗生素功能的硫氮二烯五環類的結構衍生物近期內也被發現具有導致癌細胞凋亡的生化活性。有鑑於此，我們將合成硫氮二烯五環亞胺類的衍生物來進行抗癌活性與肝毒性的篩選，同時也可以探討合成的衍生物對於人類肝腫瘤細胞株(HCC) HepG2、SK-Hep1 與初代培養鼠肝細胞的細胞毒性。實驗結果與文獻上的資料比對後發現，斑螫素與去甲基斑螫素可以抑制一些癌細胞，例如HL60、HT29、L1210、等等，但是斑螫素肝毒性過高，在初代培養鼠肝細胞內的半致死劑量(IC50)濃度僅21μM，因此而失去臨床上治療的意義。經由我們合成的硫氮二烯五環亞胺類的衍生物3-9與亞胺類的衍生物10-12對於人類肝癌細胞株(HCC)與初代培養鼠肝細胞的測試結果發現，衍生物3-9對於所有細胞並未產生毒性；而衍生物10對於HepG2細胞的半致死劑量為62μM、對於SK-Hep1細胞的半致死劑量為151μM。其他的衍生物，例如衍生物11-12，對於人類肝癌細胞的毒殺效果則與衍生物10非常接近。由於衍生物3-12對於初代培養鼠肝細胞的半致死劑量均大於200μM，以此類衍生物的化學結構特徵上，發現合成的硫氮二烯五環亞胺類的衍生物化學結構與活性的關係(SAR)證明了酸酐結構的抗癌功效與刪除橋氧結構可以減低肝毒性的作用。

關鍵字

斑螫素衍生物；硫氮二烯五環亞胺；人類肝癌細胞

並列摘要

The anticancer activities of cantharidin, norcantharidin and their analogues have been discussed by suppressing the activity of serine/threonine protein phosphatases. The thiazole derivatives are considered as a kinds of antibiotic which can induce apoptosis in human cancer cells. Synthetic thiazolylimide analogues and anhydride analogues were screened and test for their anticancer activities and cytotoxic effects on human hepatocellular carcinoma cell (HCC) lines HepG2, SK-Hep1 and primary cultured rat hepatocytes. Experimental deta had shown that cantharidin, norcantharidin and their analogues displayed an anticancer effect due to their inhibition activities on these cell lines (HL60, HT29, L1210, etc.). However, cantharidin cannot be used as an anticancer reagent because of its high cytotoxicity in vitro (IC50 = 21μM in primary cultured rat hepatocytes). Synthetic cantharidin analogues with aminothiazole structure 3-9 and anhydride structure 10-12 were screened and tested for anticancer activities and cytotoxic effects on human hepatocellular carcinoma cell (HCC) lines HepG2, Sk-Hep1 and primary cultured rat hepatocytes. From the results of our experiments, We observed compounds 3-9 did not perform as expected, with regard to anticancer activity and they exhibited lower cytotoxicity. Compound 10 promoted apoptosis in HepG2 (IC50 = 62μM) and SK-Hep1 (IC50 = 151μM) cell lines. Compounds 11 and 12 had a similar anticancer potentiality to compound 10. After treatment with compounds 3-12 no cytotoxicity reaction was observed in primary cultured rat hepatocytes (IC50 > 200μM). In order to investigate and study the structure activity relationship (SAR) of these analogues, we suggest that anhydride ether oxygen such as in compounds 1,2,10-12 may be correlated with HCC survival and the elimination of bridging ether oxygen on the ring such as 10-12 can decrease their cytotoxicities.

並列關鍵字

Cantharidin anhydride analogues ； Aminothiazole analogues ； Hepatocellular carcinoma cell

參考文獻

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經化學修飾之斑螫素衍生物對於人類肝癌細胞作用之研究

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