Centre for Green Chemistry, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
Eur J Med Chem. 2010 May;45(5):1717-23. doi: 10.1016/j.ejmech.2010.01.004. Epub 2010 Jan 14.
Cantharidin (1) and norcantharidin (2) are potent protein phosphatase 1 and 2A inhibitors that also display high levels of anticancer activity against a broad range of tumor cells lines. Surprisingly, Delta-5,6-ethyl norcantharidin (3, cis-tetrahydrofurano[3,4-c]furan-1,3-dione) displays neither phosphatase inhibition nor anticancer activity. This suggests that the 5,6-ethyl bridge is pivotal to both anti-cancer and protein phosphatase activity. Additionally bioisosteric replacement of the ethereal oxygen has no effect on biological activity nor does modification of the anhydride moiety. Unlike the parent norcantharidin, anhydride ring opening has no effect on either protein phosphatase inhibition or anti-cancer activity. Additionally, this work highlights the discovery of the octyl substituted, cis-5-benzyl-2-hexyltetrahydro-2H,3aH-pyrrolo[3,4-c]pyrrole-1,3-dione, 9p, and the octyl substituted, cis-octyltetrahydro-5H-furo[3,4-c]pyrrole-4,6-dione, 8p, as two new cytotoxic agents which are equipotent (9p) with, and more potent (8p) than norcantharidin.
斑蝥素（1）和去甲斑蝥素（2）是有效的蛋白磷酸酶 1 和 2A 抑制剂，对广泛的肿瘤细胞系表现出高水平的抗癌活性。令人惊讶的是，Delta-5,6-乙基去甲斑蝥素（3，顺式四氢呋喃[3,4-c]呋喃-1,3-二酮）既没有磷酸酶抑制作用，也没有抗癌活性。这表明 5,6-乙基桥对于抗癌和蛋白磷酸酶活性都是至关重要的。此外，醚氧的生物等排体替代对生物活性没有影响，也不会影响酸酐部分的修饰。与去甲斑蝥素不同，酸酐环的打开对蛋白磷酸酶抑制或抗癌活性都没有影响。此外，这项工作还揭示了取代的辛基顺式-5-苄基-2-己基四氢-2H,3aH-吡咯并[3,4-c]吡咯-1,3-二酮 9p 和取代的辛基顺式-辛基四氢-5H-呋喃并[3,4-c]吡咯-4,6-二酮 8p 的发现，它们是两种新的细胞毒性剂，与去甲斑蝥素具有同等效力（9p），且比去甲斑蝥素更有效（8p）。
