Synthesis and biological activity of Delta-5,6-norcantharimides: importance of the 5,6-bridge.
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.
Thaqi
Ali
A
Centre for Green Chemistry, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
Scott
Janet L
JL
Gilbert
Jayne
J
Sakoff
Jennette A
JA
McCluskey
Adam
A
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002193:Cantharidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D002193:Cantharidin