Synthesis and biological activity of Δ-5,6-norcantharimides: Importance of the 5,6-bridge

Ali Thaqi, Janet L. Scott, Jayne Gilbert, Jenette A. Sakoff, Adam McCluskey

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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, Δ-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.
Original languageEnglish
Pages (from-to)1717-1723
JournalEuropean Journal of Medicinal Chemistry
Volume45
Issue number5
DOIs
Publication statusPublished - May 2010

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norcantharidin
Bioactivity
Pyrroles
Anhydrides
Phosphoprotein Phosphatases
Cantharidin
Protein Phosphatase 1
Protein Phosphatase 2
Cytotoxins
Tumor Cell Line
Phosphoric Monoester Hydrolases
Tumors
Neoplasms
Display devices
Cells
Oxygen

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Synthesis and biological activity of Δ-5,6-norcantharimides: Importance of the 5,6-bridge. / Thaqi, Ali; Scott, Janet L.; Gilbert, Jayne; Sakoff, Jenette A.; McCluskey, Adam.

In: European Journal of Medicinal Chemistry, Vol. 45, No. 5, 05.2010, p. 1717-1723.

Research output: Contribution to journalArticle

Thaqi, Ali ; Scott, Janet L. ; Gilbert, Jayne ; Sakoff, Jenette A. ; McCluskey, Adam. / Synthesis and biological activity of Δ-5,6-norcantharimides: Importance of the 5,6-bridge. In: European Journal of Medicinal Chemistry. 2010 ; Vol. 45, No. 5. pp. 1717-1723.
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