Illudalic acid is a fungal metabolite isolated from Omphalotus olearus with known biological activity against the human leukocyte common antigen-related phosphatase LAR. Here, we present a total synthesis of the parent compound along with a series of analogs. We have screened this panel of compounds for inhibitory activity against a library of protein tyrosine phosphatase (PTP) enzymes. As expected, illudalic acid is a moderately potent inhibitor of LAR activity with an IC50 value of 2.1 ± 0.2 µM. Interestingly, illudalic acid also inhibits several other PTPs, but is most potent against the receptor-type PTPs including LAR, CD45 and PTPµ. Illudalic acid shows time-dependent inhibition of PTP activity, characteristic of covalent inhibition, and a detailed kinetic and mechanistic analysis has been carried out. Finally, illudalic acid analog IA-25 also inhibits LAR, but does not inhibit any of the other PTPs tested, indicating that PTP selectivity can be obtained through modest structural changes.

Synthesis and biological evaluation of illudalic acid derivatives: Inhibition of protein tyrosine phosphatase activity

2019 Fall National Meeting

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