1 research outputs found
Orally Active Fumagillin Analogues: Transformations of a Reactive Warhead in the Gastric Environment
Semisynthetic
analogues of fumagillin, <b>1</b>, inhibit methionine aminopeptidase-2
(MetAP2) and have entered the clinic for the treatment of cancer.
An optimized fumagillin analogue, <b>3</b> (PPI-2458), was found
to be orally active, despite containing a spiroepoxide function that
formed a covalent linkage to the target protein. In aqueous acid, <b>3</b> underwent ring-opening addition of water and HCl, leading
to four products, <b>4–7</b>, which were characterized
in detail. The chlorohydrin, but not the diol, products inhibited
MetAP2 under weakly basic conditions, suggesting reversion to epoxide
as a step in the mechanism. In agreement, chlorohydrin <b>6</b> was shown to revert rapidly to <b>3</b> in rat plasma. In
an ex vivo assay, rats treated with purified acid degradants demonstrated
inhibition of MetAP2 that correlated with the biochemical activity
of the compounds. Taken together, the results indicate that degradation
of the parent compound was compensated by the formation of active
equivalents leading to a pharmacologically useful level of MetAP2
inhibition