Orally Active Fumagillin Analogues: Transformations of a Reactive Warhead in the Gastric Environment

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• 作者：Christopher C. Arico-Muendel ; Heather Blanchette ; Dennis R. Benjamin ; Teresa M. Caiazzo ; Paolo A. Centrella ; Jennifer DeLorey ; Elisabeth G. Doyle ; Steven R. Johnson ; Matthew T. Labenski ; Barry A. Morgan ; Gary O鈥橠onovan ; Amy A. Sarjeant ; Steven Skinner ; Charles D. Thompson ; Sarah T. Griffin ; William Westlin ; Kerry F. White
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：4
• 期：4
• 页码：381-386
• 全文大小：330K
• 年卷期：v.4,no.4(April 11, 2013)
• ISSN：1948-5875

文摘

Semisynthetic analogues of fumagillin, 1, inhibit methionine aminopeptidase-2 (MetAP2) and have entered the clinic for the treatment of cancer. An optimized fumagillin analogue, 3 (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, 3 underwent ring-opening addition of water and HCl, leading to four products, 4鈥?, 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 6 was shown to revert rapidly to 3 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.

Keywords:

Fumagillin; MetAP2; PPI-2458; angiogenesis inhibitor; irreversible inhibitor