RK-805, an endothelial-cell-growth inhibitor produced by Neosartorya sp., and a docking model with methionine aminopeptidase-2

We found that a fungus Neosartorya sp. produced an angiogenesis inhibitor, RK-805. By spectroscopic analyses and semi-synthetic methods from fumagillin, the structure of RK-805 was identified as 6-oxo-6-deoxyfumagillol, which has not been reported as a natural product. RK-805 preferentially inhibited the growth of human umbilical vein endothelial cells (HUVECs) rather than that of human normal fibroblast in cell proliferation assays and blocked endothelial cell migration induced by vascular endothelial growth factor (VEGF). Moreover, RK-805 selectively inhibited methionine aminopeptidase-2 (MetAP2), but not methionine aminopeptidase-1 (MetAP1). The docked structure of RK-805 complexed with human MetAP2 indicated that not only a covalent bond between a nucleophilic imidazole nitrogen atom of His231 and the carbon of the reactive spirocyclic epoxide of RK-805, but also a hydrogen bond between NH (Asn329) and the carbonyl group of RK-805 at C-6 promote close contact in the binding pocket of the enzyme. Taken together, these results suggest that structure activity relationships of RK-805 derivatives at both C-4 and C-6, in comparison with ovalicin and TNP-470, would be useful for development of new angiogenesis inhibitors.