Angiogenesis is a complex process involving several distinct and sequential steps; abnormal angiogenesis often occurs in pathological conditions such as cancer, rheumatoid arthritis, diabetic retinopathy, and other chromic inflammatory diseases. Inhibition of angiogenesis is emerging as a promising strategy for the treatment of angiogenesis-related diseases. Several natural product based angiogenesis inhibitors are currently undergoing clinical trials. Recently, Osada and co-workers, isolated a small amount of azaspirene from the fungus Neosartorya sp. Azaspirene displayed a 27.1 mu/M inhibition of cell migration in human umbilical vein endothelial cells (HUVECs). These results suggest that azaspirene is a promising angiogenesis inhibitor. For potential drug therapy to be possible, there must be significant quantities of the desired agents available.
The specific aim of this proposal is to prepare analogs of azaspirene by fluorous mixture synthesis, a synthetic technology that has been established in the Curran research group. We plan to investigate the structural and biological understanding in this area by providing access to azaspirene-like drug candidates. The established techniques of fluorous mixture synthesis will allow us to make a series of azaspirene analogs in a highly efficient manner. These analogs can then be evaluated to gain a better understanding of the mode of action and structural activity relationships.
