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The development of specific anti-angiogenic agents that could serve as anticancer chemotherapeutic agents is an important goal. In 2006, Kobayashi isolated the cortistatins from the marine sponge Corticium simplex. Cortistatin A 12 is the most active member of this family. It exhibits antiproliferative activity against human umbilical vein endothelial cells at nM concentrations. The total synthesis of the cortistatins and designed materials with cortistatin-like properties is one of the goals of our laboratory. We have developed these methods and have applied them to the first total syntheses of several molecules of biological importance, including manzamine A, 1, saudin, 2 , and ingenol, 3. Current efforts in our laboratory are focused toward the synthesis of nakadomarin, 4, a structurally complex hexacyclic alkaloid that displays a range of promising biological activities including cytotoxic activity against murine lymphoma L1210 cells, inhibitory activity against cyclin dependent kinase 4, and anti-microbial activity against a fungus and a Gram-positive bacterium. We have also demonstrated that manipulation of the structure of 1 via Grubbs metathesis leads to the formation of novel structures, i.e., 5, with antibacterial properties comparable to those of ciprofloxacin.
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