Angiogenesis, a formation of new blood capillaries from preexisting blood vessels, is critical for tumor growth and metastasis. A growing tumor needs an extensive network of capillaries to provide nutrients and oxygen etc. In addition, the new blood vessels provide a way for tumor cells to enter in the circulation and to metastasize to another organ. Therefore, substances that inhibit the angiogenesis have a considerable potential to be therapeutic agents. In the course of our study on the bioactive substances from marine organisms, we focused on a search for anti-angiogenic substances and isolated bastadins from the Indonesian marine sponge of Ianthella basta. Bastadins were cyclic tetramers of brominated-tyrosine. Among of them, bastadin 6, a major constituent, showed a selective growth inhibition against human umbilical vein endothelial cells (HUVECs) whereas it showed a weak growth inhibition against fibroblast (3Y1) and tumor cells (KB3-1, K562, Neuro2A). The effect was enhanced under the basic fibroblast growth factor (bFGF)- or vascular endothelial growth factor (VEGF)-dependent proliferative conditions. Bastadin 6 also inhibited in vitro VEGF-induced migration and bFGF-induced tube formation of HUVEC. Moreover, bastadin 6 almost completely blocked VEGF and bFGF-induced neovascularization in the in vivo mouse corneal assay. We also studied total synthesis of bastadin 6 in order to establish a practical synthetic method for further biological analysis. According to the reported method by Sih et al., utilizing the enzymatic oxidative coupling of bromophenols as the key reaction, we developed an improved synthetic route by changing starting materials and reaction conditions, and achieved a convergent total synthesis of bastadin 6.
