Superpotent Banca alkaloids: added molecular complexity further destroys the dimer dimer interface of tubulin

摘要

Disclosed are previously difficult to obtain synthetically derived variants of 20'-hydroxy-vinca derived compounds such as vinblastine, vincristine or vindesine. These are surprisingly 100-fold more active than natural products (IC50 vs. 7 nM of 50-75 pM, HCT116) and are now available as a result of the progress of total synthesis of natural products. An illustrative new super-strong vinblastine has a much higher affinity, thanks to the strategic placement of C20'-urea extended along the added conformationally well-defined tight and flanking protein-protein interface It may bind to tubulin and further disrupt tubulin's head-to-tail α / β dimer-dimer interaction. The complexity of the added molecules was used to significantly enhance target binding and functional biological activity. This is a general approach to improving the properties of other natural products that target protein-protein interactions. Also disclosed are pharmaceutical compositions containing a superpotent 20'-hydroxy-vinca derivative compound and methods of treating cancerous cells with the compound. [Selection figure] None