CAS: 10603-45-9; 3-Bromo-1-Methylpyrrolidine

相似化合物

569660-89-5 569660-97-5 939793-16-5

专利信息

专利号:US-10975101-B2
优先权日:2016-05-31
标题:Ultra-potent vinca alkaloids: added molecular complexity further disrupts the tublin dimer-dimer interface
发明人：BOGER DALE
权利人:SCRIPPS RESEARCH INST
摘要:Synthetically-derived and previously inaccessible modifications of 20′-hydroxy-vinca derivative compounds such as vinblastine, vincristine or vindesine are disclosed that are a stunning 100-fold more active than the natural product (IC 50 's 50-75 pM vs 7 nM, HCT116), and are now accessible as a result of advances in the total synthesis of the natural product. Illustrative new ultra-potent vinblastines bind tubulin with much higher affinity and likely further disrupt the tubulin head-to-tail α/β dimer-dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid and extended C20′-urea along the adjacent protein-protein interface. Added molecular complexity was used to markedly enhance target binding and functional biological activity, and represents a general approach to improving the properties of other natural products targeting a protein-protein interaction. A pharmaceutical composition containing an ultra-potent 20′-hydroxy-vinca derivative compound and a method of treating cancerous cells with such a compound are also disclosed.