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Ultra-potent vinca alkaloids: added molecular complexity further disrupts the tublin dimer-dimer interface
Ultra-potent vinca alkaloids: added molecular complexity further disrupts the tublin dimer-dimer interface
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机译:超高效的vinca生物碱:增加分子复杂性进一步破坏了Tublin二聚体二聚体界面
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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 (IC50'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.
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