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ULTRA-POTENT VINA ALKALOIDS: ADDED MOLECULAR COMPLEXITY FURTHER DISRUPTS THE TUBLIN DIMER-DIMER INTERFACE
ULTRA-POTENT VINA ALKALOIDS: ADDED MOLECULAR COMPLEXITY FURTHER DISRUPTS THE TUBLIN DIMER-DIMER INTERFACE
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机译:潜在的挥发性有机碱:增加的分子复杂性进一步破坏了都柏林二聚体-二聚体的界面
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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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机译:公开了合成衍生的20'-羟基-长春花碱衍生物化合物(如长春碱,长春新碱或长春地辛)的合成修饰,其活性比天然产品高出100倍(IC 50 Sub> 50-75 pM vs. 7 nM,HCT116),由于天然产物总合成的进展,现在可以使用。说明性的新超强效长春碱以高得多的亲和力结合微管蛋白,并可能通过战略性地添加额外的构象良好定义的,刚性的和延伸的C20'-而进一步破坏微管蛋白从头至尾的α/β二聚体-二聚体相互作用。尿素沿着相邻的蛋白质-蛋白质界面。增加的分子复杂性被用来显着增强靶标结合和功能性生物学活性,并且代表改善针对蛋白质-蛋白质相互作用的其他天然产物的性质的一般方法。还公开了包含超有效的20'-羟基-长春花碱衍生物化合物的药物组合物和用这种化合物治疗癌细胞的方法。
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