Carney, Daniel W.; Lukesh, John C. III; Brody, Daniel M.; Brutsch, Manuela M.; Boger, Dale L. published the artcile< Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer-dimer interface>, Application of C4H3NO3, the main research area is ultrapotent vinblastine derivative preparation tubulin binding cancer; chemical synthesis; drug design; protein–protein interaction; tubulin; vinblastine.
Approaches to improving the biol. properties of natural products typically strive to modify their structures to identify the essential pharmacophore, or make functional group changes to improve biol. target affinity or functional activity, change phys. properties, enhance stability, or introduce conformational constraints. Aside from accessible semisynthetic modifications of existing functional groups, rarely does one consider using chem. synthesis to add mol. complexity to the natural product. In part, this may be attributed to the added challenge intrinsic in the synthesis of an even more complex compound Herein, we report synthetically derived, structurally more complex vinblastines inaccessible from the natural product itself that are a stunning 100-fold more active (IC50 values, 50-75 pM vs. 7 nM; HCT116), and that are now accessible because of advances in the total synthesis of the natural product. The newly discovered ultrapotent vinblastines, which may look highly unusual upon first inspection, 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 continuing protein-protein interface. In this case, the added mol. complexity was used to markedly enhance target binding and functional biol. activity (100-fold), and likely represents a general approach to improving the properties of other natural products targeting a protein-protein interaction.
Proceedings of the National Academy of Sciences of the United States of America published new progress about Colorectal carcinoma. 672948-03-7 belongs to class chlorides-buliding-blocks, and the molecular formula is C4H3NO3, Application of C4H3NO3.
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