Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer-dimer interface
| Autor: | Dale L. Boger, Daniel M. Brody, Daniel W. Carney, John C. Lukesh, Manuela M. Brütsch |
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| Rok vydání: | 2017 |
| Předmět: |
Nanotechnology
Chemistry Techniques Synthetic 010402 general chemistry Vinblastine 01 natural sciences Chemical synthesis Protein Structure Secondary Protein–protein interaction chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship Tubulin Cell Line Tumor Humans Urea Protein Interaction Domains and Motifs Vinca Alkaloids Biological Products Multidisciplinary Natural product Binding Sites biology 010405 organic chemistry Total synthesis Biological activity HCT116 Cells Antineoplastic Agents Phytogenic Tubulin Modulators 0104 chemical sciences chemistry Biological target Drug Design Physical Sciences Biophysics biology.protein Pharmacophore Protein Multimerization Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 113(35) |
| ISSN: | 1091-6490 |
| Popis: | Approaches to improving the biological properties of natural products typically strive to modify their structures to identify the essential pharmacophore, or make functional group changes to improve biological target affinity or functional activity, change physical properties, enhance stability, or introduce conformational constraints. Aside from accessible semisynthetic modifications of existing functional groups, rarely does one consider using chemical synthesis to add molecular 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 molecular complexity was used to markedly enhance target binding and functional biological activity (100-fold), and likely represents a general approach to improving the properties of other natural products targeting a protein–protein interaction. |
| Databáze: | OpenAIRE |
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