title: Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer-dimer interface.
abstract: 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.
authors: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037.
authors: Daniel W
authors: DW
authors: Carney
authors: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037.
authors: John C
authors: JC
authors: Lukesh
authors: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037.
authors: Daniel M
authors: DM
authors: Brody
authors: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037.
authors: Manuela M
authors: MM
authors: Brütsch
authors: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037 Boger@scripps.edu.
authors: Dale L
authors: DL
authors: Boger
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology; D014508:Urea / Q000737:chemistry*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014748:Vinca Alkaloids / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; D014404:Tubulin; D050257:Tubulin Modulators; D014748:Vinca Alkaloids; C009667:vindoline; D014747:Vinblastine; D014508:Urea; C017836:catharanthine
keywords: chemical synthesis; drug design; protein–protein interaction; tubulin; vinblastine