Diversity-oriented synthesis as a tool for identifying new modulators of mitosis

Ibbeson, Brett M.; Laraia, Luca; Alza, Esther; Connor, Cornelius J. O’; Tan, Yaw Sing; Davies, Huw M. L.; McKenzie, Grahame J.; Venkitaraman, Ashok R.; Spring, David R.

doi:10.1038/ncomms4155

Cited by 77 publications

(53 citation statements)

References 48 publications

(52 reference statements)

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“…6). Substitution of the isoindoline was well tolerated and the series displayed a trend where electron-donating substituents (30,(35)(36)(37)(38)(39) proved slightly more potent than compounds bearing electron-withdrawing substituents (31)(32)(33)(34). Within the former series, further alkylation (37)(38)(39) or acylation (40-53) of the aniline 36 was well tolerated.…”

Section: Resultsmentioning

confidence: 90%

“…This is further complicated by the fact that the manufacture of DE-81 filter paper has been discontinued. As a consequence, we elected to examine a commercially available boron-dipyrromethene (BODIPY)-vinblastine fluorescent probe to assess tubulin binding and to develop and generalize its use in a direct competitive binding assay (30)(31)(32)(33)(34). Although introduced and used principally to visualize protein driven efflux from cells, BODIPY-vinblastine exhibits a significant increase in fluorescence intensity (FI) upon binding to tubulin.…”

Section: Resultsmentioning

confidence: 99%

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Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer–dimer interface

Carney

Lukesh

Brody

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer–dimer interface

Carney

Lukesh

Brody

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…While Lewis acids like BF 3 .OEt 2 or TMSOTf provided only fragmentation products of the azepinone, AlCl 3 yielded an inseparable complex mixture of products (Supplementary Table 2). In a successful case (cascade III), catalytic trifluoroacetic acid (TFA) transformed azepinone 11a into allyl indole (13a; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…S tructural diversity has a profound impact on the performance of a compound collection exposed to biological screenings [1][2][3] . Probe and drug discovery research, therefore, beseech quality-based compound libraries rich in structural diversity 4,5 .…”

mentioning

confidence: 99%

De novo branching cascades for structural and functional diversity in small molecules

et al. 2015

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The limited structural diversity that a compound library represents severely restrains the discovery of bioactive small molecules for medicinal chemistry and chemical biology research, and thus calls for developing new divergent synthetic approaches to structurally diverse and complex scaffolds. Here we present a de novo branching cascades approach wherein simple primary substrates follow different cascade reactions to create various distinct molecular frameworks in a scaffold diversity phase. Later, the scaffold elaboration phase introduces further complexity to the scaffolds by creating a number of chiral centres and incorporating new hetero-or carbocyclic rings. Thus, employing N-phenyl hydroxylamine, dimethyl acetylenedicarboxylate and allene ester as primary substrates, a compound collection of sixty one molecules representing seventeen different scaffolds is built up that delivers a potent tubulin inhibitor, as well as inhibitors of the Hedgehog signalling pathway. This work highlights the immense potential of cascade reactions to deliver compound libraries enriched in structural and functional diversity.

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“…One important strategy, named diversity-oriented synthesis, aims to efficiently synthesize libraries of structurally complex and functionally diverse small molecules, using cheminformatic analysis. The 3D structures of the library are very diverse, allowing one to screen for target effects based upon 3D structure, a major step forward (58).…”

Section: New Approaches To Therapeutic Discoverymentioning

confidence: 99%

Challenging Roadblocks to Cancer Cure

Loda

2016

Cancer Research

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The Pezcoller Symposium in Trento, Italy, June 2015, focused entirely on the question of why advanced cancer cure is so uncommon despite the extraordinarily rapid growth of invaluable therapeutic information. Participants were asked to define and to critically evaluate real and potential obstacles to permanent disease eradication. High-level concepts on potential road blocks to cures as well as opportunities for intervention in diverse areas of investigation ranging from genomic alterations to metabolism, microenvironment, immunity, and mechanotransduction were discussed. Provocative concepts and novel therapeutic avenues were proposed. What follows is a critical analysis of the highlights of this meeting. Cancer Res; 76(17); 4924-30. Ó2016 AACR.

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Diversity-oriented synthesis as a tool for identifying new modulators of mitosis

Cited by 77 publications

References 48 publications

Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer–dimer interface

Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer–dimer interface

De novo branching cascades for structural and functional diversity in small molecules

Challenging Roadblocks to Cancer Cure

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