A two-directional strategy for the diversity-oriented synthesis of macrocyclic scaffolds

O’Connell, Kieron M. G.; Beckmann, Henning S. G.; Laraia, Luca; Horsley, Helen; Bender, Andreas; Venkitaraman, Ashok R.; Spring, David R.

doi:10.1039/c2ob26272j

Cited by 35 publications

(28 citation statements)

References 43 publications

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“…[12][13][14] Natural products are (typically) complex molecules that have enjoyed notable success in drug discovery. To fill this gap, several creative strategies for the generation of such compounds have been devised, including diversity-oriented synthesis, [21][22][23][24][25][26][27] biology-oriented synthesis, [28] synthesis of naturalproduct-inspired scaffolds, [29][30][31][32] synthesis of chiral, conformationally constrained oligomers, [33,34] and synthesis of compounds to probe biological/chemical space. For example, FK506 (Tacrolimus) binds simultaneously to the proteins FKBP12 and calcineurin, [16] vinblastine binds tubulin and inhibits its assembly into microtubules, [17] and ET-743 (Yondelis) selectively and covalently alkylates specific sequences within the minor groove of DNA.…”

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Synthesis of Complex and Diverse Compounds through Ring Distortion of Abietic Acid

et al. 2013

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Many compound screening collections are populated by members that possess a low degree of structural complexity. In an effort to generate compounds that are both complex and diverse, we have developed a strategy that uses natural products as a starting point for complex molecule synthesis. Herein we apply this complexity-to-diversity approach to abietic acid, an abundant natural product used commercially in paints, varnishes, and lacquers. From abietic acid we synthesize a collection of complex (as assessed by fraction of sp(3) -hybridized carbons and number of stereogenic centers) and diverse (as assessed by Tanimoto analysis) small molecules. The 84 compounds constructed herein, and those created through similar efforts, should find utility in a variety of biological screens.

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Synthesis of Complex and Diverse Compounds through Ring Distortion of Abietic Acid

et al. 2013

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“…An example of a final compound, 10, synthesized using this approach is shown in Scheme 2. The linker units between the reactive groups can be regarded as 'scaffold elements' in the sense that different combinations of appropriately functionalized scaffold elements will lead directly to distinct macrocycle scaffolds (with two distinct scaffolds accessible for every combination of reactive linear precursors, depending on the macrocyclisation process employed)[28]. In principle therefore the combinatorial variation of scaffold elements could be used to rapidly and efficiently access a large range of unique scaffolds.…”

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Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

Galloway¹,

Spring²

2013

Diversity Oriented Synthesis

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Medicinal chemistry research has traditionally focused upon a limited set of biological targets. Many other human disease-related targets have been termed ‘undruggable’ as they have proved largely impervious to modulation by small molecules. However, it is becoming increasingly evident that such targets can indeed be modulated; they are simply being challenged with the wrong types of molecules. Traditionally, screening libraries were composed of large numbers of structurally similar compounds. However, library size is not everything; the structural diversity of the library, which is largely dictated by the range of molecular scaffolds present, is crucial. Diversity-oriented synthesis (DOS) generates small molecule libraries with high levels of scaffold, and thus structural, diversity. Such collections should provide hits against a broad range of targets with high frequency, including ‘undruggable’ targets. Examples in the area of scaffold diversity generation taken from the author’s laboratories are given.

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“…One avenue to identify an antimitotic compound is by conducting a phenotypic screen for mitotic arrest. Therefore we focused our attention on a high-content screen using automated microscopy 35,36 . The screen was performed using U2OS osteosarcoma cells, which were incubated for 20 h with all of the library compounds, stained for the mitotic marker phosphohistone H3 and imaged on a Cellomics Arrayscan high-content microscope.…”

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

et al. 2014

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The synthesis of diverse three-dimensional libraries has become of paramount importance for obtaining better leads for drug discovery. Such libraries are predicted to fare better than traditional compound collections in phenotypic screens and against difficult targets. Herein we report the diversity-oriented synthesis of a compound library using rhodium carbenoid chemistry to access structurally diverse three-dimensional molecules and show that they access biologically relevant areas of chemical space using cheminformatic analysis. Highcontent screening of this library for antimitotic activity followed by chemical modification identified 'Dosabulin', which causes mitotic arrest and cancer cell death by apoptosis. Its mechanism of action is determined to be microtubule depolymerization, and the compound is shown to not significantly affect vinblastine binding to tubulin; however, experiments suggest binding to a site vicinal or allosteric to Colchicine. This work validates the combination of diversity-oriented synthesis and phenotypic screening as a strategy for the discovery of biologically relevant chemical entities.

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A two-directional strategy for the diversity-oriented synthesis of macrocyclic scaffolds

Cited by 35 publications

References 43 publications

Synthesis of Complex and Diverse Compounds through Ring Distortion of Abietic Acid

Synthesis of Complex and Diverse Compounds through Ring Distortion of Abietic Acid

Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

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

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