A Planning Strategy for Diversity‐Oriented Synthesis

Burke, Martin D.; Schreiber, Stuart L.

doi:10.1002/anie.200300626

Cited by 1,424 publications

(788 citation statements)

References 80 publications

(35 reference statements)

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“…DOS requires a forward "synthetic analysis" of the different reaction steps, initiating from simple and similar starting materials towards complex and diverse products (Fig. 1) [8,9]. In this context, the two terms "structural complexity" and "diversity" should be closer examined.…”

Section: Concepts For Small Molecule Synthesismentioning

confidence: 99%

Biology-inspired synthesis of compound libraries

Kaiser

Wetzel

Kumar

et al. 2008

Cell. Mol. Life Sci.

148

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Section: Concepts For Small Molecule Synthesismentioning

confidence: 99%

Biology-inspired synthesis of compound libraries

Kaiser

Wetzel

Kumar

et al. 2008

Cell. Mol. Life Sci.

148

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“…2 ). A successful DOS must address the four principal types of structural diversity mentioned previously 1,4,18,44,46 . Th e most challenging facet of DOS, and of central importance to its success, is the ability to effi ciently incorporate skeletal diversity into a compound collection 1,3,9,10,19,47,48 .…”

mentioning

confidence: 99%

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

2010

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Biologically active molecules can be identifi ed through the screening of small-molecule libraries. Defi ciencies in current compound collections are evidenced by the continuing decline in drugdiscovery successes. Typically, such collections are comprised of large numbers of structurally similar compounds. A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and thus function, is crucial. Diversity-oriented synthesis (DOS) aims to generate such structural diversity in an effi cient manner. Recent years have witnessed signifi cant achievements in the fi eld, which help to validate the usefulness of DOS as a tool for the discovery of novel, biologically interesting small molecules.S mall molecular mass chemical entities (so-called small molecules) have always been of interest in chemistry and biology because of their ability to exert powerful eff ects on the functions of macromolecules that comprise living systems 1 -3 . Indeed, the small-molecule modulation of protein function represents the basis for both medicinal chemistry (wherein molecules are sought to chemically modify disease states) and chemical genetics (wherein molecules are used as ' probes ' to study biological systems 3 -8 . Such chemical modulators are most commonly identifi ed by screening collections or ' libraries ' of small molecules. However, a crucial consideration is what compounds to use 3,9,10 . A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and more importantly function, is a crucial consideration. Th e effi cient creation of functionally diverse small-molecule collections presents a formidable challenge.Traditionally, when a specifi c biological molecule or family of molecules is targeted, the compounds used in the screening process are usually selected or designed on the basis of knowledge of the target structure or the structure of known natural ligands 3,9,11 . Th e selection criteria are dramatically complicated if the subsequent screening is ' unbiased ' ; that is, when the precise nature of the biological target is unknown (for example, in a random drug-discovery screen) 4,3,12 . In such situations, the structural features required in the small molecules cannot be defi ned a priori and it can be argued that the screening of a library of compounds that has been designed to interact with one specifi c biological target (or family of related targets) is not logical, whereas the random screening of many such ' focused ' collections can be extremely time and cost demanding.In general, the identifi cation of biologically active small molecules may be aided by screening functionally diverse compound libraries (that is, libraries that display a broad range of biological activities), as it has been argued that a greater sample of the bioactive chemical universe (that is, of all bioactive molecules) increases the chance of identifying a compound with the desired properties 3,10,13,14 . As a corollary, ...

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“…20 Initial studies were performed on model system 29 in solution, which allowed convenient monitoring of reaction progress by thin-layer chromatography (Scheme 6). Monomer 24, synthesized using chemistry analogous to that employed in the synthesis of 10 (see Supporting Information), was exposed to PhI(OAc)2, yielding 25.…”

Section: Solution-phase Reaction Developmentmentioning

confidence: 99%

Synthesis of a 10,000-Membered Library of Molecules Resembling Carpanone and Discovery of Vesicular Traffic Inhibitors

et al. 2006

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Split-and-pool synthesis of a 10,000-membered library of molecules resembling the natural product carpanone has been achieved. The synthesis features development of solid-phase multicomponent reactions between nitrogen nucleophiles, enones, and hydroxylamines, and a solid-phase application of the Huisgen cycloaddition affording substituted triazoles. The synthesis was performed in highcapacity (500 μm) polystyrene beads using a one bead-one stock solution strategy that enabled phenotypic screens of the resulting library. Using whole-cell fluorescence imaging, we discovered a series of molecules from the carpanone-based library that inhibit exocytosis from the Golgi apparatus. The most potent member of this series has an IC 50 of 14 μM. We also report structureactivity relationships for the molecules exhibiting this interesting phenotype. These inhibitors of exocytosis may be useful reagents for the study of vesicular traffic.

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A Planning Strategy for Diversity‐Oriented Synthesis

Cited by 1,424 publications

References 80 publications

Biology-inspired synthesis of compound libraries

Biology-inspired synthesis of compound libraries

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

Synthesis of a 10,000-Membered Library of Molecules Resembling Carpanone and Discovery of Vesicular Traffic Inhibitors

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