Skeletal diversity construction via a branching synthetic strategy

Wyatt, Emma E.; Fergus, Suzanne; Galloway, Warren R. J. D.; Bender, Andreas; Fox, David J.; Plowright, Alleyn T.; Jessiman, Alan S.; Welch, Martin; Spring, David R.

doi:10.1039/b607710b

Cited by 96 publications

(55 citation statements)

References 29 publications

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“…Other examples of the use of a pluripotent functional group strategy to generate scaff old diversity in a DOS context can be found in recent reports and reviews 18,49 .…”

Section: Increasing Structural Diversitymentioning

confidence: 99%

“…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 . Th e effi cient generation of multiple molecular scaffolds is regarded as one of the most eff ective methods of increasing the overall structural diversity of a collection of molecules and has been reported to increase the odds of addressing a broad range of biological targets (relative to a single-scaff old library) 3,9,10,14,15,18,19,49 . …”

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confidence: 99%

“…(for example, solid-phase synthesis 55 and fl uorous-based tags 49,57 ) that facilitate product isolation and purifi cation 11 . One of the criticisms that is commonly levelled at DOS is that the method adds little to the understanding and development of synthetic chemistry.…”

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confidence: 99%

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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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“…Other examples of the use of a pluripotent functional group strategy to generate scaff old diversity in a DOS context can be found in recent reports and reviews 18,49 .…”

Section: Increasing Structural Diversitymentioning

confidence: 99%

mentioning

confidence: 99%

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

2010

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“…[9][10][11][12][13][14][15] Whereas compound collections of a common scaffold decorated with diverse building blocks have been synthesized efficiently, [16] there are limited examples of the synthesis of small molecules with a high degree of skeletal diversity (usually by a build-couple-pair strategy). [17][18][19][20][21][22][23][24] Previously, we have used a diazoacetate starting unit to mimic natures divergent synthetic strategy with acetyl CoA (by a pluripotent functional-group strategy) to synthesize compounds with natural-product scaffolds (e.g. cocaine and warfarin).…”

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confidence: 99%

Anti‐MRSA Agent Discovery Using Diversity‐Oriented Synthesis

et al. 2008

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“…Such strategies range from the exploration of unconventional sources of natural compounds (9,10) to the development of synthetic methodologies for the preparation of natural product-like libraries (11)(12)(13)(14)(15) through the diversification of natural product mixtures by combinatorial biosynthesis and related techniques (16 -21).…”

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Chemically engineered extracts as an alternative source of bioactive natural product-like compounds

López

Ramallo²,

Sierra³

et al. 2007

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

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The access to libraries of molecules with interesting biomolecular properties is a limiting step in the drug discovery process. By virtue of a long molecular evolution process, natural products are recognized as biologically validated starting points in structural space for library development. We introduce here a strategy to generate natural product-like libraries. A semisynthetic mixture of compounds was produced by diversification of a natural product extract through the chemical transformation of common chemical functionalities in natural products into chemical functionalities rarely found in nature. The resulting mixture showed antifungal activity against Candida albicans, whereas the starting extract did not show such activity. Bioguided fractionation led to the isolation of a previously undescribed active semisynthetic pyrazole. The result illustrates how biological activity can be generated by designed chemical diversification of a natural product mixture, and represents the proof of principle of an alternative strategy for producing natural product-like libraries from natural products libraries.diversity ͉ natural products N atural products have been invaluable as platforms for developing front-line drugs (1-3). This value is in part due to the fact that their chemical diversity is complementary to the diversity found in synthetic libraries (4). Natural products are sterically more complex and have broader diversity of ring systems compared with synthetic and combinatorial counterparts (4, 5). Those structural features are the result of a long evolutionary selection process (6). Less than one-fifth of the ring systems found in natural products are represented in current trade drugs (7). On the other hand, drug and combinatorial molecules tend to include a higher number of nitrogen-, sulfur-, and halogen-containing groups (4,5,8).Because the identification of new chemotypes for drug development remains an urgent need in many therapeutic areas, innovative strategies for natural products to contribute their full range of chemical diversity are being developed. Such strategies range from the exploration of unconventional sources of natural compounds (9, 10) to the development of synthetic methodologies for the preparation of natural product-like libraries (11-15) through the diversification of natural product mixtures by combinatorial biosynthesis and related techniques (16 -21).We report here a strategy to generate bioactive compounds through chemical diversification of inactive natural product mixtures (i.e., natural extracts). Natural product extracts are natural libraries of complex composition, mostly uncharacterized, that usually contain a high number of molecules with different scaffolds and functionalities.Provided that a significant proportion of the different molecules present in a given extract is chemically altered, a considerable number of compounds will be generated; hence, changes in the biological properties of the mixture could be expected (22, 23).Our approach to modify as many compounds a...

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Skeletal diversity construction via a branching synthetic strategy

Abstract: A branching synthetic strategy was used to efficiently generate structurally diverse scaffolds, which span a broad area of chemical descriptor space, and their biological activity against MRSA was demonstrated.

Cited by 96 publications

References 29 publications

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

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

Anti‐MRSA Agent Discovery Using Diversity‐Oriented Synthesis

Chemically engineered extracts as an alternative source of bioactive natural product-like compounds

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