Generating Diverse Skeletons of Small Molecules Combinatorially

Burke, Martin D.; Berger, Eric M.; Schreiber, Stuart L.

doi:10.1126/science.1089946

Cited by 379 publications

(162 citation statements)

References 22 publications

Supporting

Mentioning

157

Contrasting

Unclassified

Order By: Relevance

“…One example for such a reaction cascade is the introduction of terminal olefins with different chain lengths and subsequent ring closing metathesis. Other reactions used include for instance ring expansion and aldol reactions [13,14]. Another synthetic approach towards skeletal diversity as an example for implementing structural diversity in compound libraries is illustrated in Figure 4 [15].…”

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

View full text Add to dashboard Cite

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Scaff old diversity is thus intrinsically linked to shape, and thus functional, diversity. Indeed, there is a widespread consensus that increasing the scaff old diversity in a small-molecule library is one of the most eff ective ways of increasing its overall structural diversity 3,10,15,19,21 and small multiple scaff old libraries are generally regarded as being superior to large single-scaff old libraries in terms of biorelevant diversity 3,10,14 . Compounds in libraries that are based around diff erent molecular skeletons will display chemical information diff erently in 3D space, thus increasing the range of potential biological binding partners for the library as a whole 3 .…”

Section: Diversity In Compound Collectionsmentioning

confidence: 99%

“…Nature ' sees ' molecules as three-dimensional (3D) surfaces of chemical information; a given biological macromolecule will therefore only interact with those small molecules that have a complementary 3D binding surface 1,3,19 . Th at is, a given biological macromolecule imposes a degree of shape selection for binding partners; molecules possessing signifi cant shape similarity would thus be expected to generate similar pharmacological responses 20 .…”

Section: Diversity In Compound Collectionsmentioning

confidence: 99%

“…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 . 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 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

2010

View full text Add to dashboard Cite

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, ...

show abstract

“…One of the limitations of diversity oriented synthesis is the difficulty in generating high scaffold diversity in as few synthetic steps as possible [3][4][5][6]. As illustrated in Fig.…”

Section: Introductionmentioning

confidence: 99%

1,2,4‐Trisubstituted Cyclopentanes as Platforms for Diversity

Guan

Bissantz

Bergstrom

et al. 2012

Archiv der Pharmazie

View full text Add to dashboard Cite

Despite their simplicity, relatively few examples of 1,2,4 (1,3,4)-amino-, azido-, and hydroxysubstituted cyclopentanes are reported in the literature. We found that cyclopent-3-en-1-ol can be transformed into a significant variety of compounds of this class by relatively common and efficient synthetic procedures. Stereochemical control of epoxidation of the cyclopentene double bond can be achieved by varying the substitutents at C4. The C4 substituent and epoxide functional group can be converted into a variety of intermediates with differential protection designed for use in applications requiring regiospecific control for further elaboration of the cyclopentane scaffold.

show abstract

Generating Diverse Skeletons of Small Molecules Combinatorially

Cited by 379 publications

References 22 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

1,2,4‐Trisubstituted Cyclopentanes as Platforms for Diversity

Contact Info

Product

Resources

About