Structural Diversity of Organic Chemistry. A Scaffold Analysis of the CAS Registry

Lipkus, Alan H.; Yuan, Qiong; Lucas, Karen A.; Funk, Susan A.; Bartelt, William F.; Schenck, Roger J.; Trippe, Anthony J.

doi:10.1021/jo8001276

Cited by 284 publications

(277 citation statements)

References 36 publications

(62 reference statements)

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“…In particular, there is a demand for compounds with atypical molecular scaff olds. Th e known universe of organic chemistry is generally dominated by a remarkably small number of molecular scaff olds; for example, in a recent study of known cyclic molecules, 0.25 % of the molecular frameworks were found in 50 % of known compounds 9,42 . Th is scenario demonstrates a clear need for novel molecular scaff olds to explore and exploit uncharted regions of chemical space 43 .…”

Section: New Compound Collectionsmentioning

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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Section: New Compound Collectionsmentioning

confidence: 99%

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

2010

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“…Recent analyses of large data sets of synthetic compounds have indicated that a major part of them is presented by a small percentage of scaffolds and the same is true for drug molecules 65 . The redundancy in the scaffolds representing compound libraries that are used in the discovery research severely restrains the biological scope of the small molecules.…”

Section: Discussionmentioning

confidence: 98%

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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“…2 In this regard, the development of new macrocyclic scaffolds has been of interest 3,4 due to a view that there is a lack of macrocyclic scaffolds in screening collections. 5,6 Motivated to address this, we approached the convergent assembly of a macrocycle, which could be concisely assembled, and facilitate decoration of the scaffold with pharmacophoric groups.…”

Section: Supporting Information Placeholdermentioning

confidence: 99%

Decorated Macrocycles via Ring-Closing Double-Reductive Amination. Identification of an Apoptosis Inducer of Leukemic Cells That at Least Partially Antagonizes a 5-HT2 Receptor

et al. 2015

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Structural Diversity of Organic Chemistry. A Scaffold Analysis of the CAS Registry

Cited by 284 publications

References 36 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

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

Decorated Macrocycles via Ring-Closing Double-Reductive Amination. Identification of an Apoptosis Inducer of Leukemic Cells That at Least Partially Antagonizes a 5-HT2 Receptor

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