Discovery of Chemical Reactions through Multidimensional Screening

Beeler, Aaron B.; Su, Shun; Singleton, C. A.; Porco, John A.

doi:10.1021/ja0674744

Cited by 188 publications

(111 citation statements)

References 61 publications

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“…Both protein-binding frequencies and selectivities are increased among compounds having: (i) increased content of sp 3 -hybridized atoms relative to commercial compounds, and (ii) intermediate frequency of stereogenic elements relative to commercial (low frequency) and natural (high frequency) compounds. Encouragingly, these favorable structural features are increasingly accessible using modern advances in the methods of organic synthesis (21)(22)(23)(24)(25)(26) and commonly targeted by academic organic chemists as judged by the compounds used in this study that were contributed by 6. Analysis of binding promiscuity among hit compounds.…”

Section: Discussionmentioning

confidence: 99%

Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles

Clemons

Bodycombe²,

Carrinski³

et al. 2010

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

324

333

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Using a diverse collection of small molecules generated from a variety of sources, we measured protein-binding activities of each individual compound against each of 100 diverse (sequence-unrelated) proteins using small-molecule microarrays. We also analyzed structural features, including complexity, of the small molecules. We found that compounds from different sources (commercial, academic, natural) have different protein-binding behaviors and that these behaviors correlate with general trends in stereochemical and shape descriptors for these compound collections. Increasing the content of sp 3 -hybridized and stereogenic atoms relative to compounds from commercial sources, which comprise the majority of current screening collections, improved binding selectivity and frequency. The results suggest structural features that synthetic chemists can target when synthesizing screening collections for biological discovery. Because binding proteins selectively can be a key feature of high-value probes and drugs, synthesizing compounds having features identified in this study may result in improved performance of screening collections. S mall-molecule probe-and drug-discovery activities in academia and the pharmaceutical industry often begin with highthroughput screening. Many thousands of small molecules are tested with the expectation that each has potential as a discovery lead. Thus, assembling or synthesizing compound collections for small-molecule screening represents an important step in discovery success, particularly when selecting among compounds from a variety of synthetic and natural sources. Unbiased methods to evaluate the assay performance of compounds from different sources, and to relate performance to chemical structure (defined by computed structural properties) (1, 2), can provide guidance to one element of more valuable small-molecule screening collections.Comparative analyses between compounds often involve cheminformatic analysis of compound structures (3-5) or retrospective analysis of compound performance by mining the literature (6-8) or historical data (9, 10). For example, intermediate molecular complexity has been suggested as theoretically preferable for drug leads (11), and this relationship is supported by evidence mined from historical data (9). In this study, we performed unbiased comparisons of compounds from natural and synthetic sources by first identifying compounds with unknown activities and then exposing them to a common assay platform. We identified a compound collection comprising three subsets: (i) 6,152 compounds from commercial sources that are representative of many common screening collections (commercial compounds; CC); (ii) 6,623 compounds assembled from the academic synthetic chemistry community using, e.g., diversity-oriented synthesis (diverse compounds; DC); and (iii) 2,477 naturally occurring compounds (natural products; NP). We then (i) analyzed distributions of stereochemical and shape complexity for each set;(ii) measured protein-binding activities of each membe...

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Section: Discussionmentioning

confidence: 99%

Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles

Clemons

Bodycombe²,

Carrinski³

et al. 2010

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

324

333

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“…Gratifyingly, switching the catalyst to CuA C H T U N G T R E N N U N G (OTf) 2 furnished the highly substituted pyrrole 6aa in 45% yield (Table 1, entry 4). To identify suitable conditions for the tandem process, [11] the series of Lewis acids from Table 1 was screened. Fortunately, indiumA C H T U N G T R E N N U N G (III) chloride provided the best results in comparison to other Lewis acids investigated and was effective in catalytic quantities (10 mol%) ( Table 1, entry 1).…”

mentioning

confidence: 99%

Indium(III) Chloride‐Catalyzed Propargylation/Amination/Cycloisomerization Tandem Reaction: One‐Pot Synthesis of Highly Substituted Pyrroles from Propargylic Alcohols, 1,3‐Dicarbonyl Compounds and Primary Amines

et al. 2008

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A convenient one-pot propargylation/amination/cycloisomerization tandem process has been developed for the synthesis of highly substituted pyrroles derivatives from propargylic alcohols, 1,3-dicarbonyl compounds and primary amines using indium(III) chloride as a multifunctional catalyst. This method provides a flexible and rapid route to substituted pyrroles.National Natural Science Foundation of China [20772098, 30572250]; New Century Excellent Talents in Fujian Province Universit

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“…According to previous literature reports, the existence of B is supported by substituent effects and regio-and stereoselectivities. 22,36,93,94,122 In our case, A competitive elimination in D also occurred, furnishing naphthalene 4-2 as the product. With the selection of an appropriate gold catalyst, the elimination could be controlled.…”

Section: Resultssupporting

confidence: 48%

Expanding the frontier of gold-catalyzed cyclizations and rational ligand design.

Malhotra¹

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Discovery of Chemical Reactions through Multidimensional Screening

Abstract: Multidimensional reaction screening of ortho-alkynyl benzaldehydes with a variety of catalysts and reaction partners was conducted in an effort to identify new chemical reactions. Reactions affording unique products were selected for investigation of preliminary scope and limitations.

Cited by 188 publications

References 61 publications

Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles

Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles

Indium(III) Chloride‐Catalyzed Propargylation/Amination/Cycloisomerization Tandem Reaction: One‐Pot Synthesis of Highly Substituted Pyrroles from Propargylic Alcohols, 1,3‐Dicarbonyl Compounds and Primary Amines

Expanding the frontier of gold-catalyzed cyclizations and rational ligand design.

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