Click Chemistry In Situ: Acetylcholinesterase as a Reaction Vessel for the Selective Assembly of a Femtomolar Inhibitor from an Array of Building Blocks

Lewis, Warren G.; Green, Luke G.; Grynszpan, Flavio; Radić, Zoran; Carlier, Paul R.; Taylor, Palmer; Finn, M. G.; Sharpless, K. Barry

doi:10.1002/1521-3773(20020315)41:6<1053::aid-anie1053>3.0.co;2-4

Cited by 697 publications

(233 citation statements)

References 60 publications

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“…More importantly, the cycloaddition reaction can be conducted in aqueous solution in the absence of deleterious reagents, thus allowing direct screening and identification of hits from the library. In fact, click chemistry has found increasing applications in lead discovery and optimization for a number of enzymes including the PTPs (27)(28)(29)(30)(31). The azide-containing building blocks were synthesized in a one-pot procedure, in which alkyl or aryl amines were reacted with the acyl chloride linkers in N,N-Dimethylformamide (DMF), followed by S N 2 reaction with sodium azide to generate the corresponding azides.…”

Section: Resultsmentioning

confidence: 99%

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Zhou¹,

He²,

Zhang

et al. 2010

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

215

205

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Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.combinatorial chemistry | pathogen-host interaction | phosphatase inhibitor | signaling mechanism

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Section: Resultsmentioning

confidence: 99%

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Zhou¹,

He²,

Zhang

et al. 2010

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

215

205

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“…The in situ click chemistry for drug discovery is dependent on irreversibly reacting reagents that are inert under physiological conditions, 27 as shown earlier by the discovery of highly potent inhibitors of acetylcholine esterase, [28][29][30][31] carbonic anhydrase II 32 and HIV-1 protease. 33 …”

Section: Introductionmentioning

confidence: 99%

Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry

et al. 2009

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In situ click chemistry is a target-guided synthesis technique for discovering potent protein ligands by assembling azides and alkynes into triazoles inside the affinity site of a target protein. We report the rapid discovery of a new and potent inhibitor of bacterial chitinases by the use of in situ click chemistry. We observed a target-templated formation of a potent triazole inhibitor of the chitinase-catalyzed chitin hydrolysis, through in situ click chemistry between a biologically active azide-containing scaffold and structurally unrelated alkyne fragments. Chitinase inhibitors have chemotherapeutic potential as fungicides, pesticides and antiasthmatics. Argifin, which has been isolated and characterized as a cyclopentapeptide natural product by our research group, shows strong inhibitory activity against chitinases. As a result of our efforts at developing a chitinase inhibitor from an azide-bearing argifin fragment and the application of the chitinase template and a library of alkynes, we rapidly obtained a very potent and new 1,5-disubstituted triazole inhibitor against Serratia marcescens chitinase (SmChi) B. The new inhibitor expressed 300-fold increase in the inhibitory activity against SmChiB compared with that of argifin. To the best of our knowledge, our finding of an enzyme-made 1,5-disubstituted triazole, using in situ click chemistry is the second example reported in the literature.

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“…The diversity of chemical structures of the 1,2,3-triazole family and their useful biological activities made these compounds attractive targets in synthetic organic chemistry and many studies have been reported on the synthesis of these compounds [7][8][9]. The title compound is isomorphous with the ethyl 1-(4-bromophenyl)-5-methyl-1H-1,2,3-triazole-4 carboxylate analogue, reported by Singh, et al [10].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of ethyl 1-(4-chlorophenyl)-5-methyl-1H-1,2,3-triazole-4 carboxylate, C₁₂H₁₂ClN₃O₂

Brito

Kesternich

Pérez-Fehrmann

et al. 2017

Zeitschrift Für Kristallographie - New Crystal Structures

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Click Chemistry In Situ: Acetylcholinesterase as a Reaction Vessel for the Selective Assembly of a Femtomolar Inhibitor from an Array of Building Blocks

Cited by 697 publications

References 60 publications

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry

Crystal structure of ethyl 1-(4-chlorophenyl)-5-methyl-1H-1,2,3-triazole-4 carboxylate, C₁₂H₁₂ClN₃O₂

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Click Chemistry In Situ: Acetylcholinesterase as a Reaction Vessel for the Selective Assembly of a Femtomolar Inhibitor from an Array of Building Blocks

Cited by 697 publications

References 60 publications

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry

Crystal structure of ethyl 1-(4-chlorophenyl)-5-methyl-1H-1,2,3-triazole-4 carboxylate, C12H12ClN3O2

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Crystal structure of ethyl 1-(4-chlorophenyl)-5-methyl-1H-1,2,3-triazole-4 carboxylate, C₁₂H₁₂ClN₃O₂