Inhibitors of HIV‐1 Protease by Using In Situ Click Chemistry

Whiting, Matthew; Muldoon, John; Lin, Ying‐Chuan; Silverman, Steven M.; Lindstrom, William M.; Olson, Arthur J.; Kolb, Hartmuth C.; Finn, M. G.; Sharpless, K. Barry; Elder, John H.; Fokin, Valery V.

doi:10.1002/ange.200502161

Cited by 111 publications

(59 citation statements)

References 28 publications

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“…This means that the target biomolecule is incubated with a mixture of azide and alkyne substrates and only those which fit best into the binding sites of the biomolecule can react to form the triazole product (Scheme 37). [107] For example, potent inhibitors of acetylcholinesterase, [108] carbonic anhydrase, [109] HIV-protease [110] and chitinase [111] have been identified by this approach.…”

Section: In Situ Click Chemistry For Lead Identificationmentioning

confidence: 99%

Highly Active Dinuclear Copper Catalysts for Homogeneous Azide–Alkyne Cycloadditions

et al. 2012

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It is better to light a candle than to curse the dark. AbstractThe copper-catalyzed azide-alkyne cycloaddition for the synthesis of 1,4-disubstituted 1,2,3-triazoles (CuAAC) is a variant of Huisgen's 1,3-dipolar cycloaddition which disburdens the thermal reaction from its major drawbacks such as poor regioselectivity, long reaction times and harsh conditions. In contrast to the widely used "black box" reagent mixtures, a molecularly defined, highly active catalyst system for homogeneous CuAAC reactions has been developed in this PhD project. In dependence on the postulated stepwise mechanism, its most important structural feature is the presence of two copper(I) ions irreversibly bound in the same catalyst molecule.A highly modular and profitable synthesis for bistriazolium hexafluorophosphate salts as precursors for the ancillary ligand system was devised. In analogy to the CuAAC catalyst systems of general formula [(NHC) 2 Cu]PF 6 described in literature, novel dinuclear copper(I) complexes with a bistriazolylidene ligand backbone and 1,3-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene (IPr) as sacrificial ligand were prepared.However, these complexes did not show the expected high catalytic activity, most probably due to the strong coordination of the IPr ligands. In consequence, another family of dinuclear copper(I) complexes with m-coordinated acetate as labile ligand was synthesized by reaction of the bistriazolium hexafluorophosphate ligand precursors with copper(I) acetate in the presence of a base.The broad applicability and high catalytic activity of one of these bistriazolylidene dicopper acetate complexes was confirmed by a series of gaschromatographically mo-

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Section: In Situ Click Chemistry For Lead Identificationmentioning

confidence: 99%

Highly Active Dinuclear Copper Catalysts for Homogeneous Azide–Alkyne Cycloadditions

et al. 2012

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“…The Huisgen cycloaddition can be carried out in vitro under CuAAC conditions, [23][24][25][26][27][28][29][30][31][32] and examples of a copper-free, in situ Click reaction have been reported in which the reaction is catalysed by bringing the reaction partners into close proximity on a protein surface. [33,34] Reaction conditions have recently been developed that allow in vivo Huisgen cycloaddition of strained cyclic alkynes that are highly reactive towards azides in the absence of a catalyst [35,36] with application to the selective labelling of biomolecules in live mice.…”

Section: Introductionmentioning

confidence: 99%

1,2,3‐Triazoles in Peptidomimetic Chemistry

2011

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The ability to synthesise small peptidomimetics that mimic the secondary structure of proteins is an ever expanding area of research directed at sourcing new medicinal agents and biological probes. A significant current challenge is to mimic protein epitopes under physiological conditions using small peptidomimetics that are easy to prepare. The copper‐ and ruthenium‐catalysed Huisgen cycloaddition reactions provide such a general synthetic method, with the resulting 1,2,3‐triazoles being good peptide bond mimics. The ability to prepare both 1,4‐ and 1,5‐substituted 1,2,3‐triazoles under these chemically benign conditions provides both “linear” and “bent” peptidomimetics. Examples of the use of 1,2,3‐triazoles to define the geometry and properties of a peptidomimetic abound. This review highlights such successes but also describes a number of failures in order to guide and inspire future efforts of chemists in this area.

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“…[16][17][18][19][20] These studies implemented libraries of small-molecule building blocks functionalized with either azide or acetylene groups. During the screening of the target protein with the molecular libraries, the protein plays an active role in the selection and covalent assembly of a new inhibitor.…”

mentioning

confidence: 99%

“…[16][17][18][19][20] In the screen in Scheme 1, the triazole product represents a very small fraction of the peptide on the bead, and so only the variable region of the peptide is identified during the peptide-sequencing step. Thus, we sought to confirm the validity of the in situ screen in multiple ways.…”

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confidence: 99%

Iterative In Situ Click Chemistry Creates Antibody‐like Protein‐Capture Agents

et al. 2009

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Auf Proteinfang: Iterative Klick‐Reaktionen (siehe Schema des dritten Liganden‐Screenings) und eine Methode zum Aufbau von Bibliotheken mit einer Verbindung pro Kügelchen ermöglichten die Synthese von selektiven, hoch affinen Proteineinfangagentien aus einzelnen Fragmenten. Die resultierenden Liganden sind wasserlöslich und (bio)chemisch sowie thermisch stabil. Durch Kupfer(I)‐katalysierte Cycloadditionen sind sie im Gramm‐Maßstab zugänglich.

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Inhibitors of HIV‐1 Protease by Using In Situ Click Chemistry

Cited by 111 publications

References 28 publications

Highly Active Dinuclear Copper Catalysts for Homogeneous Azide–Alkyne Cycloadditions

Highly Active Dinuclear Copper Catalysts for Homogeneous Azide–Alkyne Cycloadditions

1,2,3‐Triazoles in Peptidomimetic Chemistry

Iterative In Situ Click Chemistry Creates Antibody‐like Protein‐Capture Agents

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