In Situ Click Chemistry:  Enzyme Inhibitors Made to Their Own Specifications

Manetsch, Roman; Krasinski, Antoni; Radić, Zoran; Raushel, Jessica; Taylor, Palmer; Sharpless, K. Barry; Kolb, Hartmuth C.

doi:10.1021/ja046382g

Cited by 400 publications

(270 citation statements)

References 45 publications

Supporting

Mentioning

258

Contrasting

Unclassified

Order By: Relevance

“…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.

216

205

View full text Add to dashboard Cite

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

show abstract

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.

216

205

View full text Add to dashboard Cite

show abstract

“…The average relative reactivation potency for 64 triazoles (versus 2-PAM) was 0.15 Ϯ 0.02 (range 0.003-0.82) and for the remaining 71 reactivators 0.11 Ϯ 0.03 (range 0 -0.88), suggesting that the triazole, with its relatively strong dipole (4 -5 Debye) but absent a charge at this pH, had no appreciable effect on reactivity. The triazole moiety was earlier observed to contribute synergistically to the total energy of binding of high affinity AChE inhibitors (23).…”

Section: Reactivation Of Op-hache Conjugates-nearlymentioning

confidence: 98%

New Structural Scaffolds for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases

Sit

Radić

Gerardi

et al. 2011

Journal of Biological Chemistry

Self Cite

117

121

View full text Add to dashboard Cite

We describe here the synthesis and activity of a new series of oxime reactivators of cholinesterases (ChEs) that contain tertiary amine or imidazole protonatable functional groups. Equilibration between the neutral and protonated species at physiological pH enables the reactivators to cross the blood-brain barrier and distribute in the CNS aqueous space as dictated by interstitial and cellular pH values. Our structure-activity analysis of 134 novel compounds considers primarily imidazole aldoximes and N-substituted 2-hydroxyiminoacetamides. Reactivation capacities of novel oximes are rank ordered by their relative reactivation rate constants at 0.67 mM compared with 2-pyridinealdoxime methiodide for reactivation of four organophosphate (sarin, cyclosarin, VX, and paraoxon) conjugates of human acetylcholinesterase (hAChE). Rank order of the rates differs for reactivation of human butyrylcholinesterase (hBChE) conjugates. The 10 best reactivating oximes, predominantly hydroxyimino acetamide derivatives (for hAChE) and imidazole-containing aldoximes (for hBChE) also exhibited reasonable activity in the reactivation of tabun conjugates. Reactivation kinetics of the lead hydroxyimino acetamide reactivator of hAChE, when analyzed in terms of apparent affinity (1/K ox ) and maximum reactivation rate (k 2 ), is superior to the reference uncharged reactivators monoisonitrosoacetone and 2,3-butanedione monoxime and shows potential for further refinement. The disparate pH dependences for reactivation of ChE and the general base-catalyzed oximolysis of acetylthiocholine reveal that distinct reactivator ionization states are involved in the reactivation of ChE conjugates and in conferring nucleophilic reactivity of the oxime group.It has become increasingly apparent that efficient reinstatement of CNS acetylcholinesterase (AChE) 2 activity inhibited in organophosphate (OP)-intoxicated individuals is required for sustained symptom recovery. In particular, nerve agent OPs already used by terrorists, but also active metabolites of OP-based pesticides, readily cross the bloodbrain barrier (BBB). The exposure to OP doses close to lethality results in initial severe motor convulsions and epileptic seizures. Accumulating evidence points to these seizure events being linked to irreversible long term compromise of cognitive functions and alteration of CNS electrical excitability. Once accumulated into hydrophobic sites, OPs that do enter the CNS are retained and partition slowly back into the circulation. For example, victims of Tokyo subway nerve gas attack in 1995 were found to suffer from both short and long term symptoms of OP exposure (1-4). Accordingly, comprehensive protection from and treatment of OP intoxication to minimize the longer term consequences require administration of antidotes capable of reactivating OP-inhibited AChE in the CNS. Current therapy directed to reactivating inhibited AChE is limited to the peripheral circulation because commonly used quaternary pyridinium aldoxime reactivators do not cross the BBB at ...

show abstract

“…105 LC/MS analysis revealed three new hit compounds -TZ2PA5, TA2PZ6, and TA2PZ5 -in addition to the TZ2PA6. All of the products were identified as syn-isomers with dissociation constants in femtomolar and picomolar range.…”

Section: 102-104mentioning

confidence: 99%

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Maraković

Šinko

2017

ACSi

View full text Add to dashboard Cite

Modern drug discovery is mainly based on the de novo synthesis of a large number of compounds with a diversity of chemical functionalities. Though the introduction of combinatorial chemistry enabled the preparation of large libraries of compounds from so-called building blocks, the problem of successfully identifying leads remains. The introduction of a dynamic combinatorial chemistry method served as a step forward due to the involvement of biological macromolecular targets (receptors) in the synthesis of high affinity products. The major breakthrough was a synthetic method in which building blocks are irreversibly combined due to the presence of a receptor. Here we present various receptor-based combinatorial chemistry approaches. Huisgen's cycloaddition (1,3-dipolar cycloaddition of azides and alkynes) forms stabile 1,2,3-triazoles with very high receptor affinity that can reach femtomolar levels, as the case with acetylcholinesterase inhibitors shows. Huisgen's cycloaddition can be applied to various receptors including acetylcholinesterase, acetylcholine binding protein, carbonic anhydrase-II, serine/threonine-protein kinase and minor groove of DNA.

show abstract

In Situ Click Chemistry: Enzyme Inhibitors Made to Their Own Specifications

Cited by 400 publications

References 45 publications

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

New Structural Scaffolds for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Contact Info

Product

Resources

About