Rapid Assembly and in Situ Screening of Bidentate Inhibitors of Protein Tyrosine Phosphatases

Srinivasan, Rajavel; Uttamchandani, Mahesh; Yao, Shao Q.

doi:10.1021/ol052895w

Cited by 110 publications

(74 citation statements)

References 13 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.

223

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.

223

205

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“…Then, the product was extracted with EtOAc (3 × 15 mL). The organic solution was dried over Na 2 SO 4 methyl 2-hydroxy-5-(5-(3-methoxy-3-oxoprop-1-enyl)furan-2-yl)benzoate 8 -A suspension of aldehyde 7 (0.125 g, 0.51 mmol), methyl diethyl phosphonoacetate (0.105 mL, 0.56 mmol) and LiOH (0.014 g, 0.56 mmol) in THF (10 mL) was stirred at r.t under Ar for 4h. After the usual work-up, purification by silica gel column chromatography with hexanes/EtOAc (6:1) as eluent was done to give 0.128 g of a pale yellow solid (84%).…”

Section: Methyl 5-(5-formylfuran-2-yl)-2-hydroxybenzoate 7-5-bromo-2-mentioning

confidence: 99%

“…However, many inhibitors identified so far are peptide-based, and because of the conserved nature of the active site among phosphotyrosine binding pockets, obtaining selectivity is often difficult. Only very recently, several examples point to fragment-based approaches as possible route for the identification of potent and selective protein phosphatase inhibitors [4,5]. A first example in designing selective PTP1B inhibitors was recently reported by Szczepankiewicz et al [5].…”

Section: Introductionmentioning

confidence: 99%

“…Another example on the use of fragment-based approaches to obtain inhibitors of a PTP is the application of the "click chemistry" [4]. In this case, Srinivasan et al employed alkynecontaining compounds targeting the PTP active site of PTP1B and azide-containing compounds targeting an already known secondary aryl-phosphate binding site near the catalytic site.…”

Section: Introductionmentioning

confidence: 99%

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Development of Molecular Probes for Second-Site Screening and Design of Protein Tyrosine Phosphatase Inhibitors

et al. 2007

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We report on the design, synthesis and evaluation of series of furanyl-salicyl-nitroxide derivatives, as effective chemical probes for second site screening against phosphotyrosine phosphatases (PTPs) using NMR-based techniques. The compounds have been tested against a panel of PTPs to asses their ability to inhibit a broad spectrum of these phosphatases. The utility of the derived compounds is illustrated with the phosphatase YopH, a bacterial toxin from Yersinia pestis. Novel chemical fragments were identified during a NMR-based screen for compounds that are capable to bind on the surface of YopH in regions adjacent the catalytic site in presence of the spin-labeled compounds. Our data demonstrate the value of the derived chemical probes for NMR-based second-site screening in PTPs.

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“…16 As a result, it has been widely applied in manȳ elds, including, biochemistry, 17 macromolecular chemistry 18 and surface chemistry. 19 In the area of self-assembled monolayer (SAM), there have been a few reports of click chemistry on gold, 20 silica 21 and glass 22 surfaces. In this paper, we report our work on functionalizing the surface of quartz with pyrene using click chemistry and the relationship between surface coverage and pyrene monomer/excimer formation upon photoexcitation.…”

Section: Introductionmentioning

confidence: 99%

Pyrene Emission From Monolayers "Clicked" Onto Quartz

Song

Gorelik

Hobley

et al. 2013

J. Mol. Eng. Mater.

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A series of quartz surfaces were modi¯ed with a series of crosslinkers and functional groups in order to obtain an azide-terminated monolayer, which was then used to immobilize pyrene onto the surface via alkyne-azide \click" chemistry. During the course of the immobilization, di®erent ratios of tert-butyl diphenyl chlorosilane were used to control the distribution and hence the photophysical properties of the pyrene on the surface. The preparative surface reactions and photophysical properties were investigated with contact angle, X-ray photoelectron spectroscopy, UV-visible absorption and emission spectroscopy. High surface coverage was achieved of just under 1molecule per nm 2 . At this coverage all emission from the pyrene was in the form of excimer emission. Excimer emission dominated at all surface coverages greater than 0.45 molecules per nm 2 . Below this coverage the monomer emission could also be observed. The conclusions that can be drawn are important for understanding the interactions of neighboring molecules in molecular monolayers. Our results suggest that at high surface coverage a substantial number of the pyrene molecules are already close enough to their neighbors that pairs of them can be directly excited to form excimer with no requirement for di®usion. This can be stated because the long wavelength end of the pyrene absorption and excitation spectra show a broad tail that is assigned to a charge transfer band resulting from an electron being directly transferred from a ground state pyrene to a neighboring pyrene molecule. Furthermore, absorption spectra shifts also indicate that the pyrene molecules undergo some interactions on the surface when they are closely packed.

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Rapid Assembly and in Situ Screening of Bidentate Inhibitors of Protein Tyrosine Phosphatases

Cited by 110 publications

References 13 publications

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Development of Molecular Probes for Second-Site Screening and Design of Protein Tyrosine Phosphatase Inhibitors

Pyrene Emission From Monolayers "Clicked" Onto Quartz

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