A facile solution and solid phase synthesis of phosphotyrosine mimetic l-4-[diethylphosphono(difluoromethyl)]-phenylalanine (F2Pmp(EtO)2) derivatives

Qabar, Maher; Urban, Ján; Kahn, Michaël

doi:10.1016/s0040-4020(97)00374-8

Cited by 27 publications

(25 citation statements)

References 16 publications

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“…As in the case of 22 , t -BuOH was used as the solvent and the cis and trans isomers were separated by silica gel chromatography. Copper-cadmium cross coupling with diethyl bromodifluoromethylphosphonate 37 provided phosphonate 28 . Acidolytic removal of the tert -butyl ester followed by esterification with pentachlorophenol gave intermediate 29a .…”

Section: Resultsmentioning

confidence: 99%

Potent and Selective Phosphopeptide Mimetic Prodrugs Targeted to the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3

et al. 2011

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Signal transducer and activator of transcription 3 (Stat3), a target for anticancer drug design, is activated by recruitment to phosphotyrosine residues on growth factor and cytokine receptors via its SH2 domain. We report here structure-activity relationship studies on phosphopeptide mimics targeted to the SH2 domain of Stat3. Inclusion of a methyl group on the β-position of the pTyr mimic, 4-phosphocinfnamide, enhanced affinity 2–3 fold. Bis-pivaloyloxymethyl prodrugs containing β-methyl cinnamide, dipeptide scaffolds Haic and Nle-cis-3,4-methanoproline, and glutamine surrogates were highly potent, completely inhibiting phosphorylation of Stat3 Tyr705 at 0.5–1 µM in a variety of cancer cell lines. The inhibitors were selective for Stat3 over Stat1, Stat5, Src, and p85 of PI3K, indicating ability to discriminate individual SH2 domains in intact cells. At concentrations that completely inhibited Stat3 phosphorylation, the prodrugs were not cytotoxic to a panel of tumor cells, thereby showing clear distinction between cytotoxicity and effects downstream of activated Stat3.

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Section: Resultsmentioning

confidence: 99%

Potent and Selective Phosphopeptide Mimetic Prodrugs Targeted to the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3

et al. 2011

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“…Starting with iodobenzaldehyde, Horner-Emmons coupling with tert -butyl (diethylphosphono)acetate gave the iodocinnamate, 2 . Copper-cadmium cross coupling of 2 with diethyl bromodifluoromethyl-phosphonate17 provided the diethyl phosphonate 3 . Since phenolic esters are stable to trimethylsilyliodide (TMSI)-mediated dealkylation of phosphate and phosphonate esters.,18 we employed the pentachlorophenyl ester to serve as both protection and activation of the carboxyl group.…”

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confidence: 99%

Synthesis of Phosphatase-Stable, Cell-Permeable Peptidomimetic Prodrugs That Target the SH2 Domain of Stat3

2009

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The synthesis of prodrugs targeted to the SH2 domain of Stat3 is reported. Using a convergent strategy, the pivaloyloxymethyl phosphonodiester of pentachlorophenyl 4-phosphonodifluoromethylcinnamate, a phosphotyrosine surrogate, was synthesized and used to acylate peptidomimetic fragments that were prepared on solid supports. Two prodrugs described here inhibited the phosphorylation of Stat3 in breast tumor cells.

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“…13 The triflate was converted to the carboxylic acid using Pd(OAc) 2 . 34,35 The crude acid was then reduced to the benzyl alcohol (12) with BH 3 -DMS complex. 36 Oxidation of the purified benzyl alcohol to the aldehyde using IBX was done using standard conditions.…”

Section: Synthesis Of Fmoc-l-brpmp(ome 2 )-Oh (16)mentioning

confidence: 99%

“…Reported derivatives of Pmp include fluoro, difluoro, chloro, and dichloro derivatives. [9][10][11][12][13] These strategies have been successfully applied to develop competitive inhibitors of a variety of PTPs. 14 0968-0896/$ -see front matter Ó 2010 Elsevier Ltd. All rights reserved.…”

Section: Introductionmentioning

confidence: 99%

A protected l-bromophosphonomethylphenylalanine amino acid derivative (BrPmp) for synthesis of irreversible protein tyrosine phosphatase inhibitors

Tulsi

Downey

Cairo

2010

Bioorganic & Medicinal Chemistry

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A facile solution and solid phase synthesis of phosphotyrosine mimetic l-4-[diethylphosphono(difluoromethyl)]-phenylalanine (F2Pmp(EtO)2) derivatives

Cited by 27 publications

References 16 publications

Potent and Selective Phosphopeptide Mimetic Prodrugs Targeted to the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3

Potent and Selective Phosphopeptide Mimetic Prodrugs Targeted to the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3

Synthesis of Phosphatase-Stable, Cell-Permeable Peptidomimetic Prodrugs That Target the SH2 Domain of Stat3

A protected l-bromophosphonomethylphenylalanine amino acid derivative (BrPmp) for synthesis of irreversible protein tyrosine phosphatase inhibitors

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