Phosphopeptide Prodrug Bearing an <i>S</i>-Acyl-2-thioethyl Enzyme-Labile Phosphate Protection

Mathé, Christophe; Philouze, Christian; Gosselin, Gilles; Imbach, Jean‐Louis

doi:10.1021/jo980437d

Cited by 22 publications

(17 citation statements)

References 38 publications

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“…The progress of the coupling reaction was monitored by HPLC. Elution peaks were correlated to those of authentic samples which were chemically synthesized according to the reported procedure [25][26]. This optimum enzymatic coupling condition was applied to the synthesis of 2a by SG and CS.…”

Section: Resultsmentioning

confidence: 99%

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Trypsin‐catalysed synthesis of oligopeptide amides: comparison of catalytic efficiency among trypsins of different origin (bovine, streptomyces griseus and chum salmon)

Sekizaki

Itoh

Toyota

et al. 2002

Journal of Peptide Science

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A procedure has been developed for the synthesis of oligopeptide amide using inverse substrates as acyl donors with amino acid amide instead of p-nitroanilide as acyl acceptor and trypsins of different origin (bovine, Streptomyces griseus and chum salmon trypsins) as the catalyst. The effectiveness of this procedure was demonstrated by the synthesis of a pentapeptide, Boc-[Leu5]-enkephalin amide, as a model compound. The method was the first enzymatic method shown to be successful at each successive coupling step for the synthesis of the oligopeptide. Bovine and chum salmon trypsins were superior to Streptomyces griseus trypsin as the catalyst.

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Section: Resultsmentioning

confidence: 99%

“…Acyl acceptors (a-d) were purchased from Calbiochem-Novabiochem International, Inc. The other peptide amide and authentic samples were prepared according to the reported procedure [25,26]. (15).…”

Section: Methodsmentioning

confidence: 99%

Trypsin‐catalysed synthesis of oligopeptide amides: comparison of catalytic efficiency among trypsins of different origin (bovine, streptomyces griseus and chum salmon)

Sekizaki

Itoh

Toyota

et al. 2002

Journal of Peptide Science

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“…To overcome this low water-solubility setback, one effective strategy is to convert the water-insoluble parent drugs into hydrophilic prodrugs by covalently attaching appropriate solubilizing moieties such as phosphates [34,35], sugars [36,37], and amino acids [38,39] that can enzymatically release the parent drugs. Phosphate-type water-soluble prodrugs of HIV-1 PR inhibitors were reported by Thaisrivongs and co-workers [32].…”

Section: Hiv Protease Inhibitorsmentioning

confidence: 99%

Design of Potent Aspartic Protease Inhibitors to Treat Various Diseases

Nguyen

Hamada

Kimura

et al. 2008

Archiv der Pharmazie

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In this retrospective, personal review covering our research from the late 1980s until 2007, we outline nearly two-decade worth of our own work on several aspartic protease inhibitors including those affecting renin, HIV-1 protease, plasmepsins, b-secretase, and HTLV-I protease and we report on aspartic protease inhibitors as potential drugs to treat hypertension, AIDS, malaria, Alzheimer's disease and adult T-cell leukemia, HTLV-I associated myelopathy / tropical spastic paraparesis, and various, respectively, associated diseases. Herein, we describe our methods for rational substrate-based drug design of peptidomimetics that potently inhibit the activity of renin, HIV-1 protease, plasmepsins, b-secretase, and HTLV-I protease accordingly, using an appropriately selected inhibitory residue that contained a hydroxymethylcarbonyl isostere. Although this non-hydrolyzable isostere mimics the transition state that is formed during protein cleavage of a substrate, the isostere-containing inhibitor is not cleaved. We highlight our optimization studies in which we used various techniques and tools such as truncation studies, natural and non-natural amino acid substitution studies, various moieties to promote chemical and pharmacological stability, X-ray crystallography, computer-assisted docking and dynamic simulations, quantitative structure-activity relationship studies, and various other methods that this review can barely mention.

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“…12-14 Another approach that has been used is the generation of phosphotyrosine prodrugs in the form of phosphoesters that are simply activated by enzymatic hydrolysis. 15 However, due to the ubiquitous presence of esterases, this type of approach cannot be considered selective. We have developed previously a series of cell membrane permeable nucleoside phosphoramidate prodrugs that deliver nucleotides intracellularly.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Phosphotyrosine Peptidomimetic Prodrugs

et al. 2006

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A novel approach to the intracellular delivery of aryl phosphates has been developed that utilizes a phosphoramidate-based prodrug approach. The prodrugs contain an ester group that undergoes reductive activation intracellularly with concomitant expulsion of a phosphoramidate anion. This anion undergoes intramolecular cyclization and hydrolysis to generate aryl phosphate exclusively with a t1/2 = ∼ 20 min. Phosphoramidate prodrugs (8-10) of phosphate-containing peptidomimetics that target the SH2 domain were synthesized. Evaluation of these peptidomimetic prodrugs in a growth inhibition assay and, in a cell-based transcriptional assay, demonstrated that the prodrugs had IC 50 values in the low micromolar range. Synthesis of phosphorodiamidate analogs containing a P-NH-Ar linker (16 -18) was also carried out in the hope that the phosphoramidates released might be phosphatase-resistant. Comparable activation rates and cell-based activities were observed for these prodrugs, but the intermediate phosphoramidate dianion underwent spontaneous hydrolysis with a t 1/2 = ∼ 30 min.

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Phosphopeptide Prodrug Bearing an S-Acyl-2-thioethyl Enzyme-Labile Phosphate Protection

Cited by 22 publications

References 38 publications

Trypsin‐catalysed synthesis of oligopeptide amides: comparison of catalytic efficiency among trypsins of different origin (bovine, streptomyces griseus and chum salmon)

Trypsin‐catalysed synthesis of oligopeptide amides: comparison of catalytic efficiency among trypsins of different origin (bovine, streptomyces griseus and chum salmon)

Design of Potent Aspartic Protease Inhibitors to Treat Various Diseases

Design and Synthesis of Phosphotyrosine Peptidomimetic Prodrugs

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