N-Benzyloxyamino Phosphinyl Peptides

Elhaddadi, Mohamed; Jacquier, Robert; Petrus, C.; Petrus, Francoise

doi:10.1080/10426509108036828

Cited by 12 publications

(5 citation statements)

References 23 publications

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“…Thus, to increase the product yield we have significantly prolonged the time of the reaction. This methodology gives at least satisfactory results in contrast to the unsuccessful application of the standard peptide coupling agents 1 …”

Section: Resultsmentioning

confidence: 99%

The Most Potent Organophosphorus Inhibitors of Leucine Aminopeptidase. Structure-Based Design, Chemistry, and Activity

et al. 2003

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A new class of very potent inhibitors of cytosol leucine aminopeptidase (LAP), a member of the metalloprotease family, is described. The X-ray structure of bovine lens leucine aminopeptidase complexed with the phosphonic acid analogue of leucine (LeuP) was used for structure-based design of novel LAP inhibitors and for the analysis of their interactions with the enzyme binding site. The inhibitors were designed by modification of phosphonic group in the LeuP structure toward finding the substituents bound at the S' side of the enzyme. This resulted in two classes of compounds, the phosphonamidate and phosphinate dipeptide analogues, which were synthesized and evaluated as inhibitors of the enzyme. The in vitro kinetic studies for the phosphinate dipeptide analogues revealed that these compounds belong to the group of the most effective LAP inhibitors found so far. Their further modification at the P1 position resulted in more active inhibitors, hPheP[CH(2)]Phe and hPheP[CH(2)]Tyr (K(i) values 66 nM and 67 nM, respectively, for the mixture of four diastereomers). The binding affinities of these inhibitors toward the enzyme are the highest, if considering all compounds containing a phosphorus atom that mimic the transition state of the reaction catalyzed by LAP. To evaluate selectivity of the designed LAP inhibitors, additional tests toward aminopeptidase N (APN) were performed. The key feature, which determines their selectivity, is structure at the P1' position. Aromatic and aliphatic substituents placed at this position strongly interact with the LAP S1' binding pocket, while a significant increase in binding affinity toward APN was observed for compounds containing aromatic versus leucine side chains at the P1' position. The most selective inhibitor, hPheP[CH(2)]Leu, binds to LAP with 15 times higher affinity than to APN. One of the studied compounds, hPheP[CH(2)]Tyr, appeared to be very potent inhibitor of APN (K(i) = 36 nM for the mixture of four diastereomers). The most promising LAP inhibitors designed by computer-aided approach, the phosphonamidate dipeptide analogues, were unstable at pH below 12, because of the P-N bond decomposition, which excluded the possibility of determination of their binding affinities toward LAP.

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Section: Resultsmentioning

confidence: 99%

The Most Potent Organophosphorus Inhibitors of Leucine Aminopeptidase. Structure-Based Design, Chemistry, and Activity

et al. 2003

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“…The resulting mixture was stirred at room temperature for 12 h and further stirred for 24 h after addition of DIEA and ethyl glycine. The current route is an efficient method for the synthesis of phosphinopeptides in satisfactory yields when compared with previous methods. − …”

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confidence: 98%

“…Phosphonopeptides are generally prepared via the reaction of aminoalkylphosphonochloridates with amino acid esters or peptide esters and the direct condensation of phosphonate monoesters with amino acid esters or peptide esters . Phosphinopeptides containing a phosphinamide bond have been prepared via the reaction of aminoalkylphosphinic chlorides with amino acid esters or peptide esters, the direct condensation of aminoalkylphosphinic acids and amino esters or peptide esters in the presence of coupling reagents, such as DCC, BOP, and DPPA, with additives HOBt or DMAP in low yields, and the enzyme-catalyzed coupling of ethyl aminoalkylphosphinate and amino esters in satisfactory yields …”

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confidence: 99%

Synthesis of Phosphinopeptides via the Mannich Ligation

Cai

et al. 2007

Org. Lett.

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Phosphinopeptides are a class of unnatural peptides containing a tetrahedral phosphorus atom and have potential for use as enzyme inhibitors. A series of phosphinopeptides were synthesized via the Mannich-type reaction of aryldichlorophosphines, aldehydes, and N-protected amino amides or peptide amides and subsequent aminolysis with amino esters or peptide esters. The current method named the Mannich ligation is an efficient route to synthesis of phosphinopeptides through convergent condensation.

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“…To date, several efficient synthetic routes have been developed for synthesis of phosphonopeptides and phosphinopeptides . The formation methods of the phosphinamide bond in phosphinopeptides generally include the reaction of N-protected aminoalkylphosphinic chlorides with amino acid esters or peptide esters, the direct condensation of aminoalkylphosphinic acids and amino esters or peptide esters in the presence of coupling reagents, such as DCC, BOP, DPPA, with additives HOBt or DMAP, in low yields, the enzyme-catalyzed coupling reaction of ethyl aminoalkylphosphinate and amino esters in satisfactory yields, and the Mannich ligation of amino amides, aldehydes, aryldichlorophosphines, and amino/peptide esters …”

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confidence: 99%