Peptidyl β-homo-aspartals: Specific inhibitors of interleukin-1β converting enzyme and its homologues (caspases)

Bajusz, S.; Fauszt, I; Németh, Klára; Barabás, Éva; Juhász, Attila; Patthy, Miklós

doi:10.1016/s0960-894x(98)00244-3

Cited by 9 publications

(3 citation statements)

References 11 publications

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“…This indicates that aldehyde 3 is about 270 and 40 times more potent than MG-132 and bortezomib, respectively. , It was found that more hydrophobic and hindered groups as side chains at P2 and P3 positions (counting from the C end) of tripeptides result in enhanced of proteasome inhibitory activity . A great number of studied TPAs as well as 3 contain side chains of noncoded amino acids, but they very rarely have the opposite to natural absolute configuration at any of α-carbon. ,, It is caused by the troublesome synthesis and very narrow access to commercially available precursors of peptides with non-natural configuration.…”

Section: Introductionmentioning

confidence: 99%

“…15 A great number of studied TPAs as well as 3 contain side chains of noncoded amino acids, 25 but they very rarely have the opposite to natural absolute configuration at any of R-carbon. 4,26,27 It is caused by the troublesome synthesis and very narrow access to commercially available precursors of peptides with non-natural configuration. Generally, N-benzyloxycarbonyl tripeptide aldehydes, including MG-132, are synthesized by the classical coupling of N-protected amino acid with a dipeptide containing a C-terminal Weinreb amide group.…”

Section: Introductionmentioning

confidence: 99%

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Studies of the Synthesis of All Stereoisomers of MG-132 Proteasome Inhibitors in the Tumor Targeting Approach

et al. 2010

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MG-132 is a tripeptide aldehyde (Z-l-leu-l-leu-l-leu-H, 2) proteasome inhibitor that exerts antitumor activity and enhances cytostatic/cytotoxic effects of chemo- and radiotherapy. Because of a troublesome synthesis of tripeptides with a non-natural configuration and modified side chains of amino acids, only two stereoisomers of MG-132 have been reported. Here, we propose a new approach to the synthesis of tripeptide aldehydes based on the Ugi reaction. Chiral, enantiomerically stable 2-isocyano-4-methylpentyl acetates were used as substrates for Ugi reaction resulting in a formation of tripeptide skeletons. Further functionalization of the obtained products led to a synthesis of tripeptide aldehydes. All stereoisomers of MG-132 were synthesized and studied as potential inhibitors of chymotrypsin-like, trypsin-like, and peptidylglutamyl peptide hydrolyzing activities of proteasome. These studies demonstrated the influence of absolute configuration of chiral aldehydes on the cytostatic/cytotoxic effects of the synthesized compounds and revealed that only (S,R,S)-(-)-2 stereoisomer is a more potent proteasome inhibitor than MG-132.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Studies of the Synthesis of All Stereoisomers of MG-132 Proteasome Inhibitors in the Tumor Targeting Approach

et al. 2010

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“…Thus the β-aldehyde group may be accessible to additional interactions within the active site region, perhaps interacting with free amino or imidazole groups. Basjuz et al (1998) have recently reported the observation that trypsin and thrombin can be inhibited by a compound containing the C-terminal β-homoarginine aldehyde moiety, Boc-()Phe-Pro-Arg-CH 2 CHO (IC50 l 0.19 µ (thrombin); 1.76 µ (trypsin)). While such compounds were shown to be substantially less potent than the comparable peptide α-aldehydes, this work clearly indicates that both enzymes can interact with the β-aldehyde group.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and kinetic evaluation of peptide α-keto-β-aldehyde-based inhibitors of trypsin-like serine proteases

Lynas¹,

Martin²,

Walker³

2001

Journal of Pharmacy and Pharmacology

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New, synthetic peptide analogues bearing a C-terminal basic alpha-keto-beta-aldehyde moiety were prepared as novel inhibitors of the trypsin-like serine proteases. The compounds, Ac-Leu-Leu-Arg-COCHO, Ac-Arg-Gln-Arg-COCHO and Boc-Val-Leu-Lys-COCHO were evaluated kinetically against trypsin and three other trypsin-like serine proteases, tryptase, plasmin and thrombin, all of which are implicated as mediators of important disease processes. Results illustrate that alpha-keto-beta-aldehydes are potent inhibitors, with similar potency to comparable peptide aldehydes, and intriguingly, appearto act, in some instances, by a novel mechanism of action. Ac-Leu-Leu-Arg-COCHO, an analogue of the natural product leupeptin, is a potent, tight-binding inhibitor of trypsin (Ki(final) = 1.9 microM), plasmin (Ki(final) = 4.9 microM) and tryptase (Ki(final) = 1.2 microM) and an irreversible inactivator of thrombin (k2nd 4,500 M(-1).min(-1)). Boc-Val-Leu-Lys-COCHO was found to be a tight-binding inhibitor of its target protease plasmin (Ki(final) = 3.1 microM) and was inactive against thrombin. Ac-Arg-Gln-Arg-COCHO was a slow-binding inhibitor of tryptase (Ki(final) = 1.6 microM) and also irreversibly inactivated trypsin (k2nd = 8,920 M(-1) min(-1)). Peptides or peptidomimetics with a C-terminal basic alpha-keto-beta-aldehyde function thus provide a useful new molecular template for the development of new therapeutic agents against a wide range of disorders, such as coagulopathies and asthma, which may be mediated by the aberrant activity of trypsin-like serine proteases.

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Asymmetric Access to Peptidyl β³‐Aldehydes by Coupling of N‐Phthalyl α‐Amino Acids with a Synthetic Heterocyclic β‐Amino Aldehyde Precursor

et al. 2006

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Asymmetric access to novel N‐protected (di)peptidyl β3‐aldehydes (“β3‐PAs”) has been achieved through direct coupling of a chiral non‐racemic 6‐alkoxytetrahydrooxazinone with N‐phthalyl L‐α‐amino acids. Kinetic resolution allows for the fruitful use of racemic amino acids in this process. Acidic hydrolysis of the diastereomerically pure, coupling products leads to the title N‐phthalyl‐β3‐PAs in high yields. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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Peptidyl β-homo-aspartals: Specific inhibitors of interleukin-1β converting enzyme and its homologues (caspases)

Cited by 9 publications

References 11 publications

Studies of the Synthesis of All Stereoisomers of MG-132 Proteasome Inhibitors in the Tumor Targeting Approach

Studies of the Synthesis of All Stereoisomers of MG-132 Proteasome Inhibitors in the Tumor Targeting Approach

Synthesis and kinetic evaluation of peptide α-keto-β-aldehyde-based inhibitors of trypsin-like serine proteases

Asymmetric Access to Peptidyl β³‐Aldehydes by Coupling of N‐Phthalyl α‐Amino Acids with a Synthetic Heterocyclic β‐Amino Aldehyde Precursor

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Peptidyl β-homo-aspartals: Specific inhibitors of interleukin-1β converting enzyme and its homologues (caspases)

Cited by 9 publications

References 11 publications

Studies of the Synthesis of All Stereoisomers of MG-132 Proteasome Inhibitors in the Tumor Targeting Approach

Studies of the Synthesis of All Stereoisomers of MG-132 Proteasome Inhibitors in the Tumor Targeting Approach

Synthesis and kinetic evaluation of peptide α-keto-β-aldehyde-based inhibitors of trypsin-like serine proteases

Asymmetric Access to Peptidyl β3‐Aldehydes by Coupling of N‐Phthalyl α‐Amino Acids with a Synthetic Heterocyclic β‐Amino Aldehyde Precursor

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Asymmetric Access to Peptidyl β³‐Aldehydes by Coupling of N‐Phthalyl α‐Amino Acids with a Synthetic Heterocyclic β‐Amino Aldehyde Precursor