.alpha.-Diketone and .alpha.-keto ester derivatives of N-protected amino acids and peptides as novel inhibitors of cysteine and serine proteinases

Angelastro, Michael R.; Mehdi, Shujaath; Burkhart, Joseph P.; Peet, Norton P.; Bey, Philippe

doi:10.1021/jm00163a002

Cited by 142 publications

(59 citation statements)

References 2 publications

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“…The third RSÀ X series (RS = Cbz-Ala-Ala; X = OH, H, CH 3 , COCH 3 ) was studied on the serine protease elastase. The syntheses of the aldehyde, the methyl ketone, and the methyl diketone derivatives (X = H, CH 3 , and COCH 3 , respectively) followed the approach of Angelastro et al [9] The trifluoromethyl ketone TS analogue (X = CF 3 ) was prepared according to Walter et al [10] The corresponding inhibition constants are presented in Tables 1 and 2. The same trend is observed for all three different recognition sites CbzPhe, Cbz-Gly-Leu-Phe, and Cbz-Ala-Ala in all examined enzymes; the stability of the TC as a function of varied CS fragment decreases in the following order:…”

Section: Experimental Validation Of the Conceptmentioning

confidence: 99%

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Enzyme Isoselective Inhibitors: A Tool for Binding‐Trend Analysis

et al. 2006

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A transition-state analogue inhibitor that covalently reversibly binds to an enzyme formally consists of two parts: the chemical site, CS and the recognition site, RS. We have experimentally and theoretically demonstrated that the trend of binding affinity in a series of isoselective inhibitors (with identical RS and different CS fragments) depends mainly on their CS fragments. Isoselective inhibitors have the same affinity trend toward different enzymes of the same family with a common catalytic mechanism. Thus, very good correlation between experimentally determined and theoretically calculated Ki values was demonstrated. A practical outcome is the application of the described method as a tool for an expert analysis in virtual screening of inhibitor libraries and in the design of new enzyme inhibitors.

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Section: Experimental Validation Of the Conceptmentioning

confidence: 99%

“…[28] The aldehyde, methyl ketone, and methyl diketone were synthesized according to the general procedure of Angelastro et al [9,29] Cbz-Phe-H, [30] Cbz-Phe-CH 3 , [31] and Cbz-Phe-COCH 3 [29] were characterized according to pub-A C H T U N G T R E N N U N G lished data.…”

Section: Synthesismentioning

confidence: 99%

Enzyme Isoselective Inhibitors: A Tool for Binding‐Trend Analysis

et al. 2006

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“…Among the important structures that are found in many bioactive compounds [1,2], and applications in organic synthesis are 1,2-diketones [3]. 1,2-Diketones are utilized as intermediates in the synthesis of chiral ligands, pharmaceuticals, and biologically active compounds [4][5][6], photoinitiators [7][8][9][10], precursors of porphyrins [11][12][13], preparation of variety of heterocycles [14][15][16][17][18][19][20][21], and natural products [22,23].…”

Section: Introductionmentioning

confidence: 99%

Oxidation of benzoins to benzils in the presence of porphyrin sensitizers by air and sunlight or visible light

et al. 2013

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In this work, two new aerobic routes are introduced for the oxidation of a variety of benzoins to benzils by using molecular oxygen in the presence of porphyrins as sensitizers, using white light or sunlight in acetonitrile under mild conditions. The methods have a wide range of applications, do not involve cumbersome work-up, exhibit chemoselectivity and proceed under mild reaction conditions. The resulting products are obtained in good yields in a reasonable time.

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“…These inhibitors permanently inactivate calpain by displacing the active site cysteine thiol to form a sulfide. Reversible inhibitors include peptidyl aldehydes [13,14] and activated ketones [15,16] like a-ketoesters, a-keto-acids, and a-keto-amides. These inhibitors inactivate calpain in a transient manner by forming a reversible covalent bond (hemithioacetal or hemithioketal) with the cysteine thiol [17].…”

Section: Introductionmentioning

confidence: 99%

QSAR studies on peptide α-ketoamides and α-ketohydroxamate derivatives as calpain I inhibitors

Dondapati

Gódi

Babu

2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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Quantitative Structure Activity Relationship (QSAR) studies were conducted on 34 peptide a-ketoamide and a-ketohydroxamate derivatives of Calpain I using multiple linear regression (MLR) procedure. The activity contributions of these compounds were determined from regression equation and the validation procedures that analyze the predictive ability of QSAR models were described. Among forty six descriptors that were considered in generating the QSAR model, three descriptors such as LogP, Heat of formation and HOMO resulted in a statistically significant model with 0.877 r 2 and 0.937 q 2 respectively. The inter-correlation between descriptors was 0.42. The proposed QSAR model indicates an increase in logP value increases hydrophobicity in order to achieve cellular permeability and an increase in heat of formation as well as decrease in HOMO energy favors better binding and activity towards development of potent calpain I inhibitors.

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.alpha.-Diketone and .alpha.-keto ester derivatives of N-protected amino acids and peptides as novel inhibitors of cysteine and serine proteinases

Cited by 142 publications

References 2 publications

Enzyme Isoselective Inhibitors: A Tool for Binding‐Trend Analysis

Enzyme Isoselective Inhibitors: A Tool for Binding‐Trend Analysis

Oxidation of benzoins to benzils in the presence of porphyrin sensitizers by air and sunlight or visible light

QSAR studies on peptide α-ketoamides and α-ketohydroxamate derivatives as calpain I inhibitors

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