Inhibition of cathepsin G by 2-amino-3,1-benzoxazin-4-ones: Kinetic investigations and docking studies

Gütschow, Michael; Kuerschner, Lars; Pietsch, Markus; Ambrozak, Agnieszka; Neumann, Ulf; Günther, Robert; Hofmann, Hans‐Jörg

doi:10.1016/s0003-9861(02)00054-1

Cited by 14 publications

(8 citation statements)

References 27 publications

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“…In any event, these results clearly indicate that chemical substitution of polysaccharides by both anionic and hydrophobic residues leads to a very efficient class of CatG inhibitor, represented here by RG1150 and RG1192 compounds. Moreover, this class of molecules constitutes to our knowledge, one of the most powerful reversible inhibitors of CatG, characterized by K i values lower or far lower than those previously reported including natural GAG (our results and [15,22]), DNA [23], proteins [24,25] as well as synthetic molecules [26–28].…”

Section: Resultssupporting

confidence: 54%

“…We show that the extent of inhibition varied with the nature of the substituted groups and revealed that a combination of both anionic and hydrophobic groups yielded to a very efficient inhibitor. Kinetic studies indicate that at physiologic ionic strength, the best CatG inhibitor (RG1192) has a K i value of 0.11 nM, a value lower or far lower than those previously reported for CatG reversible inhibitors [15,22–28]. Interestingly, while RG1150 and RG1192 inhibited CatG activity and protected matrix proteins from proteolysis in a similar way, only RG1192 presented in vivo tissue repair activity.…”

Section: Discussionmentioning

confidence: 77%

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Heparin‐like dextran derivatives as well as glycosaminoglycans inhibit the enzymatic activity of human cathepsin G

et al. 2003

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Some synthetic dextran derivatives that mimic the action of heparin/heparan sulfate were previously shown to inhibit neutrophil elastase and plasmin. Here we report that these derivatized dextrans also inhibit cathepsin G (CatG). Dextran containing carboxymethyl and benzylamide groups (RG1150) as well as those containing carboxymethyl, sulfate and benzylamide groups (RG1192), were the most e⁄cient inhibitors of CatG activity. RG1192 and RG1150 bind CatG with a K i of 0.11 and 0.17 nM, respectively, while carboxymethylated sulfated dextran (RG1503) as well as heparin, heparan sulfate and dermatan sulfate bind CatG with a 7-to 30-fold lower a⁄nity. Variation of K i with ionic strength indicates that ionic interactions account for 26% of the RG1503^CatG binding energy, while binding of RG1192 or RG1150 to CatG is mainly governed by non-electrostatic interactions. This, together with the fact that these compounds both protect ¢bronectin and laminin against CatG-mediated degradation, suggest that speci¢c dextran derivatives can contribute to the regulation of CatG activity.

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Section: Resultssupporting

confidence: 54%

Section: Discussionmentioning

confidence: 77%

Heparin‐like dextran derivatives as well as glycosaminoglycans inhibit the enzymatic activity of human cathepsin G

et al. 2003

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“…35 Certain thieno [1,3]oxazin-4-ones acted as alternate substrate inhibitors being hydrolyzed by CEase under steady-state conditions via an acylation-deacylation mechanism, similar to the interaction of 3,1-benzoxazin-4-ones and analogous thieno [1,3]oxazin-4-ones with serine proteases. [36][37][38][39][40][41] 2-Diethylamino-6,7-dihydro-4H,5Hcyclopenta [4,5]thieno [2,3-d] [1,3]oxazin-4-one was shown to significantly inhibit the CEase-catalyzed cleavage of cholesterol esters in isolated human high-density lipoproteins. In that study, matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to investigate the extracts of human lipoproteins after treatment with CEase and to monitor the effects of the inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Tricyclic 1,3-Oxazin-4-ones and Kinetic Analysis of Cholesterol Esterase and Acetylcholinesterase Inhibition

Pietsch

Gütschow

2005

J. Med. Chem.

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A series of thieno[1,3]oxazin-4-ones and thieno[1,3]thiazin-4-ones were synthesized and investigated as inhibitors of the alpha/beta hydrolases cholesterol esterase (CEase) and acetylcholinesterase (AChE). The introduction of a cycloaliphatic five- or six-membered ring fused at the thiophene was favorable for CEase inhibition. Such compounds were analyzed as true alternate substrate inhibitors. 6,7-Dihydro-2-(dimethylamino)-4H,5H-cyclopenta[4,5]thieno[2,3-d][1,3]oxazin-4-one (33) exhibited a K(i) value of 630 nM and excelled in its low susceptibility to CEase-catalyzed degradation. Compound 33 and its analogues did not inhibit AChE. The introduction of a tetrahydropyrido ring with bulky hydrophobic substituents at the basic nitrogen provided inhibitors of AChE which were completely inactive toward CEase. 7-Benzyl-5,6,7,8-tetrahydro-2-(N-3,4-dimethoxybenzyl-N-methylamino)-4H-pyrido[4',3':4,5]thieno[2,3-d][1,3]oxazin-4-one (21) had the IC(50) value of 330 nM for AChE inhibition. A residual enzymatic activity at an infinite inhibitor concentration and thus a catalytically active ternary enzyme-substrate-inhibitor complex was concluded. To specify kinetic parameters of inhibition, a new method was derived to characterize selected thieno[1,3]oxazin-4-ones as hyperbolic mixed-type inhibitors of AChE.

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“…Human cathepsin G was assayed spectrophotometrically at 405 nm at 25 °C [ 7 , 8 ]. Assay buffer was 20 mM Tris HCl buffer, 150 mM NaCl, pH 8.4.…”

Section: Methodsmentioning

confidence: 99%

“…Their interaction with serine hydrolases involves the acylation of the active-site serine due to enzymatic ring cleavage, followed by slow deacylation of the acyl-enzyme intermediate [ 1 ]. 2-Amino and 2-alkylthio substituted 4 H -3,1-benzoxazin-4-ones have been characterised as potent inhibitors of human leukocyte elastase (HLE) [ 2 , 3 , 4 , 5 ], cathepsin G [ 6 , 7 ], chymase [ 8 ], C1r serine protease of the complement system [ 9 , 10 ], thrombin [ 11 ], and human cytomegalovirus protease [ 12 ]. 6-Methyl-2- p -tolylamino-4 H -3,1-benzoxazin-4-one (URB754) was identified as a potent inhibitor of the endocannabinoid-deactivating enzyme monoacylglycerol lipase [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

2-Amino- and 2-Alkylthio-4H-3,1-benzothiazin-4-ones: Synthesis, Interconversion and Enzyme Inhibitory Activities

et al. 2009

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The synthetic access to 2-sec-amino-4H-3,1-benzothiazin-4-ones 2 was explored. Compounds 2 were available from methyl 2-thioureidobenzoates 1, 2-thioureidobenzoic acids 3, and novel 2-thioureidobenzamides 6, respectively, under different conditions. 2-Alkylthio-4H-3,1-benzothiazin-4-ones 5 have been prepared from anthranilic acid following a two step route. Both, benzothiazinones 2 and 5 underwent ring cleavage reactions to produce thioureas 1 and 6, respectively. Twelve benzothiazinones were evaluated as inhibitors against a panel of eight proteases and esterases to identify one selective inhibitor of human cathepsin L, 2b, and one selective inhibitor of human leukocyte elastase, 5i.

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Inhibition of cathepsin G by 2-amino-3,1-benzoxazin-4-ones: Kinetic investigations and docking studies

Cited by 14 publications

References 27 publications

Heparin‐like dextran derivatives as well as glycosaminoglycans inhibit the enzymatic activity of human cathepsin G

Heparin‐like dextran derivatives as well as glycosaminoglycans inhibit the enzymatic activity of human cathepsin G

Synthesis of Tricyclic 1,3-Oxazin-4-ones and Kinetic Analysis of Cholesterol Esterase and Acetylcholinesterase Inhibition

2-Amino- and 2-Alkylthio-4H-3,1-benzothiazin-4-ones: Synthesis, Interconversion and Enzyme Inhibitory Activities

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