Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors

Chiba, Takashi; Ohwada, Jun; Sakamoto, Hiroshi; Kobayashi, Takamitsu; Fukami, Takaaki A.; Irie, Masayasu; Miura, Takaaki; Ohara, Kazuhiro; Koyano, Hiroshi

doi:10.1016/j.bmcl.2012.10.045

Cited by 26 publications

(27 citation statements)

References 19 publications

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“…The binding patterns exhibited here not only match the known key features of ligand-protein interactions revealed by previous structural studies of GLOI-GSH analogue inhibitor complexes, [11] but also shed new light on non-GSH analogue inhibitor development. Two binding features-chelation with a Zn 2 + ion at the active center and interactions with the classical hydrophobic subpocket-that have been successfully employed in seeking highly active GSH analogue inhibitors and the recently developed azaindole-substituted N-hydroxypyridones (K i > 11 nm) do not apply to the interactions between zopolrestat and indomethacin with GLOI.…”

supporting

confidence: 72%

Zopolrestat as a Human Glyoxalase I Inhibitor and Its Structural Basis

Zhai

Zhang

et al. 2013

ChemMedChem

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Glyoxalase I (GLOI, EC 4.4.1.5) is the first and rate-limiting zinc metalloenzyme in the glyoxalase system. GLOI catalyzes the conversion of an a-oxoaldehyde and glutathione (GSH) to an S-2-hydroxyacylglutathione, which is subsequently catalyzed to nontoxic d-lactate and GSH by glyoxalase II (GLOII, EC 3.1.2.6). As a ubiquitous cellular detoxification pathway, the glyoxalase system prevents toxic reactive dicarbonyl species from producing carbonyl stress and forming advanced glycation end products (AGEs) on proteins, lipids, or nucleic acids.[1]The potential of GLOI as an antitumor target dates back to 1969, when Vince and Wadd [2] showed that inhibitors can induce elevated concentrations of methylglyoxal in cancer cells, which ultimately leads to apoptosis. Since that time, highly active GLOI inhibitors based on GSH have been synthesized and have shown promise for inhibiting carcinogenesis and overcoming drug resistance both in vitro and in vivo. [3] However, the inherent structural similarity of these inhibitors to GSH makes them unattractive for drug development.[4] Non-GSH analogue GLOI inhibitors, such as curcumin, [5] methyl-gerfelin, [6] and some natural flavonoid compounds, are far from approval as clinical agents.The discovery by Sato et al. [7] in 2007 that indomethacin, a widely used nonsteroidal anti-inflammatory drug, is a moderate human GLOI inhibitor (K i = 18 mm) provided an interesting case of a non-GSH analogue GLOI inhibitor via drug repositioning. Inspired by that discovery, here, we report that zopolrestat, a powerful aldose reductase inhibitor developed by Pfizer in the 1990s for treatment of diabetic complications, is a potent competitive human GLOI inhibitor with an in vitro K i value of 1.2 mm (Figure 1). Since zopolrestat is structurally dissimilar to GSH and has been evaluated in phase III clinical trials, it will likely have better pharmacokinetic and metabolic prosperities than other known GLOI inhibitors.[8] As such, zopolrestat can serve as a useful template molecule for the design and synthesis of novel GLOI inhibitors.To develop binding models for new inhibitor design, we determined crystal structures of indomethacin and zopolrestat in complex with mouse GLOI (mGLOI) at resolutions of 2.0 and 2.5 , respectively (Figure 2).Mammalian GLOI is a homodimeric enzyme. For both crystal structures, only one of the two active sites (I and II) located at the interface of the two peptide chains (A and B), shows a well-defined inhibitor molecule by a 2Fo-Fc electron density map ( Figure S1 in the Supporting Information). The electron densities in the other active site are too diffuse to confidently locate the inhibitor molecule. To the best of our knowledge, such a difference in the interactions between a ligand and the two active sites of mammalian GLOI has not previously been reported in the literature. It is interesting to note that in a previous study of Plasmodium falciparum monomeric GLOI, [9] two different K i values were observed for curcumin and glutathione-derived transition-state...

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confidence: 72%

Zopolrestat as a Human Glyoxalase I Inhibitor and Its Structural Basis

Zhai

Zhang

et al. 2013

ChemMedChem

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“…[4][5][6][7][8][9][10][11][12][13][14][15][16] One of the most employed compounds that are derivatives of S-(N-aryl-N-hydroxycarbamoyl) glutathione originally prepared by Creighton and colleagues. [4][5][6][7][8] For example, compounds 1-3 are good inhibitors of human GLO1 (hGLO1), with reported comparable K i value of 46, 10, and 14 nM, respectively (Fig.…”

Section: Design Synthesis and Biological Evaluation Of Potent Human mentioning

confidence: 99%

“…12) A few other promising hGLO1 inhibitors worth mentioning are novel 7-azaindole substituted N-hydroxypyridones, 13) 4-bromoacetoxy-1-(S-glutathionyl)-acetoxy butane 14) (4BAB) and chiral unnatural azide carboxylate. 15) Another recent report has described potent GLO1 inhibitor based on derivatives of 2,4-diaminopyrimidine.…”

Section: Design Synthesis and Biological Evaluation Of Potent Human mentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Potent Human Glyoxalase I Inhibitors

Tian

Zhai²,

Xiao

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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Several glutathione derivatives bearing the S-(N-aryl-N-hydroxycarbamoyl) or S-(C-aryl-N-hydroxycarbamoyl) moieties (10, 10′, 13-15) were synthesized, characterized, and their human glyoxalase I (hGLO1) inhibitory activity was evaluated. Compound 10 was proved to be the effective hGLO1 inhibitor with a K i value of 1.0 nM and the inhibition effect of compound 10 on hGLO1 was nearly ten-fold higher than that of the strongest inhibitor 2 (K i =10.0 nM) which has been reported in the field of glutathione-type hGLO1 inhibitors. Its diethyl ester prodrug 10′ was able to penetrate cell membrane and had good inhibitory effect on the growth of NCI-H522 cell xenograft tumor model.

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“…Crystallographic studies indicate that the ability to chelate Zn 2+ at the active center of GLOI plays an essential role for the high inhibitory activity of GSH analog inhibitors (GIP) [3] and non-GSH analog inhibitors (MGI [15] and azaindole-substituted N-hydroxypyridones [16] ). Docking and molecular dynamic simulation analyses also suggest that coordination with Zn 2+ is required for the inhibition of GLOI by curcumin, NSAIDs and flavonoids [10,18,19] .…”

Section: +mentioning

confidence: 99%

“…At present, non-GSH analog inhibitors, such as methylgerfelin (MGI) [15] , azaindole-substituted N-hydroxypyridones [16] , flavonoids [10] , curcumin and its derivatives [17] , and nonsteroidal anti-inflammatory drugs (NSAIDs) [5] , have been identified or synthesized (see Supplementary Table S1 for representative structures and inhibition levels of GLOI inhibitors). Crystallographic studies indicate that the ability to chelate Zn 2+ at the active center of GLOI plays an essential role for the high inhibitory activity of GSH analog inhibitors (GIP) [3] and non-GSH analog inhibitors (MGI [15] and azaindole-substituted N-hydroxypyridones [16] ).…”

Section: +mentioning

confidence: 99%

Structural basis for 18-β-glycyrrhetinic acid as a novel non-GSH analog glyoxalase I inhibitor

et al. 2015

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Aim: Glyoxalase I (GLOI), a glutathione (GSH)-dependent enzyme, is overexpressed in tumor cells and related to multi-drug resistance in chemotherapy, making GLOI inhibitors as potential anti-tumor agents. But the most studied GSH analogs exhibit poor pharmacokinetic properties. The aim of this study was to discover novel non-GSH analog GLOI inhibitors and analyze their binding mechanisms. Methods: Mouse GLOI (mGLOI) was expressed in BL21 (DE3) pLysS after induction with isopropyl-β-D-1-thiogalactopyranoside and purified using AKTA FPLC system. An in vitro mGLOI enzyme assay was used to screen a small pool of compounds containing carboxyl groups. Crystal structure of the mGLOI-inhibitor complex was determined at 2.3 Å resolution. Molecular docking study was performed using Discovery Studio 2.5 software package. Results: A natural compound 18-β-glycyrrhetinic acid (GA) and its derivative carbenoxolone were identified as potent competitive non-GSH analog mGLOI inhibitors with K i values of 0.29 μmol/L and 0.93 μmol/L, respectively. Four pentacyclic triterpenes (ursolic acid, oleanolic acid, betulic acid and tripterine) showed weak activities (mGLOI inhibition ratio <25% at 10 μmol/L) and other three (maslinic acid, corosolic acid and madecassic acid) were inactive. The crystal structure of the mGLOI-GA complex showed that the carboxyl group of GA mimicked the γ-glutamyl residue of GSH by hydrogen bonding to the glutamyl sites (residues Arg38B, Asn104B and Arg123A) in the GSH binding site of mGLOI. The extensive van der Waals interactions between GA and the surrounding residues also contributed greatly to the binding of GA and mGLOI. Conclusion: This work demonstrates a carboxyl group to be an important functional feature of non-GSH analog GLOI inhibitors.

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Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors

Cited by 26 publications

References 19 publications

Zopolrestat as a Human Glyoxalase I Inhibitor and Its Structural Basis

Zopolrestat as a Human Glyoxalase I Inhibitor and Its Structural Basis

Design, Synthesis and Biological Evaluation of Potent Human Glyoxalase I Inhibitors

Structural basis for 18-β-glycyrrhetinic acid as a novel non-GSH analog glyoxalase I inhibitor

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