Inhibition of glyoxalase Iin vitro by flavones

Brandt, Richard B.; Laux, Jerome E.; Thomson, Colin; Johnson, Morris A.; Gross, Marvin A.

doi:10.1002/qua.560260720

Cited by 6 publications

(3 citation statements)

References 7 publications

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“…1158 Other transition state mimetic inhibitors include coumarins and flavones, with the most active being 7,8-dihydroxy-4-phenylcoumarin (Glo1i-8, human Glo1 IC 50 = 3.5 μM) and myricetin (human Glo1 IC 50 = 5 μM). 1159,1167 Further exploration of transition state mimetics was performed analyzing methylated and nonmethylated enediol transition state mimics, which in combination with spectral data indicated that the enediol mimicking moiety of many transition state based inhibitors is involved in metal coordination. 1171 A computational analysis of previously published transition state mimics, demonstrated that the most important motif for activity was a α-hydroxy-α,β-unsaturated carbonyl group attached to a fused ring carbon, such as that present in flavones like myricetin.…”

Section: Lyases (Ec 4x)mentioning

confidence: 99%

“…More active inhibitors included maltol (Glo1i-3, yeast Glo1, K i = ∼400 μM), squaric acid (Glo1i-4, human Glo1, IC 50 = 120 μM), and 2,3-dihydroxy-benzoic acid (Glo1i-5, IC 50 = 280 μM). , An expansion of potential transition state mimetics, including 2,3-dihydroxypyridine (Glo1i-6, human Glo1, IC 50 = 530 μM) and polyphenolic benzohydroxamic acids such as 2,3,4-trihydroxybenzohydroxamic acid (Glo1i-7, human Glo1, IC 50 = 210 μM), were reported . Other transition state mimetic inhibitors include coumarins and flavones, with the most active being 7,8-dihydroxy-4-phenylcoumarin (Glo1i-8, human Glo1, IC 50 = 3.5 μM) and myricetin (human Glo1, IC 50 = 5 μM). , Further exploration of transition state mimetics was performed by analyzing methylated and nonmethylated enediol transition state mimics, which in combination with spectral data indicated that the enediol mimicking moiety of many transition state-based inhibitors is involved in metal coordination . A computational analysis of previously published transition state mimics demonstrated that the most important motif for activity was an α-hydroxy-α,β-unsaturated carbonyl group attached to a fused ring carbon, such as that present in flavones like myricetin .…”

Section: Lyases (Ec 4x)mentioning

confidence: 99%

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Targeting Metalloenzymes for Therapeutic Intervention

et al. 2018

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Metalloenzymes are central to a wide range of essential biological activities, including nucleic acid modification, protein degradation, and many others. The role of metalloenzymes in these processes also makes them central for the progression of many diseases and, as such, makes metalloenzymes attractive targets for therapeutic intervention. Increasing awareness of the role metalloenzymes play in disease and their importance as a class of targets has amplified interest in the development of new strategies to develop inhibitors and ultimately useful drugs. In this Review, we provide a broad overview of several drug discovery efforts focused on metalloenzymes and attempt to map out the current landscape of high-value metalloenzyme targets.

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Section: Lyases (Ec 4x)mentioning

confidence: 99%

Section: Lyases (Ec 4x)mentioning

confidence: 99%

Targeting Metalloenzymes for Therapeutic Intervention

et al. 2018

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“…The latter was a deviation from the original hypothesis which suggested compartmentalization of promine. A postdoctoral investigator in the same lab later found evidence that the natural inhibitor was a avonoid [4]. Also, another student working with wild carrot cells in suspension culture found that somatic embryogenesis therein was enhanced by the addition of buthionine sulfoximine [BSO, a speci c inhibitor of glutathione (GSH) biosynthesis] whereas GSH addition blocked somatic embryogenesis [5].…”

Section: Introductionmentioning

confidence: 99%

Revisiting Szent-Györgyi's Cancer Hypothesis

Johnson¹,

Smits²

2021

Preprint

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Rationale for this communication • -The promine/retine hypothesis on the control of cancer never reached a definite conclusion.• -The chemical natures of promine and retine remain unsettled though usually assumed to be glyoxalases and methylglyoxal.• -Many years ago we published some data that indicated the hypothesis may be operating in plants in which glyoxalase I may exist in normal cells in an inhibited state rather than compartmentalized as in early versions of the hypothesis.• -Manju Ray in India has published many papers claiming that methylglyoxal can be used to successfully treat cancer in humans.• -We present here previously unpublished data that shows depriving glyoxalase I of GSH allows methylglyoxal to kill mouse lymphoma cells. During treatment of two human cancer cell lines, killing of one line was enhanced by blocking thioredoxin as well as GSH.It is hoped that what is conveyed here may reignite interest in the near term. Nuclear methodology and statistics can be found in Figure 1. The data show a strong interaction between the hypothesis and thiols. It is concluded that the hypothesis has yet to be thoroughly investigated.

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Inhibition of glyoxalase I in vitro by coumarin and coumarin derivatives

Brandt

Laux

Yates

et al. 2009

Int. J. Quantum Chem.

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Previous reports from these laboratories on the inhibition of glyoxalase I (S-lactoyl-glutathione methylglyoxal lyase, isomerizing; EC 4.4.1.5) (Glo I) have been presented for various flavones and other compounds. We report here the inhibition of Glo I by coumarin and various coumarin derivatives. Human red blood cell Glo I was purified 7000-fold and the concentration of various coumarins was determined for 50% inhibition (I,) of enzyme activity. These compounds resemble the transition state of the methylglyoxal hemimercaptal as previously reported. The I, varies from 3.5 pA4 to I .9 mM for the compounds tested with the parent compound coumarin having an I, of 1.9 mM. The most inhibitory compounds had hydroxyls at various positions on the coumarin ring system and a phenyl or similar group at the 3 or 4 position on the pyrone ring. Molecular electrostatic potential maps were calculated for three of the compounds tested and they provide suggestive evidence for the inhibitory regions of the molecules.

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Inhibition of glyoxalase Iin vitro by flavones

Cited by 6 publications

References 7 publications

Targeting Metalloenzymes for Therapeutic Intervention

Targeting Metalloenzymes for Therapeutic Intervention

Revisiting Szent-Györgyi's Cancer Hypothesis

Inhibition of glyoxalase I in vitro by coumarin and coumarin derivatives

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