Inhibition of Glyoxalase I: The First Low-Nanomolar Tight-Binding Inhibitors

More, Swati S.; Vince, Robert

doi:10.1021/jm900382u

Cited by 49 publications

(42 citation statements)

References 31 publications

(54 reference statements)

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“…This was in accordance with our observations with the properties of similar previously reported analogues and derivatives of Ψ-GSH. 21,22 Formation of the γ-glutamyl cysteine amide bond is a rate-limiting step in the synthesis of GSH, a fact that compounds the GCL deficiency in aging and Alzheimer's disease afflicted tissue. 15 Provision of a γ-glutamyl cysteine motif in such cases would address that crucial deficiency.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Potential of a γ-Glutamyl-Transpeptidase-Stable Glutathione Analogue against Amyloid-β Toxicity

Vince

2012

ACS Chem. Neurosci.

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The antioxidant properties of glutathione (GSH) and their relevance to oxidative stress induced pathological states such as Alzheimer's disease is well-established. The utility of GSH itself as a pharmacotherapeutic agent for such disorders is limited because of the former's lability to breakdown through amide cleavage by the ubiquitous enzyme γ-glutamyl transpeptidase (γ-GT). In the present study, a GSH analogue, Ψ-GSH, where the γ-glutamylcysteine amide linkage is replaced with a ureide linkage, was synthesized. Ψ-GSH was found to be stable toward γ-GT mediated breakdown. Ψ-GSH fulfilled four cardinal properties of GSH, namely, traversing across the blood brain barrier (BBB) via the GSH active uptake machinery, replacing GSH in the glyoxalase-I mediated detoxification of methylglyoxal, protecting cells against chemical oxidative insult, and finally lowering the cytotoxicity of amyloid-β peptide. These results validate Ψ-GSH as a viable metabolically stable replacement for GSH and establish it as a potential preclinical candidate for treatment of oxidative stress mediated pathology.

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Section: ■ Results and Discussionmentioning

confidence: 99%

“…22,23 The cell culture media MEM, F12, and fetal bovine serum (FBS) were obtained from Invitrogen (Carlsbad, CA).…”

Section: ■ Methodsmentioning

confidence: 99%

Potential of a γ-Glutamyl-Transpeptidase-Stable Glutathione Analogue against Amyloid-β Toxicity

Vince

2012

ACS Chem. Neurosci.

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“…According to the similar approach, 10′ was prepared (Chart 1). Compound 6 has previously been reported 17) (Fig. 2).…”

Section: Resultsmentioning

confidence: 84%

“…2). On the other hand, intermediate 7 was synthesized from tert-butoxycarbonyl (Boc)-L-Glu(OBn)-OH using modified procedure 17) (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

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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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Synthesis of Carbapenems Containing Peptidoglycan Mimetics and Inhibition of the Cross‐Linking Activity of a Transpeptidase of l,d Specificity

Saidjalolov

Edoo

Fonvielle

et al. 2021

Chemistry A European J

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The carbapenem class of β‐lactams has been optimized against Gram‐negative bacteria producing extended‐spectrum β‐lactamases by introducing substituents at position C2. Carbapenems are currently investigated for the treatment of tuberculosis as these drugs are potent covalent inhibitors of l,d‐transpeptidases involved in mycobacterial cell wall assembly. The optimization of carbapenems for inactivation of these unusual targets is sought herein by exploiting the nucleophilicity of the C8 hydroxyl group to introduce chemical diversity. As β‐lactams are structure analogs of peptidoglycan precursors, the substituents were chosen to increase similarity between the drug and the substrate. Fourteen peptido‐carbapenems were efficiently synthesized. They were more effective than the reference drug, meropenem, owing to the positive impact of a phenethylthio substituent introduced at position C2 but the peptidomimetics added at position C8 did not further improve the activity. Thus, position C8 can be modified to modulate the pharmacokinetic properties of highly efficient carbapenems.

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Inhibition of Glyoxalase I: The First Low-Nanomolar Tight-Binding Inhibitors

Cited by 49 publications

References 31 publications

Potential of a γ-Glutamyl-Transpeptidase-Stable Glutathione Analogue against Amyloid-β Toxicity

Potential of a γ-Glutamyl-Transpeptidase-Stable Glutathione Analogue against Amyloid-β Toxicity

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

Synthesis of Carbapenems Containing Peptidoglycan Mimetics and Inhibition of the Cross‐Linking Activity of a Transpeptidase of l,d Specificity

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