Kinetics and Mechanism of the Alkaline Hydrolysis of Maleimide

Khan, M. Niyaz

doi:10.1002/jps.2600731227

Cited by 38 publications

(23 citation statements)

References 22 publications

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“…On incubation of U73122 with PBS, the compound was chemically unstable and readily underwent hydrolysis of the maleimide group, a reaction that has been previously characterized with maleimide itself (Khan, 1984). U73122 readily formed a conjugate with glutathione, a ubiquitous thiol source present in cells.…”

Section: Discussionmentioning

confidence: 98%

The Phosphoinositide-Specific Phospholipase C Inhibitor U73122 (1-(6-((17β-3-Methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) Spontaneously Forms Conjugates with Common Components of Cell Culture Medium

Wilsher

Court²,

Ruddle³

et al. 2007

Drug Metab Dispos

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Section: Discussionmentioning

confidence: 98%

The Phosphoinositide-Specific Phospholipase C Inhibitor U73122 (1-(6-((17β-3-Methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) Spontaneously Forms Conjugates with Common Components of Cell Culture Medium

Wilsher

Court²,

Ruddle³

et al. 2007

Drug Metab Dispos

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“…Hydrolysis of maleimides to maleimic acids can compete with thiol modification (23). Hydrolysis of NEM was also reported to be catalyzed by antibody H11 (24) and the Raines group reported that both molybdate and chromate could catalyze the hydrolysis of the imido group in a maleimide conjugate (25).…”

Section: Discussionmentioning

confidence: 99%

Reversibility of Covalent Electrophile−Protein Adducts and Chemical Toxicity

Lin

Saleh

Liebler

2008

Chem. Res. Toxicol.

106

109

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The biotin-tagged electrophiles 1-biotinamido-4-(4′-[maleimidoethylcyclohexane]-carboxamido)butane (BMCC) and N-iodoacetyl-N-biotinylhexylenediamine (IAB) have been used as model electrophile probes in complex proteomes to identify protein targets associated with chemical toxicity. Whereas IAB activates stress signaling and apoptosis in HEK293 cells, BMCC does not. Cysteine Michael adducts formed from BMCC and non-biotinylated analogs rapidly disappeared in the intact cells, whereas the adducts were stable in BMCC-treated subcellular fractions, even in the presence of the cellular reductants reduced glutathione, NADH and NADPH. In contrast, cysteine thioether adducts formed from IAB and its non-biotinylated analogs were stable in intact cells. Loss of the BMCC adduct in cells was reduced at 4 °C, which suggests the involvement of a metabolic process in adduct removal. Model studies with a glutathione-BMCC conjugate indicated rapid hydrolysis of the adducted imide ring, but neither the conjugate nor its hydrolysis product dissociated to release the electrophile in neutral aqueous buffer at significant rates. The results suggest that low BMCC toxicity reflects facile repair that results in transient adduction, which fails to trigger damage signaling pathways.

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“…The maleimide ring is known to undergo hydrolysis to maleamic acid in a pH-dependent manner, especially quickly in alkaline media 19,20 . HPLC analysis of buffered aqueous solutions of maleimides 1-12 revealed that Scheme 1.…”

Section: N-benzylmaleimidementioning

confidence: 99%