Reactivity of hydrazinophthalazine drugs with the lipid peroxidation products acrolein and crotonaldehyde

The nucleophilic drug hydralazine strongly inhibits cell toxicity mediated by acrolein, a short chain 2-alkenal formed during lipid peroxidation. We here report the chemistry of acrolein-trapping by hydralazine, and show that together with its structural analogue dihydralazine, it also readily traps...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2004-09, Vol.2 (18), p.2578
Main Authors: Kaminskas, Lisa M, Pyke, Simon M, Burcham, Philip C
Format: Article
Language:English
Subjects:
Acrolein - chemistry
Acrolein - toxicity
Aldehydes - chemistry
Aldehydes - toxicity
Animals
Cells, Cultured
Chromatography, High Pressure Liquid
Culture Media
Hepatocytes - drug effects
Hepatocytes - metabolism
Hydralazine - chemistry
Hydralazine - pharmacology
Kinetics
Lipid Peroxidation
Mice
Molecular Structure
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Summary:The nucleophilic drug hydralazine strongly inhibits cell toxicity mediated by acrolein, a short chain 2-alkenal formed during lipid peroxidation. We here report the chemistry of acrolein-trapping by hydralazine, and show that together with its structural analogue dihydralazine, it also readily traps crotonaldehyde. Isolable reaction products included (1E)-acrylaldehyde phthalazin-1-ylhydrazone (E-APH), (1Z)-acrylaldehyde phthalazin-1-ylhydrazone (Z-APH), (1E,2E)-but-2-enal phthalazin-1-ylhydrazone (E-BPH) and (1Z,2E)-but-2-enal phthalazin-1-ylhydrazone (Z-BPH). Concentration-dependent formation of (1E)-acrylaldehyde phthalazin-1-ylhydrazone was observed in the culture media of cells co-exposed to hydralazine and the acrolein precursor allyl alcohol. These aldehyde-sequestering properties of hydrazinophthalazine drugs may contribute to the protection they provide against 2-alkenal-mediated toxicity.
ISSN:1477-0520
1477-0539
DOI:10.1039/B408796H