Retention mechanism of imidazoles in connective tissue. III. Aldehyde adduct formation of a 4(5H)(or 5(4H))-imidazolone product in vitro

Article abstract of DOI:10.1248/bpb.21.958

2-Methylimidazole (2MI), as well as imidazole, has been thought to undergo cupro-ascorbate (Cu-VC)-catalyzed oxidative transformation in vitro to become a reactive species capable of combining with aldehydes intrinsic to connective-tissue proteins. We attempted to seize the essence of the above reaction through obtaining the structural information of an aldehyde-bonding species. As major products from 2MI in the in vitro Cu-VC system, 2- hydroxymethylimidazole (2(OH)MI) and 2-methyl-4(SH)(or 5(4H))-imidazolone (2MIone) were identified by mass-spectral and chromatographic comparison with the corresponding authentic standards synthesized. The in situ addition of acetaldehyde or propionaldehyde as a simple protein-aldehyde model to the system resulted in the deducible formation of an aldol condensate, 2-methyl- 4(or 5)-ethylidene-4(SH)(or 5(4H))-imidazolone (2MEIone) or its possible analogue with a propylidene moiety, respectively. The authentic compound of 2MIone directly reacted with acetaldehyde and easily afforded the products assignable to the isomers of 2MEIone through the ethylidene moiety at physiological pH and temperature, whereas neither 2MI or 2(OH)MI reacted at all. These results suggest that a 4(SH)(or 5(4H))-imidazolone product, although simply a monooxygenated form, is sufficiently reactive to give aldol condensation-typed covalent adducts with aldehydes, even under physiological conditions, probably having an activated methylene moiety in the ring structure. Based on the present results, we discussed the mechanism of the retention of imidazole-containing drugs in connective tissue.

Full text of DOI:10.1248/bpb.21.958

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