Active-site directed irreversible inhibition of diamine oxidase by a homologous series of aziridinylalkylamines.
Three electrophilic homologous aminoalkylaziridine analogues of putrescine, cadaverine, and 1,3-diaminopropane were synthesized and found to represent a mechanistically distinct class of irreversible inhibitors of diamine oxidase. The putrescine analogue, N-(4-aminobutyl)aziridine gave the lowest calculated IC50 value, whereas N-(3-aminopropyl)aziridine, an analogue of the poorest substrate of the series, showed the highest IC50. The findings suggest that the aziridinylalkylamines tested are site-directed agents that form irreversible complexes at the active site of diamine oxidase. Affinity of the inhibitors for the active site appeared to be dependent on alkyl chain length, suggesting that binding promotes the reactivity of the aziridinyl group.
Conner
J W
JW
Department of Biomedicinal Chemistry, University of Maryland, Baltimore 21201.
Yuan
Z M
ZM
Callery
P S
PS
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors*; D000818:Animals; D001388:Aziridines / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003959:Diamines / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D011700:Putrescine / Q000378:metabolism; D013552:Swine
D001388:Aziridines; D003959:Diamines; C068990:N-(4-aminobutyl)aziridine; D006631:Amine Oxidase (Copper-Containing); D011700:Putrescine