Cyclophosphamide potentiation and aldehyde oxidase inhibition by phosphorylated aldehydes and acetals

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Abstract
Fourteen phosphorylated acetals and aldehydes were synthesized for testing in vitro as inhibitors or substrates of aldehyde oxidase, an enzyme involved in the conversion of aldophosphamide to inactive carboxyphosphamide, and for concurrent in vivo administration with cyclophosphamide to mice bearing [leukemia] L1210 ascites tumor cells. Five P derivatives gave Ki values of 0.1-0.3 mM compared to 0.03 mM for pyridoxal, as determined in aldehyde oxidase assays using N-methylnicotinamide as the substrate. The most active P inhibitor, ethyl phenyl(2-formylethyl)phosphinate (2b), and pyridoxal gave competitive and mixed inhibition, respectively. Three aldehydes, administered concurrently with cyclophosphamide, produced greater increases in life span of L-1210-implanted mice than did pyridoxal. All 4 agents gave an average increase in life span greater than 50% over that shown by cyclophosphamide alone.

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