Cyclophosphamide potentiation and aldehyde oxidase inhibition by phosphorylated aldehydes and acetals.
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 L1210 ascites tumor cells. Five phosphorus 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 phosphorus inhibitor, ethyl phenyl(2-formylethyl)phosphinate (2b), and pyridoxal were further shown to give competitive and mixed inhibition, respectively. Three aldehydes, administered concurrently with cyclophosphamide, produced greater increases in life span of L1210-implanted mice than did pyridoxal. All four agents gave an average increase in life span greater than 50% over that shown by cyclophosphamide alone.
D000080:Acetals / Q000138:chemical synthesis / Q000494:pharmacology*; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors*; D000447:Aldehydes / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy; D008099:Liver / Q000201:enzymology; D051379:Mice; D011817:Rabbits; D013329:Structure-Activity Relationship
D000080:Acetals; D000447:Aldehydes; D003520:Cyclophosphamide; D000445:Aldehyde Oxidoreductases