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.
A series of pyridine-2-carboxaldehyde N-oxide and pyridine-2-carboxaldehyde (thio)phosphoric hydrazones and two cupric chelates was synthesized. The hydrazones, chelates, and combinations of hydrazones and cupric chloride were tested against mice bearing P388 lymphocytic leukemia, Sarcoma 180, or Ehrlich carcinoma ascites cells. The effects of various structural modifications of the hydrazones on antineoplastic activity for this latter system were determined. In general, the pyridine-2-carboxaldehyde thiophosphoric monohydrazones containing P-phenyl or P-phenoxy substituents possessed the highest activity when concurrently administered with cupric ion, whereas the ligands themselves were inactive. Two of the compounds were prepared with P-hydroxyl groups to permit increased hydrophilicity. The ability of the hydrazones to chelate cupric, ferrous, and cobaltous salts was investigated, and discrepancies between determined and calculated log P values for three compounds are discussed.
Die Phosphor‐hydrazone (I)‐(IV) werden aus entsprechenden Hydraziden und Pyridin‐2‐aldehyd oder seinem N‐Oxid in Ethanol in Gegenwart von Essigsäure dargestellt und als solche oder als Kupfer(II)‐Chelate bzw. in Kombination mit Kupfer(II)‐chlorid auf Antitumorwirkung untersucht.
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