O-imino esters of N,N-bis(2-chloroethyl)phosphorodiamidic acid. Synthesis, X-ray structure determination, and anticancer evaluation.
Nine representatives of the title series of compounds [(ClCH2CH2)2NP(O)(NH2)ON = CRR'] were synthesized as potential anticancer prodrugs, based on the possibility of enzymatic reduction of the N-O bond to release the known cytotoxic agent phosphoramide mustard [1, (ClCH2CH2)2NP(O)(NH2)OH]. The dimethyl derivative (2, R = R' = CH3) exhibited a statistically significant, albeit low, level of anti-L1210 activity in mice. Derivative 2, which was shown by 31P NMR measurements to be very stable toward hydrolysis at 37 degrees C over a pH range of 5.7-7.4 (T1/2 congruent to 7-8 weeks), gave colorimetrically detectable amounts of alkylating material upon incubation with mouse liver slices: approximately 3-5% conversion after 20 min at 37 degrees C. A single-crystal X-ray study of 2 revealed an unusual hydrogen-bonded "ladder" and a very similar steric relationship for the NCH2CH2Cl and ON = CCH3 moieties.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D003124:Colorimetry; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D010091:Oximes / Q000138:chemical synthesis* / Q000627:therapeutic use; D010752:Phosphoramide Mustards / Q000138:chemical synthesis* / Q000627:therapeutic use; D014961:X-Ray Diffraction
D000970:Antineoplastic Agents; D010091:Oximes; D010752:Phosphoramide Mustards