O-imino esters of N,N-bis(2-chloroethyl)phosphorodiamidic acid. Synthesis, X-ray structure determination, and anticancer evaluation

Article abstract of DOI:10.1021/jm00366a029

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°C over a pH range of 5.7-7.4 (τ 1/2 ? 7-8 weeks), gave colorimetrically detectable amounts of alkylating material upon incubation with mouse liver slices: ~3-5% conversion after 20 min at 37°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.