Synthesis, base-catalyzed hydrolytic reactivity, and anticancer evaluation of O-aryl phosphorodiamidates as a novel class of pro(phosphorodiamidic acid mustards)

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Abstract
Bis(2-chloroethyl)phosphoramidic dichloride [MP(O)Cl2, M = N(CH2CH2Cl)2] was used as the starting material for the synthesis of O-aryl phosphorodiamidates having the general structure MP(O)(NHR)OAr: 9, R = H, Ar = 4-NO2C6H4; 10, R = H, Ar = C6F5; 11, R = C6H5, Ar = C6F5; 12, R = 4-MeC6H4, Ar = C6F5; and 13, R = 4-EtOC6H4, Ar = C6F5. The phosphorodiamidic chloride precursor to 13 (14) was also isolated. Kinetics for the base-catalyzed hydrolysis of compounds 9-13 were investigated by UV and NMR methods and are considered in connection with service of these compounds as pro(phosphorodiamidic acid mustards) [MP(O)(NHR)OAr .fwdarw. MP(O)(NHR)OH] via an E1cB mechanism involving the intermediacy of a mustard-bearing metaphosphorodiimide [MP(O) .dbd.NR]. Anticancer screening tests against L1210 lymphoid leukemia in mice indicated that 9-14 are inactive; similar negative results were obtained with the KB [human oral epidermoid carcinoma] cell culture, except in the case of 14 which was marginally active.