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

Abstract

Bis(2-chloroethyl)phosphoramidic dichloride [MP(O)Cl2, M = N(CH2CH2Cl)2] has been 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 leads to MP(O)(NHR)OH] via an E1cB mechanism involving the intermediacy of a mustard-bearing metaphosphorodiimide [MP(O)=NR]. Anticancer screening tests against L1210 lymphoid leukemia in mice indicated that 9--14 are inactive; similar negative results were obtained with the KB cell culture, except in the case of 14 which was marginally active.

Synthesis and Evaluation of 3-Halocyclophosphamides and Analogous Compounds as Novel Anticancer “Pro-Prodrugs”

“…Studies of such prodrugs by Zon et al (3)(4)(5)(6)(7)(8) have included labile precursors of the wellknown anticancer agent cyclophosphamide (I) (9). Since I functions as a prodrug (2,9), these in uiuo precursors of cyclophosphamide may be viewed as "pro-prodrugs."…”