Synthesis and antitumor activity of preactivated isophosphamide analogues bearing modified alkylating functionalities

Article abstract of DOI:10.1021/jm00200a013

In search of cancer chemotherapeutic agents with greater efficacy than cyclophosphamide, 4-hydroperoxyisophosphamide analogues bearing modified alkylating functionalities such as 2-bromoethyl, 2-iodoethyl, 2-methylsulfonyloxyethyl, and 2-ethylsulfonyloxyethyl groups were prepared by ozonolytic cyclization reaction of N,N'-substituted 3-butenyl phosphorodiamidates. Comparative cytotoxicity against L1210 cells and antileukemic life-span activity against L1210 implanted BDF₁ mice of the newly synthesized compounds were tabulated. The 4-hydroperoxyisophosphamide analogues which have different alkylating groups in a molecule showed slightly greater cytotoxicity in vitro than those with the same alkylating groups. Most of the compounds having different alkylating groups also showed high antileukemic activity in vivo. Among them, the highest efficacy was found for 2-[N-methyl-N-(2-chloroethyl)]amino-3-(2-methylsulfonyloxyethyl)- 4-hydroxyperoxy-1,3,2-oxazaphosphorinane 2-oxide (NSC 280122D) whose life-span activity was also greater than that of 4-hydroxyperoxyisophosphamide, cyclophosphamide, and isophosphamide. The superiority of this compound was especially apparent by oral administration.