SYNTHESIS OF NOVEL ANDROGEN-LINKED PHOSPHORAMIDE MUSTARD PRODRUGS ANDGROWTH-INHIBITORY ACTIVITY IN HUMAN BREAST-CANCER CELLS

Two steroid-linked phosphoramide mustard prodrugs, 7a and 7b, were syn thesized. The androgens testosterone and 19-nortestosterone were linke d through the 17 beta-position via an acetal bond to aldophosphamide ( 3). Proton-catalyzed, as well as cytochrome P450-mediated cleavage of the acetal bond resulted in the release of 3 which decays into the ult imate cytotoxic species, phosphoramide mustard. In a competitive cellu lar binding assay, the new prodrugs displayed similar to 10-12% affini ty to androgen binding proteins in breast cancer cells, relative to te stosterone (100%). In the sex hormone receptor negative cell line MDA- MB231, the testosterone conjugate 7a and the 19-nortestosterone conjug ate 7b have been found to be as effective as 4-hydroperoxycyclophospha mide (5). Both compounds were more active than 5 in receptor-positive cell lines. No significant differences in response were observed, howe ver, between receptor-negative and receptor-positive cell lines.