SYNTHESIS AND ANTI-HIV ACTIVITY OF SOME NOVEL CHAIN-EXTENDED PHOSPHORAMIDATE DERIVATIVES OF D4T (STAVUDINE) - ESTERASE HYDROLYSIS AS A RAPID PREDICTIVE TEST FOR ANTIVIRAL POTENCY

Novel chain-extended nucleoside phosphoramidates of the anti-human imm unodeficiency virus (HIV) drug d4T (stavudine) have been prepared as p ossible membrane-permeable prodrugs of the bio-active free 5'-monophos phates. Phosphoro-chloridate chemistry gave the target compounds in mo derate to high yields, and all materials were fully characterized by s pectroscopic and analytical methods. The compounds are related to the previously reported phenyl methoxyalaninyl derivative of d4T, which wa s shown to be a potent and selective inhibitor of HIV. In this study t he amino acid nitrogen and ester moieties were separated by methylene spacers of between two and six carbon atoms. In vitro evaluation of th ese compounds indicated an almost complete lack of anti-HIV activity, the compounds being several orders of magnitude less potent than the c orresponding a-amino acid derivatives. The reasons for the virtual lac k of anti-HIV activity appear to involve poor enzyme-mediated hydrolys is.