SYNTHESIS AND EVALUATION OF 5-HALO 2',3'-DIDEHYDRO-2',3'-DIDEOXYNUCLEOSIDES AND THEIR BLOCKED PHOSPHORAMIDATES AS POTENTIAL ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS AGENTS - AN EXAMPLE OF KINASE BYPASS

A series of 5-halo derivatives of the anti-human immunodeficiency viru s (HIV) nucleoside analogue d4T have been prepared by a general and hi ghly stereoselective route. A key step is the electrophilic addition o f N-iodosuccinimide to furanoid glycals. The 2'-iodo nucleosides thus obtained produced the corresponding 2',3'-didehydro-2',3'-dideoxynucle oside in a two-step elimination reaction upon treatment with potassium t-butoxide followed by sodium methoxide. The derivatives were rested for their ability to inhibit the replication of HIV-1 and HIV-2 in cel l culture. Replacement of the thymine 5-methyl group of the parent nuc leoside analogue (d4T) by I, CI or F resulted in compounds that showed poor antiviral activity. In view of this, we studied the application of blocked phosphate (phosphoramidate) technology to probe the efficac y of intracellular monophosphate delivery in these systems. In one cas e, significant antiviral potency was obtained in this way.