Next Generation Anti-HIV Agent 4’-Ethynylstavudine: From the Bench to the Clinic

Much attention has been paid to branched-sugar nucleosides due to their biological activities. During our ongoing research project utilizing unsaturated-sugar nucleosides, epoxy-sugar derivatives were found to be useful precursor for the stereoselective synthesis of these nucleoside derivatives on the basis of their ring opening with organoaluminum or organosilicon reagents. In this chapter, we describe novel synthetic methods for 1’ and 4’-branched-sugar nucleosides. During this research, a novel anti-HIV agent, 4’-ethynylstavudine (4’-Ed4T) has emerged.

4’-Ed4T possessed more potent anti-HIV activity than the parent compound stavudine (d4T). Other characteristic biological properties of 4’-Ed4T are as follows: 1) much less toxic to various cells and also to mitochondorial DNA synthesis than d4T, 2) better substrate for human thymidine kinase than d4T, 3) resistant not only to chemical glycosidic bond cleavage but also to catabolism by thymidine phosphorylase, 4) the activity improves in the presence of a major mutation, K103N, associated with resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs). The detailed antiviral activities, pharmacology and clinical developments (Phase I and Phase IIa) of 4’-Ed4T are described.

Keywords: 4’-ethynylstavudine (4’-Ed4T), anti-HIV-1 agent, clinical development, epoxide, NRTIs, nucleoside, organoaluminum reagent, organosilicon reagent, stavudine.