Next Generation Anti-HIV Agent 4’-Ethynylstavudine: From the Bench to the Clinic
Pp. 123-184 (62)
Kazuhiro Haraguchi, Shingo Takeda, Yutaka Kubota, Hiroki Kumamoto, Hiromichi Tanaka, Takayuki Hamasaki, Masanori Baba, Elijah Paintsil, Yung-Chi Cheng and Yasuo Urata
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.
4’-ethynylstavudine (4’-Ed4T), anti-HIV-1 agent, clinical
development, epoxide, NRTIs, nucleoside, organoaluminum reagent,
organosilicon reagent, stavudine.
Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, 10281 Komuro, Inamachi, Kita-adachi-gun, Saitama 362-0806, Japan.