Synthesis and anti-human immunodeficiency virus activity of 4'-branched (+/-)-4'-thiostavudines.
Motivated by our recent finding that 4'-ethynylstavudine (4) is a promising anti-human immunodeficiency virus type 1 (HIV-1) agent, we synthesized its 4'-thio analogue, as well as other 4'-thiostavudines having a carbon substituent at the 4'-position, as racemates in this study. Methyl 3-oxo-tetrahydrothiophen-2-carboxylate (5) was used as a starting material to construct the requisite 4-thiofuranoid glycal (13). Introduction of a thymine base was carried out by an electrophilic addition reaction to 13 using N-iodosuccinimide (NIS) and bis(trimethylsilyl)thymine. The desired beta-anomer (16beta) obtained as a major product in this reaction underwent ready elimination with activated Zn to give the 4'-carbomethoxy derivative (18). By using 18 as a common intermediate, 4'-carbon-substituted (CH2OH, CO2Me, CONH2, CH=CH2, CN, and C(triple bond)CH) 4'-thiostavudines were prepared. Among these six compounds, 4'-cyano (28) and 4'-ethynyl (29) analogues were found to show inhibitory activity against HIV-1 with ED50 values of 7.6 and 0.74 microM, respectively. The activity of 29 was comparable to that of stavudine, but 29 was not as active as 4. Optical resolution of 29 was briefly examined.
Kumamoto
Hiroki
H
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Nakai
Takahito
T
Haraguchi
Kazuhiro
K
Nakamura
Kazuo T
KT
Tanaka
Hiromichi
H
Baba
Masanori
M
Cheng
Yung-Chi
YC
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D018119:Stavudine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D018119:Stavudine