Synthesis and antiviral activities of 1'-carbon-substituted 4'-thiothymidines.
4-Thiofuranoid glycals substituted at the 1-position with methyl (5), (t-butyldimethylsilyloxy)methyl (7), and acetoxymethyl (8) groups were prepared from the 3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) (TIPDS)-4-thiofuranoid glycal (3) by way of LDA-lithiation. N-Iodosuccimide-initiated electrophilic glycosidation between silylated thymine and these 1-carbon-substituted 4-thioglycals gave the respective beta-anomers (9, 10, and 13) stereoselectively. Tin radical-mediated removal of the 2'-iodine atom from these products provided the corresponding 1'-branched 4'-thiothymidine derivatives (11, 12, and 14) in good yields. The 1'-hydroxymethyl derivative (15) served as a precursor for the preparation of the formyl (16), cyanoethenyl (17), and cyano (19) derivatives. Among the deprotected 1'-branched 4'-thiothymidines (20-25), the 1'-methyl analogue 20 showed the most potent anti-HSV-1 activity, but it was much less active than the parent compound 4'-thiothymidine.
Haraguchi
Kazuhiro
K
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. harakazu@pharm.showa-u.ac.jp
Takahashi
Haruhiko
H
Tanaka
Hiromichi
H
Hayakawa
Hiroyuki
H
Ashida
Noriyuki
N
Nitanda
Takao
T
Baba
Masanori
M
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D013872:Thionucleosides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
D000998:Antiviral Agents; D013872:Thionucleosides; C070456:4'-thiothymidine; D013936:Thymidine