Synthesis of 2-Alkylthio Analogues of AZT and Their Activity against HIV-1

p-Alkylated 3'-azido-2',3'-dideoxy-2-thiouridines (5) and their corresponding a anomers have been synthesized through two mutes: 1) by condensation of silylated 2-alkylthiopyridin-4(1H)-ones (2) with methyl 3-azido-5-O-(tert-butyldiphenyIsilyl)-2,3-dideoxy-a,-~-ethro-pentooside (3); 2) by condensation with methyl 5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-3-iodo-a,~-D- threo-pentofuranoside (7, followed by reaction of the obtained iodonucleoside (8) with sodium azide to give the protected azidonucleoside (10) and the 3',4'didehydro-2',3'-dideoxy nucleoside (11).3'-Azido-3'-deoxythymidine (AZT) was the first drug used against acquired immunodeficiency syndrome (AIDS).I4 It was demonstrated that dideoxynucleosides could suppress the replication of human immunodeficiency virus (HIV) in monocytes and macrophages in v i t r ~. ~ During the last ten years a number of 2',3'-dideoxynucleosides derivatives have been identified as being active against H N , at least in vitro, and a great deal of knowledge in terms of structure activity relations has emerged.5-"However, all of these drugs have serious dose-limiting toxicities.