SIDE-CHAIN DERIVATIVES OF BIOLOGICALLY-ACTIVE NUCLEOSIDES .1. SIDE-CHAIN ANALOGS OF 3'-AZIDO-3'-DEOXYTHYMIDINE (AZT)

Starting from 3-O-mesyl-1,2-O-isopropylidene-alpha-allofuranose (9) the anomeric mixtures of the requisite carbohydrates 1,2-di-O-acetyl-6-O-benzoyl-5-deoxy-3-O-mesyl-D-allofuranoses 17A-alpha/beta,1,2-di-O-acetyl-5,6-di-O-benzoyl-3-O-mesyl-D-allofuranoses 17B-alpha/beta, and 1,2-di-O-acetyl-5,6-di-O-benzoyl-3-O-mesyl-L-talofuranoses 17C-alpha/beta were synthesized. 1,2-Di-O-acetyl-5-O-benzoyl-6-deoxy-3-O-mesyl-D-allofuranoses 17D-alpha/beta and the corresponding L-talofuranoses 17E-alpha/beta were obtained from 6-deoxy-3,5-di-O-benzoyl-1,2-O-isopropylidene-alpha-D-allofuranose (12) and the corresponding beta-L-talofuranose 13. Coupling of these sugar derivatives with thymine gave the beta-nucleoside derivatives 18A-E. Treatment of compounds 18A-E with DBU produced the corresponding 2,3'-anhydro nucleosides 19A-E with a free 2'-OH group. After deoxygenation of 2'-O-[[(4-methylphenyl)oxy]thiocarbonyl] compounds 20A-E with tributyltin hydride the 2,3'-anhydro bridge of the 2-deoxynucleosides 21A-E was opened with LiN3 to produce the protected 3'-azido-2,3'-dideoxynucleoside derivatives 22A-G. Saponification with NaOCH3 gave 1-(3'-azido-2',3',5'-trideoxy-beta-D-allofuranosyl) thymine (2; homo-AZT), the 5'-C-(hydroxymethyl) derivatives of AZT 1-(3'-azido-2',3'-dideoxy-beta-D-allofuranosyl)thymine (3) and 1-(3'-azido-2',3'-dideoxy-alpha-L-talofuranosyl)thymine (4), and the 5-C-methyl derivatives of AZT 1-(3'-azido-2,3',6'-trideoxy-beta-D-allofuranosyl)thymine (5) and 1-(3-azido-2',3',6'-trideoxy-alpha-L-talfuranosyl)thymine (6). Compounds 2-6 were evaluated for their inhibitory effect on human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) replication in MT-4 cells and found inactive at subtoxic concentrations. Compounds 2-4 and 6 are not effective against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), vaccinia virus (VV), and vesicular stomatitis virus (VSV) at 400-mu-g/mL. 5 is slightly active against HSV-1, HSV-2, and VV at 150, 300, and 300-mu-g/mL, respectively.