Several nucleosides containing 5Ј-sulfur substituents have been discovered in nature and are involved in many important biological processes. One of the most significant processes is the S-adenosyl-L-methionine (AdoMet)-dependent transmethylations. Inhibition of these methyl transfer processes has been correlated with antiviral activity and has attracted considerable attention as a target for the discovery of new antiviral agents.3,4) S-Adenosyl-L-homocysteine (1, AdoHcy), the byproduct of these AdoMet-dependent transmethylations, and some of its structural analogs have been shown to be potent competitive product inhibitors of the AdoMet-dependent methyltransferases.5-15) Our group has also been interested in the synthesis and biological evaluation of several 5Ј-sulfur containing nucleosides. [16][17][18] In continuation of our studies and our longstanding interest in the biological activities of quinazoline derivatives, 19) we initiated an investigation on the synthesis and biological evaluation of 5Ј-sulfur containing quinazoline nucleoside derivatives.Quinazoline nucleosides were first synthesized by Stout and Robins in 1968 as pyrimidine nucleoside analogs 20) and consequent synthetic studies were contributed by Dunkel and Pfleiderer in the 1990s. [21][22][23] Quinazoline nucleosides were once used as a conformationally restricted model to study the syn-anti conformational preference of pyrimidine nucleosides in solution. 24,25) More recently, quinazoline nucleosides have been incorporated into oligonucleotides as pyrimidine nucleoside substitutes to study the binding affinity and basepairing selectivity.26) However, their biological activities are still relatively less known in literature. 4-Amino-1-(b-D-ribofuranosyl)quinazolin-2-one (3) was chosen for our study. This quinazoline nucleoside was previously synthesized from quinazoline-2,4-dione by Stout and Robins as a cytidine (2) analog, 20) and subsequently shown to display the antiviral activity against herpes simplex virus.27) Other derivatives from this nucleoside have rarely been studied. 20,21) In an effort to explore the antivirial profiles and the chemical properties of the 4-aminoquinazolin-2-one nucleoside (3), two target structures containing 5Ј-sulfur substituents (4, 5) were designed as S-adenosyl-L-homocysteine (1, AdoHcy) analogs. Herein, we report an improved synthesis of 3 and the synthesis of 5Ј-alkylthio-5Ј-deoxy quinazolinone nucleosides 4 and 5. Results and DiscussionA perusal of the literature revealed that most of 4-aminoquinazolin-2-one nucleosides were synthesized by ribosylation of quinazoline-2,4-diones followed by functional group interconversions.20,21) Our first effort was to develop a direct synthetic route from 4-aminoquinazolin-2-one 28,29) (7). The heterocycle 7 was prepared via a 1,3-dicyclohexylcarbodiimide (DCC)-mediated cyclodesulfurative annulation reaction developed in our laboratory.30,31) Anthranilamide (6) was condensed with benzoyl isothiocyanate to form the thiourea intermediate which was immediately treated wi...