Synthesis of azidothymidine-bound sulfated alkyl oligosaccharides and their inhibitory effects on AIDS virus infection in vitro

Abstract

In order to sustain an acquired immunodeficiency syndrome (AIDS) drug azidothymidine (AZT) in high level in the blood, novel AZT prodrugs, i.e., AZT-bound sulfated laminaripentaose and AZT-bound sulfated alkyl laminaripentaosides, were synthesized. AZT was introduced into the backbone of laminaripentaose and alkyl laminaripentaoside through biodegradable ester bond to give AZT-bound laminaripentaose and AZT-bound alkyl laminaripentaoside, respectively. Subsequently, they were sulfated with SO3-pyridine complex to produce AZT-bound sulfated laminaripentaose and AZT-bound sulfated alkyl laminaripentaoside. Their anti-Human Immunodeficiency Virus (HIV) activities were assayed in vitro by use of the 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) method. It was revealed that AZT-bound sulfated laminaripentaose exhibited much higher anti-HIV activity (EC50=0.20/μml-1) than AZT-free sulfated laminaripentaose (EC50=160μml-1) even when AZT was not released from sulfated laminaripentaose. and a low cytotoxicity Of CC50 above 1000 μml-1. Moreover, an alkyl group combined to the reducing end of AZT-bound sulfated alkyl laminaripentaoside increased the anti-HIV activity further (EC50=0.04-0.23 μml-1). In addition. AZT-bound sulfated alkyl laminaripentaoside possessed a very low or undetectable anticoagulant activity.