Synthesis of Azidothymidine-Bound Sulfated Alkyl Oligosaccharides and Their Inhibitory Effects on AIDS Virus Infection in vitro

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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 μg ml−1) than AZT-free sulfated laminaripentaose (EC50=160 μg ml−1) even when AZT was not released from sulfated laminaripentaose, and a low cytotoxicity of CC50 above 1000 μg ml−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 μg ml−1). In addition, AZT-bound sulfated alkyl laminaripentaoside possessed a very low or undetectable anticoagulant activity.