A Facile Synthesis And Drug Release Behaviors Of Polymeric Prodrug Of Nucleoside Monophosphate Coupled To Chitosan

In particularly, chitosan, a well-known abundant natural polysaccharide mainly composed of2-amino-2-deoxy-β-D-glucopyranose (D-glucosamine) residues, has been used extensively to deliver drugs and other biologically active components, such as peptides, proteins and oligonucleotides owing to its favorable biological properties such as low toxicity, biocompatibility and biodegradability. Nucleoside analogs have attracted much attention as anti-HIV agents since they are inhibitors of HIV reverse transcriptase (RT). Among them,2’,3’-didehydro-2’,3’-dideoxythymidine (d4T) is antiviral drug for the treatment of AIDS. However, it is found that d4T, do not exert antiviral activity directly after penetrating cells through a passive process, but is successively phosphorylated to the corresponding triphosphates by cellular kinases to terminate the viral DNA elongation through strong inhibition of HIV-RT. In addition, many adverse effects, such as peripheral neuropathy and drug resistance of d4T are frequently observed clinically.Firstly, a one-pot route is applied to synthesis d4T hydrogen phosphonate. Firstly, d4T is phosphorylated by phosphorus trichloride to give a5’-nucleoside phosphoryl dichloride intermediate, then the alcoholysis agent is added in to get the corresponding O-alkyl nucleoside hydrogen phosphonate (different alcoholysis agent to get corresponding O-alkyl phosphonate); And oligo-polyamides containing N-methyl pyrrole rings are synthesized with high yield.Secondly, a novel approach to synthesize polymer-nucleoside monophosphate prodrugs was developed. Chitosan-d4T monophosphate conjugate with reasonable degree of substitution was efficiently synthesized through Atherton-Todd reaction. The drug content of the polymeric prodrug is16.0%and the structure of it was analyzed by31P NMR and1H NMR.Thirdly, in vitro drug release studies in pH1.1and7.4indicated that a major amount of d4T monophosphate derivative and little amount of free d4T were released from the polymeric conjugate for prolonged periods, and the former can bypass the rate-limiting monophosphorylation step of d4T to improve therapy efficacy and reduce side effects. The results suggested that chitosan-nucleoside monophosphate conjugate could be a potential polymeric prodrug for antiretroviral treatment.Lastly, to enhance the hydrophilicity of chitosan, we regioselectivly synthesize3,6-O-disulfated chitosan by protected6-hydroxyl groups. The oleum was used as sulfating agent and dimethylfornamide as medium. The structure of3,6-O-disulfated chitosan was analyzed by FT-IR.