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The Activity Modification Of Anti-hiv Nucleoside Analogues

Posted on:2008-06-05Degree:MasterType:Thesis
Country:ChinaCandidate:H B ZhangFull Text:PDF
GTID:2181330434975460Subject:Pharmaceutical Engineering
Abstract/Summary:PDF Full Text Request
With enhanced antiviral activity and reduced cytotoxicity comparing to the parent nucleoside, O-alkyl-5’-H-phosphonate of d4T and phosphoramidate derivatives of d4T are the new nucleoside analogs for anti-HIV prodrugs trailed in clinic or pre-clinic. Thus they have shown promise as potent antiviral agents. It’s very important to study the methodology for the synthesis of these compounds. In this dissertation we designed a new phosphoramidate derivative of d4T and described a novel and facile method for preparing the target compound.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 corresponding0-alkyl phosphonate); And oligo-polyamides containing N-methyl pyrrole rings are synthesized with high yields.A novel approach to synthesize phosphoramidate following the Atherton-Todd reaction is described. Firstly, the4-nitro on the oligo-polyamide chain containing N-methyl pyrrole ring is deoxidized to4-amido by Pd/C under a H2pressure in THF, and the O-iso-propyl phosphonate of d4T is dissolved with THF in an ice bath, then combined the two solutions with carbon tetrachloride as chloridization agent and triethylamine as proton-trapped agent added in, and the conjugated product is given with a high yield. The reaction mentioned above made the conjugation between amine on N-methyl pyrrole ring and hydrogen phosphonate come true firstly, and it provided basis for the P-N formation on the aromatic amine. It also enriched the contents of the phosphorus chemistry, with very important methodology meanings.Finally, the Pinner reaction is applied to modify the compound mentioned above, to simulate natural products distamycin or netropsin with anti-virus activity structurally. Then we got a phosphoramidate derivative with enhanced anti-HIV and anti-tumours activities possibly.
Keywords/Search Tags:nucleoside, hydrogen phosphonate, Atherton-Todd reaction, phosphoramidate, HIV nucleoside reverse transcriptaseinhibitors (NRTIs)
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