Design, Synthesis, Characterization, And Biological Activities Of Polyamide-d4T(AZT)H-Phosphonate Conjugates

According to the report that with enhanced antiviral activity and reduce cytotoxicity comparing to the parent nucleoside, O-alkyl-5'-H-phosphonate of d4T (AZT) is the new nucleoside analogs for anti-HIV prodrug trailed in clinic or pre-clinic and have attracted considerable attention of scientists. At the same time, due to the ability of predetermined sequences in the minor groove of DNA recognize, polyamide is almost always used to delivering cytotoxic drugs to specific sequences. Through combining these two kinds of compounds, we would like to develop a series of new and potent anti-HIV prodrugs. Furthermore, the conjugates were modified to have the similar structures with distamycin, a naturally occurring antibiotic.Frist, the oligo-polyamides were synthesized with HOBt/DCC condensation method in high yield. Meanwhile, d4T (AZT) hydrogen phosphonate derivants were obtained through a one-pot route reaction. Then, the conjugates were prepared from the coupling of previously produced polyamide with d4T (AZT) hydrogen phosphonate derivants using the Atherton-Todd method in high yields. Finaly, the Pinner reaction was applied to modify the conjugates which have the similar structure with the natural products distamycin or netropsin. The target compounds: polyamide-nucleoside phosphoramidate derivatives with possibly enhanced anti-HIV and anti-tumor activities were obtained.Anti-HIV activity of Polyamide-d4T(AZT) H-phosphonate conjugates were assayed by the MTT method in vitro using the MT-4 cell line and HIV-1 IIIB strain to give the IC50 value. Monomer and dimer could significantly inhibit the HIV virus and had more active than trimer and tetramer.To better understand the structures of these new conjugates, the ESI-MSn,1HNMR,13C NMRspectra of Polyamide-d4T H-phosphonate conjugates were acquired.