Phosphonate derivatives of ddA, ddC, ddI and ddT (5f, 5e, 5c, and 5a) were prepared by condensing the 5′-aldehydes with diphenyl triphenylphosphoranylidenemethylphosphonate, reducing the resultant olefins and hydrolyzing the phosphonate phenyl esters, sequentially, with base and then C. atrox phosphodiesterase.

Syntheses of Phosphonate Analogues of Dideoxyadenosine (DDA)-, Dideoxycytidine (DDC)-, Dideoxyinosine (DDI)-, and Deoxythymidine (DDT)-5′-Monophosphates

Enzymatic phosphorylation and pyrophosphorylation of 2',3'-dideoxyadenosine-5'-monophosphate, a key metabolite in the pathway for activation of the anti-HIV (human immunodeficiency virus) agent 2',3'-dideoxyinosine

The phosphorylation of thymidine-5′-monophosphate (dTMP) by chick embryo liver thymidylate kinase (Km (dTMP) =1.2 μM) was inhibited by the 5′-monophosphate derivatives of 5-bromo-2′-deoxyuridine (5-Br-dUMP), 5-iodo-2′-deoxyuridine (5-I-dUMP), 2′,3′-dideoxythymidine (ddTMP), 3′-azido-3′-deoxythymidine (AZT-MP) and the methylene phosphonate analogue of AZT-MP with IC50 values of 8, 24, 14, 5 and 6 μM respectively. 5-Fluoro-2′-deoxyuridine (5-F-dUMP) and dUMP were poor inhibitors (IC50 values > 300 μM). 5-Br-dUMP and 5-I-dUMP were found to be significant substrates of thymidylate kinase with phosphorylation efficiencies (Vmax/Km) of 26 and 6% of that of dTMP, respectively. In contrast, AZT-MP and ddTMP were poor substrates, being phosphorylated 800-fold less efficiently than dTMP. Thymidylate kinase was also significantly inhibited by thymidine and AZT. Our data give a better insight into the topology of the dTMP binding site of this enzyme and show that the 3′-hydroxyl group of dTMP plays a critica...

Study of Analogues of Thymidine-5′-Monophosphate and Thymidine as Substrates or Inhibitors of Chick Embryo Liver Thymidylate Kinase

Chromatographic analysis (RTLC) of the urine showed that in the case of i/v injection the proportion of unchanged drug in the urine constitutes 38% of the total radioactivity, in the case of i/p administration 37%, and after p/o administration 17%; chiefly the unchanged preparation is excreted during the first three hours of observation. Four more products were detected in the urine, two of them corresponding to hydrolysis products (Rf 0.05; Rf 0.3), while two were unidentified metabolites (Rf 0.45; Rf 0.55-0.65). The hydrolysis products make a larger contribution to the total radioactivity of the urine than the identified metabolites.

Search for new drugs for the treatment of HIV infections among nucleosides and nucleotides. II

Phosphonate analogues of 5′-O-phosphoryl-2′,3′-dideoxyribofuranosyl adenine, cytosine, hypoxanthine and thymine were synthesized. The hypoxanthine and thymine analogues were inactive against HIV induced cyopathy in the CEM-4 T-cell lines. The 2′,3′-ddC and 2′,3′-ddA analogues were marginally active.

Phosphate Modified Analogues of 5′-O-Phosphorylated 2′,3′-Dideoxynucleosides: Synthesis and Anti-HIV Activity

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Phosphate Modified Analogues of 5′-O-Phosphorylated 2′,3′-Dideoxynucleosides: Synthesis and Anti-HIV Activity