Agnieszka Miazga

Synthesis, biological properties and anti-HIV-1 activity of new pyrimidine P1,P2-dinucleotides.

New homo- and hetero-P1,P2-dinucleotides were prepared with the use of multistep procedures starting from the monophosphates of 3′-fluoro-2-thiothymidine, 3′-fluoro-4-thiothymidine, AZT and 1-[(2-hydroxyethoxy)-methyl-5-propyl-6-phenylselenenyl]uracil. Anti-HIV properties of the synthesized P1,P2-dinucleotides were evaluated against laboratory syncytia inducing strain HIV-1 in CEM-T4 cells. Anti-HIV activities were in the range of 5–45 nM, and therapeutic indexes were higher than 4666–14000. Interactions of the above mentioned compounds with recombinant HIV-1 reverse transcriptase were also investigated. The obtained results point to reverse transcriptase inhibition, with somewhat lower inhibitory activity than that of their parental nucleoside-5′-triphosphates. Compound 6 may be regarded as a potent anti-HIV/AIDS drug.

Thiated Analogues of 2′,3′-Dideoxy-3′-fluorothymidine and Their Phosphorylated and Phosphonylated Derivatives: Synthesis, Interaction with HIV Reverse Transcriptase, and In Vitro Anti-HIV Activity

The search for new, modified 20,30-dideoxynucleosides, potential reverse transcriptase (RT) inhibitors, is still of special interest; bone marrow toxicity and rapidly developing resistance of currently used nucleosides point to the need for new RT inhibitors. 20,30-Dideoxy-30-fluorothymidine (FLT), a pyrimidine 30-deoxy30-substituted thymidine analogue, is one of the most potent in vitro inhibitors of HIV and its reverse transcriptase, but exhibits hematologic toxicity in vivo. It was previously shown that some 5-substituted 20,30-dideoxyuridine derivatives exhibited more selective anti-HIV activity. It appeared to us that an introduction to FLT of the substituents decreasing the pKa value for dissociation of N(3)-H, and enhancing hydrophobic properties of pyrimidine moiety may affect its inhibitory properties, with improved selectivity. It was therefore of interest to synthesize and to test the activity and cytotoxicity of hydrophobic analogues of FLT, and investigate its

Synthesis, Conformation and Biological Properties of Selenonucleosides

Abstract Synthesis, conformation and antitumour properties of novel 2- and 4-selenopyrimidine nucleosides are described.

5'-O-Ester prodrugs of potent and selective anti-HIV agent-2', 3'-dideoxy-3'-fluoro-2-thiothymidine (S2FLT): Synthesis and anti-HIV activity

Abstract Novel synthesis of 2′,3′-dideoxy-3′-fluoro-2-thiothymidine (SFLT) based on transformation of appropriately protected 1-β-D-threo-ribofuranosylthymine is presented. The synthesis and evaluation of SFLT 5′-O-ester prodrugs enzymatic hydrolysis, as well as their anti-HIV activity, is also described.

Myristoylated Derivatives of 2′,3′-didehydro-2′,3′-dideoxythymidine (stavudine) bi-Functional Prodrugs with Potent Anti-HIV-1 Activity and Low Cytotoxicity

Background: To improve in vitro antiviral activity and selectivity of stavudine (d4T), a range of its bi-functional prodrugs, 5′-O-myristoylated derivatives, have been synthesized. Methods: Stavudine 5′-O-myristoylated esters were synthesized using modified Parangs procedure. The cytotoxicity and anti-HIV activity was evaluated in the established MT-4 cell line. The level of p24 protein in culture medium was assayed, and EC50 and EC90 values were determined. Results: Excellent anti-HIV activity was obtained for stavudine derivatives 2′,3′-didehydro-2′,3′-dideoxy-5′-O-(11-thioethylundecanoyl) thymidine, 2′,3′-didehydro-2′,3′-dideoxy-5′-O-(12-thioethyldodecanoyl) thymidine and 5′-O-(12-azidododecanoyl)-2′,3′-didehydro-2′,3′-dideoxythymidine with C10 and C11 alkyl chains bearing thioethyl- and azido- substituents. These prodrugs were more potent than the parent stavudine, as is clear from their EC50 values: 2′,3′-didehydro-2′,3′-dideoxy-5′-O-(11-thioethylundecanoyl) thymidine (R=CO(CH2)10SC2H5, EC50 0.06 μM), 2′,3′-didehydro-2′,3′-dideoxy-5′-O-(12-thioethyldodecanoyl) thymidine (R=CO(CH2)11SC2H5, EC50 0.09 μM) and 5′-O-(12-azidododecanoyl)-2′,3′-didehydro-2′,3′-dideoxythymidine (R=CO(CH2)11N3, EC50 0.06 μM), while 50% cytotoxic concentration was >16.65 μM, >7.5 μM and >18.53 μM, respectively. Conclusions: Overall data demonstrate that compounds 2′,3′-didehydro-2′,3′-dideoxy-5′-O-(11-thioethylundecanoyl) thymidine, 2′,3′-didehydro-2′,3′-dideoxy-5′-O-(12-thioethyldodecanoyl) thymidine and 5′-O-(12-azidododecanoyl)-2′,3′-didehydro-2′,3′-dideoxythymidine are very potent and selective anti-HIV agents and could be useful in treatment of HIV infections of the central nervous system.

Synthesis of 2- or 4-Seleno Analogues of dUMP and FdUMP, and the Corresponding Nucleosides. Interactions with Mammalian Tumour Thymidylate Synthase of the Selenonucleotides and Inhibition of Tumor Cell Growth by the Selenonucleosides

Thymidylate synthase (EC 2.1.1.45), a target enzyme in chemotherapy, catalyzes the N5,10-methylenetetrahydrofolate-dependent C(5) methylation of dUMP. In search of its inhibitors, interactions were compared of new substrate analogues, 4-seleno-dUMP (4-Se-dUMP), 2-seleno-5-fluoro-dUMP (2-Se-FdUMP) and 4-seleno-5-fluoro-dUMP (4-Se-FdUMP), with two thymidylate synthase forms differing in sensitivities towards FdUMP inhibition, isolated from parental and FdUrd-resistant L1210 cell lines (1). The nucleoside forms of the analogues were tested as mouse leukemia L5178Y cell growth inhibitors.