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ABSTRACT:The main disadvantages of 3-azido-3-deoxythymidine (zidovudine, AZT), the most common anti-HIV drug, are toxicity and a short halflife in the organism. The introduction of an H-phosphonate group into the AZT 5 position resulted in significant improvement of its therapeutic properties and allowed a new anti-HIV drug, Nikavir (AZT H-phosphonate). In this work, we described a new group of AZT derivatives, namely, AZT 5-aminocarbonylphosphonates. The synthesized compounds displayed antiviral properties in cell cultures infected with HIV-1 and the capacity to release the active nucleoside in animals (rabbits and dogs) in a dose-dependent manner. The compounds were less toxic in MT-4 and HL-60 cell cultures and experimental animals compared with AZT. Major metabolites found in MT-4 cells after their incubation with AZT 5-aminocarbonylphosphonate 1 were AZT and AZT 5-phosphate (25 and 55%, respectively). Among the tested compounds, phosphonate 1 was the most effective AZT donor, and its longest t 1/2 and T max values in the line phosphonate 1 -AZT H-phosphonate -AZT imply that compound 1 is an extended depot form of AZT. Although bioavailability of AZT after oral administration of phosphonate 1 was lower than those of AZT H-phosphonate and AZT (8 against 14 and 49%), we expect that this reduction would not cause essential decrease of antiviral activity but noticeably decrease toxicity as a result of gradual accumulation of AZT in blood and the absence of sharp difference between C max and C min . Such a combination of properties makes the compounds of this group promising for further studies as extended-release forms of AZT.The progress toward the treatment of HIV infections has steadily increased in the past 2 decades. At the end of the 1980s, the life expectancy of HIV-infected patients was only 2 to 5 years, whereas today many patients often survive between 10 and 15 years; however, once the infection progresses to full-blown AIDS, the mortality rate is 100%. Currently, more than 20 drugs have been approved for treatment of HIV; these include inhibitors of crucial viral enzymes such as reverse transcriptase, protease, and integrase. Despite significant progress in the design of anti-HIV drugs, many problems remain, such as toxicity and side effects, as well as rapid elimination from the body, resulting in more frequent dosing. More significantly, the development of drug-resistant strains has increased dramatically. As a result, there is a critical need for more effective and less toxic therapeutics.In that regard, HIV reverse transcriptase has proven to be an attractive target. HIV reverse transcriptase inhibitors are primarily modified nucleosides that are converted by way of an intracellular cascade of phosphorylations to the corresponding triphosphates. The triphosphates are then incorporated into the growing DNA chain, which results in termination of DNA synthesis. As the efficacy of the triphosphates is low, drug doses must therefore be high, which generally leads to significant toxicity. One solution ...

A series of pyrophosphoryl (Z)-(phosphonomethoxy)but-2-enyl derivatives of pyrimidines and purines 9a-d and the corresponding phosphonates 10a-d were synthesized. The prepared compounds contain the phosphonate group as an alpha-phosphate mimic as well as an acyclic residue emulating the sugar moiety in 2',3'-dideoxy-2',3'-didehydronucleoside 5'-triphosphates known as highly potent chain terminators of DNA polymerases. Phosphonates 10a-d were obtained by alternative alkylations of the nucleic bases followed by condensation with ethyl [[(p-tolylsulfonyl)oxy]methyl]phosphonate. Pyrophosphorylation of 10a-d afforded phosphonate diphosphates 9a-d. Their substrate properties were evaluated in cell-free systems containing various DNA polymerases including viral reverse transcriptases. Compounds 9a-d manifested good terminating substrate properties toward HIV-1 and AMV reverse transcriptases. They exhibited high selectivity and were not recognized by human DNA polymerases alpha and epsilon, DNA polymerase beta from rat liver, Escherichia coli DNA polymerase I, and HSV-1 and CMV DNA polymerases. Phosphonates 10b-d displayed no activity in HIV-1-infected MT-4 cells cultures; 10a was moderately effective (ED50 = 9 microM).

A series of new 5¢-O-carbamate prodrugs of AZT have been prepared. The stability in biological media, anti-HIV properties and pharmacokinetic parameters in dogs were evaluated. The compounds display moderate anti-HIV activity in cell culture. After oral administration of carbamate IV in dogs, both intact prodrug IV and released AZT were discovered in dog blood. Pharmacokinetic parameters of the compound IV were estimated. Half-life (T 1 ⁄ 2 ) of AZT released after oral administration of IV in dogs was close to that after administration of AZT itself, and time to the maximum concentration (T max ) of AZT released from IV was two and three times longer compared with that of AZT and H-phosphonate AZT, respectively. Acute toxicity was more than five times less if compared with AZT. As a result, we consider this series of carbamate derivatives of AZT as perspective for development of anti-HIV agents.