Abstract
The main disadvantages of 3′-azido-3′-deoxythymidine (zidovudine, AZT), the most common anti-HIV drug, are toxicity and a short half-life 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 t1/2 and Tmax 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 Cmax and Cmin. Such a combination of properties makes the compounds of this group promising for further studies as extended-release forms of AZT.
Footnotes
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The work was supported in part by the President Program for Young Scientists (Project MK-4427.2007.4); the Russian Foundation for Basic Research (Project No. 08-04-00552); and the Program of Presidium of Russian Academy of Sciences on Molecular and Cellular Biology.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.022269.
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ABBREVIATIONS: AZT, 3′-azido-3′-deoxythymidine, zidovudine; HPLC, high-pressure liquid chromatography; [6-3H]-1,5′-aminocarbonylphosphonyl-3′-azido-3′-deoxy-[6-3H]thymidine; AZT-MP, 3′-azido-3′-deoxythymidine 5′-monophosphate; AUC, area under concentration-time curve from 0 to ∞.
- Received June 27, 2008.
- Accepted December 22, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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