title: 5'-aminocarbonyl phosphonates as new zidovudine depot forms: antiviral properties, intracellular transformations, and pharmacokinetic parameters.
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 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.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia. lhba-imb@mail.ru
authors.forename: Anastasia L
authors.initials: AL
authors.lastname: Khandazhinskaya
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Yanvarev
authors.forename: Maxim V
authors.initials: MV
authors.lastname: Jasko
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Shipitsin
authors.forename: Vsevolod A
authors.initials: VA
authors.lastname: Khalizev
authors.forename: Stanislav I
authors.initials: SI
authors.lastname: Shram
authors.forename: Yuriy S
authors.initials: YS
authors.lastname: Skoblov
authors.forename: Elena A
authors.initials: EA
authors.lastname: Shirokova
authors.forename: Marina K
authors.initials: MK
authors.lastname: Kukhanova
mesh_terms: D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D002460:Cell Line; D003692:Delayed-Action Preparations; D004285:Dogs; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011817:Rabbits; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D015215:Zidovudine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D003692:Delayed-Action Preparations; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine