RESUMO
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.
Assuntos
Inibidores da Transcriptase Reversa/farmacologia , Zidovudina/farmacologia , Animais , Disponibilidade Biológica , Biotransformação , Linhagem Celular , Preparações de Ação Retardada , Cães , Feminino , Espectroscopia de Ressonância Magnética , Masculino , Coelhos , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/toxicidade , Zidovudina/farmacocinética , Zidovudina/toxicidadeRESUMO
An effective synthesis of 5'-carbamoylphosphonyl-[6-3H]-AZT was developed from [6-3H]-AZT. For the synthesized compound, chemical and enzymatic stability were determined and its penetration across HL-60 cell membranes was studied.
Assuntos
Zidovudina/análogos & derivados , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Biotransformação , Cães , Desenho de Fármacos , Estabilidade de Medicamentos , Células HL-60 , Meia-Vida , Humanos , Técnicas In Vitro , Coelhos , Trítio , Zidovudina/química , Zidovudina/farmacocinética , Zidovudina/farmacologiaRESUMO
Biochemical and metabolic transformations of 3'-azido-3'-deoxythymidine 5'-choline phosphate (1) were studied using its 32P-labelled counterpart for the evaluation of possible reasons for its enhanced anti-HIV activity. An effective synthesis of 32P-labelled 1 with a specific activity >1,000 Ci/mmol was developed by esterification of 32P-phosphoric acid with choline in the presence of BrCN followed by the coupling of the resulting choline phosphate with 3'-azido-3'-deoxythymidine (AZT). Chemical and enzymatic stabilities of 1 as well as the dynamics of penetration through HL-60 cell membranes were studied at the concentrations comparable to its antiviral concentrations. The products of intracellular transformations of the studied nucleotide were identified.
Assuntos
Fármacos Anti-HIV/metabolismo , Timidina Monofosfato/análogos & derivados , Zidovudina/análogos & derivados , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Transporte Biológico , Biotransformação , Extratos Celulares/química , Didesoxinucleotídeos , Enzimas/química , Células HL-60 , Humanos , Timidina Monofosfato/síntese química , Timidina Monofosfato/química , Timidina Monofosfato/metabolismo , Zidovudina/síntese química , Zidovudina/química , Zidovudina/metabolismoRESUMO
Two series of new lipophilic phosphonoformate and phosphonoacetate derivatives of AZT and d4T were synthesized and evaluated as anti-HIV agents. The efficacy of some of the synthesized compounds in cell cultures infected with HIV-1 was higher than that of the parent nucleosides and only slightly correlated to their stability in the phosphate buffer and human blood serum. The synthesized phosphonates are most probably prodrug forms of the corresponding nucleosides.
Assuntos
Fármacos Anti-HIV/síntese química , Foscarnet/análogos & derivados , Ácido Fosfonoacéticos/análogos & derivados , Pró-Fármacos/síntese química , Estavudina/análogos & derivados , Zidovudina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Estabilidade de Medicamentos , Foscarnet/síntese química , Foscarnet/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Hidrólise , Ácido Fosfonoacéticos/síntese química , Ácido Fosfonoacéticos/farmacologia , Pró-Fármacos/farmacologia , Estavudina/síntese química , Estavudina/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Zidovudina/síntese química , Zidovudina/farmacologiaRESUMO
5'-Aminocarbonylphosphonyl and aminocarbonylmethylphosphonyl diesters of AZT and d4T were synthesized as potential anti-HIV agents.
Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Estavudina/análogos & derivados , Estavudina/síntese química , Zidovudina/análogos & derivados , Zidovudina/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Estabilidade de Medicamentos , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Organofosfonatos , Estavudina/química , Estavudina/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos , Zidovudina/química , Zidovudina/farmacologiaRESUMO
Carbocyclic alpha, gamma-bis(nucleoside)-5,5'-triphosphonates and alpha, delta-bis(nucleoside)-5,5'-tetraphosphonates (Ap4A and Gp4G) analogues were shown to be a new type of terminating substrate of HIV reverse transcriptase. They effectively inhibited the DNA synthesis catalyzed by this enzyme in model cell-free systems, but their antiviral activity both in Rat1 fibroblast cell culture bearing MLV reverse transcriptase and in HIV-infected MT-4 cells was low. When a liposome delivery system was used, the antiviral efficacy of the compounds under study was increased.