RESUMO
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
Phosphonate derivatives of acyclovir containing phosphorous acid and ethoxycarbonylphosphonic acid residues as well as their isopropyl esters were prepared. They selectively inhibited the herpes simplex virus 1 reproduction in Vero cell culture, the efficacy of esters being 3-4 times higher than that of ACV. The hydrolysis of the synthesized compounds was studied in the PBS buffer and human blood serum.