RESUMO
The synthesis and the study of two phosphorothiolate derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group and glucosyl residues associated to the phosphorus atom by a 2-oxyethyl link, are reported. These derivatives could be considered as prototypes of a new series of nucleotide prodrugs (pronucleotides).
Assuntos
Antivirais/síntese química , Nucleosídeos/síntese química , Pró-Fármacos/síntese química , Zidovudina/síntese química , Antivirais/química , Estrutura Molecular , Nucleosídeos/farmacologia , Pró-Fármacos/química , Zidovudina/análogos & derivados , Zidovudina/químicaRESUMO
Synthesis, biological activities and decomposition kinetics of novel phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a S-tButyl-2-thioethyl (tBuSATE) group and L-tyrosinyl residues are reported. All the derivatives appeared to be potent inhibitors of HIV-1 replication in various cell culture experiments. The proposed decomposition process of these mixed phosphotriesters may involve successively an esterase and then a phosphodiesterase activation.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Zidovudina/análogos & derivados , Fármacos Anti-HIV/química , Células Cultivadas , Desenho de Fármacos , Estabilidade de Medicamentos , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Pró-Fármacos/química , Replicação Viral/efeitos dos fármacos , Zidovudina/síntese química , Zidovudina/farmacologiaRESUMO
The synthesis and biological activities of phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a phenyl group or L-tyrosinyl residues are reported. The target compounds were obtained via either P(V) or P(III) chemistry from the appropriate aryl precursors. All the derivatives were evaluated for their in vitro anti-HIV activity, and they appeared to be potent inhibitors of HIV-1 replication in various cell culture experiments, with EC(50) values between the micro- and nanomolar range. Furthermore, compounds incorporating an amino- and/or acid-substituted tyrosinyl residue demonstrated significant anti-HIV effects in thymidine kinase-deficient (TK(-)) cells showing their ability to act as mononucleotide prodrugs. The proposed decomposition process of these mixed mononucleoside aryl phosphotriesters may involve esterase activation followed by phosphodiesterase hydrolysis.
Assuntos
Fármacos Anti-HIV/síntese química , Organofosfatos/síntese química , Pró-Fármacos/síntese química , Zidovudina/análogos & derivados , Zidovudina/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , HIV-1/efeitos dos fármacos , Hidrólise , Organofosfatos/química , Organofosfatos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Timidina Quinase/deficiência , Replicação Viral , Zidovudina/química , Zidovudina/farmacologiaRESUMO
The synthesis and anti-HIV activities of phenyl S-pivaloyl-2-thioethyl (tBuSATE) phosphotriesters of AZT and d4T are reported. These compounds show similar activity compared to bis(tBuSATE) phosphotriesters and appear to be able to deliver the corresponding 5'-mononucleotides inside the cells.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Estavudina/análogos & derivados , Zidovudina/análogos & derivados , Linhagem Celular , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Estavudina/síntese química , Estavudina/farmacologia , Replicação Viral/efeitos dos fármacos , Zidovudina/síntese química , Zidovudina/farmacologiaRESUMO
MonoSATE aryl phosphotriesters of AZT are able to deliver intracellularly the corresponding 5'-mononucleotide. This process requires activation by an esterase followed by a phosphodiesterase. This finding opens the way to the design of new pronucleotide series.
Assuntos
Fármacos Anti-HIV/síntese química , Desenho de Fármacos , Nucleotídeos/síntese química , Pró-Fármacos/síntese química , Zidovudina/análogos & derivados , HumanosRESUMO
The rationale for a pronucleotide approach based on the use of phosphotriesters which incorporate enzyme-mediated bio-labile protection is discussed in detail. Among the studied bio-labile phosphate protecting groups, the S-acyl-2-thioethyl (SATE) groups appeared the most promising as exemplified in cell culture systems in the case of the pronucleotides of 3'-azido-3'-deoxythymidine, 2',3'-didehydro-3'-deoxythymidine, 2',3'-dideoxyadenosine and acyclovir In vivo implementations of such bis(SATE) pronucleotides have been planned for future animal studies.
