RESUMEN
Prussian blue (PB) and its analogues on the nanometric scale are exciting nano-objects that combine the advantages of molecular-based materials and nanochemistry. Herein, we demonstrate that ultra-small PB nanoparticles of 2-3 nm can be easily labelled with radioactive (201)Tl(+) to obtain new nanoprobes as radiotracers for 201-thallium-based imaging.
Asunto(s)
Medios de Contraste , Ferrocianuros , Radioisótopos de Talio , Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Células 3T3 BALB , Medios de Contraste/química , Medios de Contraste/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Ferrocianuros/química , Ferrocianuros/farmacocinética , Humanos , Hígado/diagnóstico por imagen , Hígado/metabolismo , Pulmón/diagnóstico por imagen , Pulmón/metabolismo , Nanopartículas del Metal/química , Ratones , Radioisótopos de Talio/química , Radioisótopos de Talio/farmacocinéticaRESUMEN
Separations of the diastereoisomers of three nucleoside 5'-phosphotriester derivatives of Ara-C (tBuSATE, hydroxy tBuSATE and bishydroxy tBuSATE phenylphosphotriester derivatives; pronucleotides) were performed by HPLC using derivatized cellulose and amylose chiral stationary phases. An optimal baseline separation (Rs>1.5) was readily obtained with an amylose based chiral column (AD-H) used in normal phase mode. This stereospecific HPLC method has been associated to a solid phase extraction step using a C18 cartridge and an internal standard for the quantification of one nucleoside 5'-phosphotriester derivative in cell extracts. After optimization, this method was validated in terms of specificity, recovery, linearity, precision and accuracy and detection limit. It was applied to the determination of the apparent rate constants of disappearance and half-lives of each diastereoisomer. This enabled us to conclude that the enzymatic activity involved in the first step of the decomposition pathway of the hydroxyl tBuSATE phenylphosphotriester of Ara-C is stereoselective and is related to the nature of the pyrimidic base.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Citarabina/química , Citarabina/aislamiento & purificación , Ésteres/química , Ésteres/aislamiento & purificación , Extracción en Fase Sólida/métodos , Cinética , Estructura Molecular , EstereoisomerismoRESUMEN
Synthesis, in vitro anti-HIV activity, stability studies as well as potential for oral absorption of some novel phenyl S-acyl-2-thioethyl (SATE) phosphotriester derivatives of AZT (zidovudine; 3'-azido-2',3'- dideoxythymidine) are reported herein. These mononucleotide prodrugs (pronucleotides) are characterized by the presence of polar (amino or hydroxyl) functions on the SATE biolabile phosphate protections. Whereas pronucleotides incorporating an amino residue in the vicinity of the thioester functionality display low chemical stability, the introduction of one or two hydroxyl groups on the SATE moiety confers high resistance of the resulting prodrugs towards esterase hydrolysis. Thus, one of these pronucleotides, derivative 2, was able to cross a Caco-2 cell monolayer mainly in intact form, probing that its further development is warranted as a possible HIV-pronucleotide candidate.
Asunto(s)
Fármacos Anti-VIH/química , Profármacos/química , Zidovudina/análogos & derivados , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacología , Transporte Biológico Activo , Células CACO-2 , Línea Celular , VIH-1/efectos de los fármacos , VIH-1/fisiología , Semivida , Humanos , Profármacos/metabolismo , Profármacos/farmacología , Nucleótidos de Pirimidina/química , Nucleótidos de Pirimidina/metabolismo , Nucleótidos de Pirimidina/farmacología , Replicación ViralRESUMEN
Alkynylphosphonates belong to a very interesting family as they may be viewed as precursors to a wide range of functionalized derivatives. Considering our ongoing research on 5'-mononucleotides of biological interest, we embarked on the synthesis of such compounds. Despite a limited number of steps, the nucleosidic pathway appeared disappointing. Therefore, an osidic pathway was explored and proved to be interesting. The corresponding optimization study and the synthesis of a new series of nucleoside alkynylphosphonates are described herein.
Asunto(s)
Nucleótidos/síntesis química , Organofosfonatos/síntesis química , Alquenos/síntesis química , Alquenos/química , Nucleótidos/química , Organofosfonatos/químicaRESUMEN
Synthetic pathways to a mononucleotide prodrug of cytarabine (Ara-C) bearing S-pivaloyl-2-thioethyl (tBuSATE) groups, as biolabile phosphate protections, are reported. Using a common phosphoramidite approach, two different kinds of nucleoside protecting groups have been investigated. During this study, we observed an intermolecular migration of the Boc protecting group in the course of the tert-butyldimethylsilyl ether cleavage using tetrabutyl ammonium fluoride.
Asunto(s)
Antimetabolitos Antineoplásicos/síntesis química , Citarabina/síntesis química , Desoxirribonucleótidos/síntesis química , Profármacos/síntesis química , Citarabina/análogos & derivados , Desoxirribonucleótidos/químicaRESUMEN
This review depicts in vitro and in vivo results obtained with nucleotide prodrugs (pronucleotides) bearing S-acyl-2-thioethyl (SATE) groups as esterase-labile phosphate protections. New developments are illustrated by the design of mononucleoside mixed phosphoester derivatives leading to the selective intracellular delivery of the corresponding 5'-mononucleotide through two different enzyme-mediated activation steps.
Asunto(s)
Antivirales/farmacología , Nucleótidos/farmacología , Profármacos/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , División Celular/efectos de los fármacos , VIH-1/efectos de los fármacos , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Cinética , Nucleótidos/síntesis química , Nucleótidos/química , Organofosfatos/química , Organofosfatos/metabolismo , Organofosfatos/farmacocinética , Profármacos/síntesis química , Profármacos/química , Relación Estructura-Actividad , Factores de TiempoRESUMEN
Synthesis and biological activities of several phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group and aryl residues derived from L-tyrosine are reported. All compounds showed marked anti-HIV activity in thymidine kinase-deficient CEM cells demonstrating their ability to deliver intracellularly the parent 5'-mononucleotide.
Asunto(s)
Fármacos Anti-VIH/síntesis química , VIH/efectos de los fármacos , Zidovudina/análogos & derivados , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Transporte Biológico , Línea Celular , Didesoxinucleótidos , Humanos , Estructura Molecular , Timidina Quinasa/deficiencia , Nucleótidos de Timina/farmacocinética , Zidovudina/síntesis química , Zidovudina/farmacocinética , Zidovudina/farmacologíaRESUMEN
The stability of phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group and various aryl residues derived from L-tyrosine was evaluated in biological media. The results demonstrate that such compounds give rise to intracellular delivery of the parent mononucleotide through esterase and phosphodiesterase hydrolytic steps, successively.
Asunto(s)
VIH/efectos de los fármacos , Zidovudina/análogos & derivados , Zidovudina/química , Línea Celular , Didesoxinucleótidos , Estabilidad de Medicamentos , Humanos , Indicadores y Reactivos , Timidina Quinasa/deficiencia , Nucleótidos de Timina/farmacocinética , Tirosina/análogos & derivados , Zidovudina/farmacocinéticaRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Zidovudina/análogos & derivados , Fármacos Anti-VIH/química , Células Cultivadas , Diseño de Fármacos , Estabilidad de Medicamentos , Ésteres/síntesis química , Ésteres/química , Ésteres/farmacología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Profármacos/química , Replicación Viral/efectos de los fármacos , Zidovudina/síntesis química , Zidovudina/farmacologíaRESUMEN
We report the synthesis, in vitro anti-HIV-1 activity and stability study of a mononucleoside phosphotriester derivative of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a new biolabile phosphate-protection, namely S-pivaloyl-2-thioisopropyl (tBuSATP). This transient protection was characterized by the presence of a methyl substituent at the Calpha-position of the previously described S-pivaloyl-2-thioethyl (tBuSATE) group. Results demonstrated that the new phosphotriester entity was able to deliver selectively the corresponding 5'-mononucleotide within the infected cells. The introduction of a methyl group at the Calpha-position of the tBuSATE chain decreased the rate of this delivery.
Asunto(s)
Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Zidovudina/análogos & derivados , Zidovudina/farmacología , Estabilidad de Medicamentos , Análisis Espectral , Relación Estructura-Actividad , Zidovudina/químicaRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Organofosfatos/síntesis química , Profármacos/síntesis química , Zidovudina/análogos & derivados , Zidovudina/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Línea Celular , VIH-1/efectos de los fármacos , Hidrólisis , Organofosfatos/química , Organofosfatos/farmacología , Profármacos/química , Profármacos/farmacología , Relación Estructura-Actividad , Timidina Quinasa/deficiencia , Replicación Viral , Zidovudina/química , Zidovudina/farmacologíaRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Estavudina/análogos & derivados , Zidovudina/análogos & derivados , Línea Celular , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Estavudina/síntesis química , Estavudina/farmacología , Replicación Viral/efectos de los fármacos , Zidovudina/síntesis química , Zidovudina/farmacologíaRESUMEN
Syntheses of non ionic oligodeoxynucleoside phosphoramidates (P-NH2) and mixed phosphoramidate- phosphodiester oligomers were accomplished on automated solid supported DNA synthesizer using both H-phosphonate and phosphoramidite chemistries, in combination with t-butylphenoxyacetyl for N-protection of nucleoside bases, an oxalyl anchored solid support and a final treatment with methanolic ammonia. Thermal stabilities of the hybrids formed between these new analogues and their DNA and RNA complementary strands were determined and compared with those of the corresponding unmodified oligonucleotides, as well as of the phosphorothioate and methylphosphonate derivatives. Dodecathymidines containing P-NH2 links form less stable duplexes with DNA targets, d(C2A12C2) (deltaTm/modification -1.4 degrees C) and poly dA (deltaTm/modification -1.1 degrees C) than the corresponding phosphodiester and methylphosphonate analogues, but the hybrids are slightly more stable than the one obtained with phosphorothioate derivative. The destabilization is more pronounced with poly rA as the target (deltaTm/modification -3 degrees C) and could be compared with that found with the dodecathymidine methylphosphonate. The modification is less destabilizing in an heteropolymer-RNA duplex (deltaTm/modification -2 degrees C). As expected, the P-NH2 modifications are highly resistant towards the action of various nucleases. It is also demonstrated that an all P-NH2 oligothymidine does not elicit Escherichia coli RNase H hydrolysis of the poly rA target but that the modification may be exploited in chimeric oligonucleotides combining P-NH2 sections with a central phosphodiester section.