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dc.contributor.author
Schenfeld, Esteban Martin
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dc.contributor.author
Ribone, Sergio Roman
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dc.contributor.author
Quevedo, Mario Alfredo
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dc.date.available
2019-11-22T18:08:21Z
dc.date.issued
2018-03
dc.identifier.citation
Schenfeld, Esteban Martin; Ribone, Sergio Roman; Quevedo, Mario Alfredo; Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin; Elsevier Science; European Journal Of Pharmaceutical Sciences; 115; 3-2018; 109-118
dc.identifier.issn
0928-0987
dc.identifier.uri
http://hdl.handle.net/11336/89590
dc.description.abstract
Despite its vastly demonstrated clinical efficacy, zidovudine (AZT) exhibits several suboptimal pharmacokinetic properties. In particular, its short plasmatic half-life (t1/2 ~ 1 h) is related to its low bound fraction to whole plasmatic proteins and in particular to human serum albumin (HSA). The design of prodrugs constitutes a promising strategy to enhance AZT pharmacokinetic properties, including its affinity for HSA. Recently, we reported the synthesis and chemical stability evaluation of three novel prodrugs of AZT obtained by derivatization with dicarboxylic acids (1–3). In this work, we present the design, synthesis and evaluation of chemical and enzymatic stabilities of a novel series of double prodrugs of AZT obtained by derivatization of 1–3 with a methylated l-phenylalanine moiety (4–6). In addition, the plasmatic protein binding properties were studied both by experimental and theoretical techniques. Prodrugs 4–6 were found to be relatively stable at pH 7.4 (t1/2 between 4.1 and 57.8 h), while also demonstrated adequate stabilities in human plasma at 37 °C (t1/2 between 1.0 and 2.1 h). Also, prodrugs 4–6 were able to regenerate AZT at a rate that depended on the length of the alkyl chain in 1–3. Additionally, 4–6 exhibited a significantly increased binding to plasmatic proteins (between 52.1 and 72.5%) with respect to AZT (12%) and 1–3 (between 26 and 34%). It is noteworthy that the displacement experiments with HSA site I and II markers, demonstrated that 4–6 bound to a different site than that of AZT and 1–3. Molecular modeling studies (i.e. molecular docking and free energy of binding analysis) were applied to shed light at an atomistic level on the pharmacodynamic properties driving the interaction of 4–6 with HSA. Overall, the present work provides a state of the art contribution to the design and development of novel prodrugs of AZT with optimized pharmacokinetic properties.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Elsevier Science
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
HUMAN SERUM ALBUMIN
dc.subject
MOLECULAR MODELING
dc.subject
PRODRUGS
dc.subject
PROTEIN BINDING
dc.subject
ZIDOVUDINE
dc.subject.classification
Otras Ciencias Químicas
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dc.subject.classification
Ciencias Químicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2019-10-23T21:08:22Z
dc.journal.volume
115
dc.journal.pagination
109-118
dc.journal.pais
Países Bajos
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dc.journal.ciudad
Amsterdam
dc.description.fil
Fil: Schenfeld, Esteban Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina
dc.description.fil
Fil: Ribone, Sergio Roman. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina
dc.description.fil
Fil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina
dc.journal.title
European Journal Of Pharmaceutical Sciences
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.ejps.2018.01.024
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