Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin

Autores
Schenfeld, Esteban Martin; Ribone, Sergio Roman; Quevedo, Mario Alfredo
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
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
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
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
Materia
HUMAN SERUM ALBUMIN
MOLECULAR MODELING
PRODRUGS
PROTEIN BINDING
ZIDOVUDINE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/89590
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/89590
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albuminSchenfeld, Esteban MartinRibone, Sergio RomanQuevedo, Mario AlfredoHUMAN SERUM ALBUMINMOLECULAR MODELINGPRODRUGSPROTEIN BINDINGZIDOVUDINEhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Despite 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.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; ArgentinaFil: 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; ArgentinaFil: 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; ArgentinaElsevier Science2018-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/89590Schenfeld, 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; 109-1180928-0987CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejps.2018.01.024info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:07:57Zoai:ri.conicet.gov.ar:11336/89590instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:07:57.927CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin
title Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin
spellingShingle Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin
Schenfeld, Esteban Martin
HUMAN SERUM ALBUMIN
MOLECULAR MODELING
PRODRUGS
PROTEIN BINDING
ZIDOVUDINE
title_short Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin
title_full Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin
title_fullStr Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin
title_full_unstemmed Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin
title_sort Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin
dc.creator.none.fl_str_mv Schenfeld, Esteban Martin
Ribone, Sergio Roman
Quevedo, Mario Alfredo
author Schenfeld, Esteban Martin
author_facet Schenfeld, Esteban Martin
Ribone, Sergio Roman
Quevedo, Mario Alfredo
author_role author
author2 Ribone, Sergio Roman
Quevedo, Mario Alfredo
author2_role author
author
dc.subject.none.fl_str_mv HUMAN SERUM ALBUMIN
MOLECULAR MODELING
PRODRUGS
PROTEIN BINDING
ZIDOVUDINE
topic HUMAN SERUM ALBUMIN
MOLECULAR MODELING
PRODRUGS
PROTEIN BINDING
ZIDOVUDINE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
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
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
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
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/89590
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
0928-0987
CONICET Digital
CONICET
url http://hdl.handle.net/11336/89590
identifier_str_mv 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
0928-0987
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejps.2018.01.024
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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