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http://hdl.handle.net/10261/101502
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dc.contributor.author | Diez-Torrubia, Alberto | - |
dc.contributor.author | Cabrera, Silvia | - |
dc.contributor.author | Castro, Sonia de | - |
dc.contributor.author | García-Aparicio, Carlos | - |
dc.contributor.author | Mulder, Gwenn | - |
dc.contributor.author | De Meester, Ingrid | - |
dc.contributor.author | Camarasa Rius, María José | - |
dc.contributor.author | Balzarini, Jan | - |
dc.contributor.author | Velázquez, Sonsoles | - |
dc.contributor.author | Diez-Torrubia, Alberto | - |
dc.date.issued | 2013 | - |
dc.identifier | doi: 10.1016/j.ejmech.2013.10.001 | - |
dc.identifier | issn: 0223-5234 | - |
dc.identifier | e-issn: 1768-3254 | - |
dc.identifier.citation | European Journal of Medicinal Chemistry 70: 456- 468 (2013) | - |
dc.identifier.uri | http://hdl.handle.net/10261/101502 | - |
dc.description.abstract | We herein report for the first time the successful use of the dipeptidyl peptidase IV (DPPIV/CD26) prodrug approach to guanine derivatives such as the antiviral acyclovir (ACV). The solution- and solid-phase synthesis of the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of acyclovir are reported. The synthesis of the demanding tetrapeptide amide prodrug of ACV 3 was first established in solution and successfully transferred onto solid support by using Ellman's dihydropyran (DHP) resin. In contrast with the valyl ester prodrug (valacyclovir, VACV), the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of ACV proved fully stable in PBS. Both prodrugs converted to VACV (for 4) or ACV (for 3) upon exposure to purified DPPIV/CD26 or human or bovine serum. Vildagliptin, a potent inhibitor of DPPIV/CD26 efficiently inhibited the DPPIV/CD26-catalysed hydrolysis reaction. Both amide and ester prodrugs of ACV showed pronounced anti-herpetic activity in cell culture and significantly improved the water solubility in comparison with the parent drug. | - |
dc.description.sponsorship | We thank Ria Van Berwaer and Leentje Persoons for excellent technical assistance. We also thank the Spanish MEC/MICINN (Project SAF2009-13914-C02 and SAF2012-39760-C02), the Comunidad de Madrid (BIPEDD-2-CM ref S-2010/BMD-2457), and the KU Leuven (GOA No. 10/014) for financial support. A Juan de la Cierva contract to S.d.C. (JDC-MICINN) from the Spanish Ministry of Science and Innovation is also gratefully acknowledged. We very much appreciated the helpful discussions with Dr. Judit Tulla- Puche and Prof. Fernando Albericio (IRB Barcelona, Spain). | - |
dc.publisher | Elsevier | - |
dc.rights | closedAccess | - |
dc.subject | Acyclovir | - |
dc.subject | Antiviral | - |
dc.subject | Prodrug | - |
dc.subject | Peptide | - |
dc.subject | Solid-phase synthesis | - |
dc.title | Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme | - |
dc.type | artículo | - |
dc.identifier.doi | 10.1016/j.ejmech.2013.10.001 | - |
dc.relation.publisherversion | http://dx.doi.org/10.1016/j.ejmech.2013.10.001 | - |
dc.date.updated | 2014-09-01T11:17:33Z | - |
dc.description.version | Peer Reviewed | - |
dc.language.rfc3066 | eng | - |
dc.contributor.funder | Ministerio de Educación y Ciencia (España) | - |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | - |
dc.contributor.funder | Comunidad de Madrid | - |
dc.contributor.funder | University of Leuven | - |
dc.identifier.funder | http://dx.doi.org/10.13039/501100004837 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/100012818 | es_ES |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.openairetype | artículo | - |
item.grantfulltext | none | - |
item.cerifentitytype | Publications | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | No Fulltext | - |
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