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Title
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Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme
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Author
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Abstract
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| 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 solidphase 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. (C) 2013 Elsevier Masson SAS. All rights reserved. |
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Language
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English
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Source (journal)
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European journal of medicinal chemistry. - Paris, 1974, currens
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Publication
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Paris
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2013
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ISSN
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0223-5234
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DOI
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10.1016/J.EJMECH.2013.10.001
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Volume/pages
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70
(2013)
, p. 456-468
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ISI
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000330554400042
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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