Cyclic-Disulfide-Based Prodrugs for Cytosol-Specific Drug Delivery

Autor:	Ning Qi, Hsueh-Cheng Huang, Gabor Butora, Truyen Nguyen, Wenlang Fu, Ian W. Davies
Rok vydání:	2014
Předmět:	chemistry.chemical_classification Chemistry Molecular Conformation Protide General Chemistry General Medicine Prodrug Catalysis In vitro Cytosol Enzyme Drug Delivery Systems Biochemistry In vivo Drug delivery Prodrugs Disulfides Intracellular
Zdroj:	Angewandte Chemie. 126:14270-14274
ISSN:	0044-8249
Popis:	The cytosolic conversion of therapeutically relevant nucleosides into bioactive triphosphates is often hampered by the inefficiency of the first kinase-mediated step. Nucleoside monophosphate prodrugs can be used to bypass this limitation. Herein we describe a novel cyclic-disulfide class of nucleoside monophosphate prodrugs with a cytosol-specific, reductive release trigger. The key event, a charge-dissipating reduction-triggered cyclodeesterification leads to robust cytosolic production of the cyclic 3',5'-monophosphate for downstream enzymatic processing. The antiviral competence of the platform was demonstrated with an O-benzyl-1,2-dithiane-4,5-diol ester of 2'-C-methyluridine-3',5'-phosphate. Both in vitro and in vivo comparison with the clinically efficacious ProTide prodrug of 2'-deoxy-2'-α-fluoro-β-C-methyluridine is provided. The cytosolic specificity of the release allows for a wide range of potential applications, from tissue-targeted drug delivery to intracellular imaging.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2d3bc2d00e16e8d10d7ac47fd2fd814d https://doi.org/10.1002/ange.201407130 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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