title: Cyclic-disulfide-based prodrugs for cytosol-specific drug delivery.
abstract: 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.
authors.affiliation: Department of Process Chemistry, Merck & Co., Inc. Rahway, New Jersey 07065 (USA). gbutora@gmail.com.
authors.forename: Gabor
authors.initials: G
authors.lastname: Butora
authors.forename: Ning
authors.initials: N
authors.lastname: Qi
authors.forename: Wenlang
authors.initials: W
authors.lastname: Fu
authors.forename: Truyen
authors.initials: T
authors.lastname: Nguyen
authors.forename: Hsueh-Cheng
authors.initials: HC
authors.lastname: Huang
authors.forename: Ian W
authors.initials: IW
authors.lastname: Davies
mesh_terms: D003600:Cytosol / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D016503:Drug Delivery Systems; D008968:Molecular Conformation; D011355:Prodrugs / Q000737:chemistry*
chemical_list: D004220:Disulfides; D011355:Prodrugs
keywords: antiviral agents; drug delivery; kinase bypass; nucleosides; prodrugs