title: Convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of metformin.
abstract: A convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of antidiabetic agent, metformin, is reported in this study. These acyclic prodrugs were synthesized directly from selected disulfides with basic metformin and silver nitrate by a one-pot reaction under microwave irradiation. The prepared prodrugs had significantly increased lipophilicity, which resulted in excellent permeability of the octylthio prodrug of metformin across a Caco-2 cell monolayer. According to our preliminary in vivo studies, the octylthio prodrug was also absorbed mostly intact after oral administration in rats. In conclusion, this study shows that these types of more lipophilic sulfenamide prodrugs can be promising candidates to improve permeability and passive absorption of highly water-soluble metformin.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland. Kristiina.Huttunen@uef.fi
authors.forename: Kristiina M
authors.initials: KM
authors.lastname: Huttunen
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.forename: Krista
authors.initials: K
authors.lastname: Laine
authors.forename: Jouko
authors.initials: J
authors.lastname: Vepsäläinen
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003545:Cysteine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism; D008687:Metformin / Q000737:chemistry / Q000378:metabolism; D008872:Microwaves; D010539:Permeability; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D013416:Sulfamerazine / Q000138:chemical synthesis* / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D011355:Prodrugs; C471392:sulfenamide; D008687:Metformin; D005978:Glutathione; D003545:Cysteine; D013416:Sulfamerazine
keywords: Lipophilic; Metformin; Microwave-assisted synthesis; Prodrug; Sulfenamide