title: Design, synthesis, and evaluation of novel cyclic phosphates of 5-aminosalicylic acid as cytochrome p450-activated prodrugs.
abstract: Four novel cyclic phosphates of the anti-inflammatory agent 5-aminosalicylic acid (5-ASA) were designed and synthesized as cytochrome P450 (CYP)-activated prodrugs. These prodrugs can be used for targeting into gut wall, since these types of cyclic phosphates are known to be activated mainly by CYP3A forms, which are expressed not only in the liver but also in the small intestine and to a lesser extent in the colon. The present study shows that aromatic ring activating substituents, like chlorine, are definitely needed to obtain the desired enzymatic cleavage of the cyclic phosphate prodrugs of 5-ASA. However, the position of the activating substituent has also a strong impact on the chemical stability, and therefore, an appropriate balance between the rates of prodrug bioactivation and chemical stability needs to be taken into consideration in future studies on cyclic phosphate prodrugs of 5-ASA.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Kristiina M
authors.initials: KM
authors.lastname: Huttunen
authors.forename: Niina
authors.initials: N
authors.lastname: Tani
authors.forename: Risto O
authors.initials: RO
authors.lastname: Juvonen
authors.forename: Hannu
authors.initials: H
authors.lastname: Raunio
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D019804:Mesalamine / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D011355:Prodrugs; D019804:Mesalamine; D003577:Cytochrome P-450 Enzyme System