title: A novel approach to preparing water soluble prodrug forms of cisplatin analogues bearing chelating diamines.
abstract: A novel method for creating water soluble prodrugs of cisplatin analogues bearing chelating diamines is introduced. When 2-(amino-methyl)aniline is reacted with K2PtCl4 between a pH of 6 and 7, the neutral chelated complex [2-(aminomethyl)aniline)dichloroplatinum(II) (1) is isolated. On the other hand, when the complexation occurs under acidic conditions (i.e. pH 3), the zwitterionic, "open-ring" form [2-(ammonio-methyl)aniline-N1]trichloroplatinate(II) (2) is obtained, whereby only the aniline nitrogen is coordinated to platinum. Compound 2 has a solubility of 10 mM in acidic aqueous medium; that is ca. 20 times greater than that of 1. However, 2 rapidly converts to compound 1 at physiologic pH; thus 2 functions as a water soluble prodrug of 1. Both 1 and 2 are equally effective at halting the growth of three different human cancer cell lines in vitro, indicating that the prodrug is quantitatively converted to the parent drug in a complex, biologically relevant medium. In animal experiments, the prodrug form, when given at a dose of 25 mumol/kg three times a week for 6 weeks, significantly inhibits the growth of the MXT (M3.2) mammary tumor in BDF mice while the same dose of the parent drug has no antitumor activity.
authors.affiliation: Lehrstuhl für Pharmazeutische Chemie II, Universität Regensburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Köckerbauer
authors.forename: P J
authors.initials: PJ
authors.lastname: Bednarski
mesh_terms: D000818:Animals; D002460:Cell Line; D002614:Chelating Agents / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D013997:Time Factors; D014867:Water
chemical_list: D002614:Chelating Agents; D014867:Water; D002945:Cisplatin; D008727:Methotrexate