title: Determination of aqueous stability and degradation products of series of coumarin dimers.
abstract: The stability in aqueous solution of five classes of coumarin dimers (I-V, compounds 1-29) was studied by HPLC-MS/MS at various pH values. The relationship between chemical structure and stability is discussed. It was found that dimeric compounds with strong electron withdrawing groups (EWGs) on the α-carbon to the bridging C-atom are stable at all pH values, whereas other derivatives undergo retro-Michael addition at rates which are also affected by the substituents on the aromatic rings. In some cases formation of stable isomers or oxidation products was observed. In order to evaluate their developability and potential for progression to in vivo studies, representative compounds were tested in an in vitro microsomal stability assay.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
authors.forename: Snjezana
authors.initials: S
authors.lastname: Dragojević
authors.forename: Vitomir
authors.initials: V
authors.lastname: Sunjić
authors.forename: Vlatka
authors.initials: V
authors.lastname: Bencetić-Mihaljević
authors.forename: Jovica
authors.initials: J
authors.lastname: Ralić
authors.forename: Milan
authors.initials: M
authors.lastname: Mesić
authors.forename: Ivaylo Jivkov
authors.initials: IJ
authors.lastname: Elenkov
authors.forename: Anita Filipović
authors.initials: AF
authors.lastname: Sucić
authors.forename: Andreja Cempuh
authors.initials: AC
authors.lastname: Klonkay
authors.forename: Lidija
authors.initials: L
authors.lastname: Lerman
authors.forename: Marina
authors.initials: M
authors.lastname: Ilijas
authors.forename: Vesna
authors.initials: V
authors.lastname: Gabelica-Marković
authors.forename: Ivica
authors.initials: I
authors.lastname: Malnar
mesh_terms: D000818:Animals; D002244:Carbon / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003374:Coumarins / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D008956:Models, Chemical; D010100:Oxygen / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: D003374:Coumarins; D012997:Solvents; D014867:Water; D002244:Carbon; C030123:coumarin; D010100:Oxygen