Determination of aqueous stability and degradation products of series of coumarin dimers

• Published in: Journal of pharmaceutical and biomedical analysis 2011-01, Vol.54 (1), p.37-47
• Main Authors: Dragojević, Snježana, Šunjić, Vitomir, Bencetić-Mihaljević, Vlatka, Ralić, Jovica, Mesić, Milan, Elenkov, Ivaylo Jivkov, Sučić, Anita Filipović, Klonkay, Andreja Čempuh, Lerman, Lidija, Ilijaš, Marina, Gabelica-Marković, Vesna, Malnar, Ivica
• Format: Article
• Language: English
• Subjects: Analysis; Analytical, structural and metabolic biochemistry; Animals; aqueous solutions; Aqueous stability; Biological and medical sciences; Carbon - chemistry; Chemistry, Pharmaceutical - methods; Chromatography, High Pressure Liquid - methods; coumarin; Coumarin dimers; Coumarins - chemistry; Decomposition rate; Fundamental and applied biological sciences. Psychology; General pharmacology; HPLC-DAD–MS analysis; Hydrogen-Ion Concentration; in vivo studies; isomers; Kinetics; Male; Mass Spectrometry - methods; Medical sciences; Metabolic stability; Mice; Microsomes, Liver - drug effects; Models, Chemical; oxidation; Oxygen - chemistry; Pharmacology. Drug treatments; Solvents - chemistry; Water - chemistry
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2010.08.002

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.