Determination of aqueous stability and degradation products of series of coumarin dimers.
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.
Dragojević
Snjezana
S
GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
Sunjić
Vitomir
V
Bencetić-Mihaljević
Vlatka
V
Ralić
Jovica
J
Mesić
Milan
M
Elenkov
Ivaylo Jivkov
IJ
Sucić
Anita Filipović
AF
Klonkay
Andreja Cempuh
AC
Lerman
Lidija
L
Ilijas
Marina
M
Gabelica-Marković
Vesna
V
Malnar
Ivica
I
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*
D003374:Coumarins; D012997:Solvents; D014867:Water; D002244:Carbon; C030123:coumarin; D010100:Oxygen