RESUMO
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.
Assuntos
Química Farmacêutica/métodos , Cumarínicos/química , Água/química , Animais , Carbono/química , Cromatografia Líquida de Alta Pressão/métodos , Concentração de Íons de Hidrogênio , Cinética , Masculino , Espectrometria de Massas/métodos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Modelos Químicos , Oxigênio/química , Solventes/químicaRESUMO
Aryl-substituted 4-hydroxycoumarins (1-57) were investigated by electrospray ionisation (ESI) mass spectrometry. Their fragmentation in the ion source or in the collision cell of a triple quadrupole mass spectrometer was investigated. The effect of the substituents in the aromatic ring on the fragmentation of the 4-hydroxycoumarin derivatives is shown. The influence of the tautomerism on the formation of quasimolecular ions and mass spectral fragmentation was explained. Mass spectral studies on some deuterated compounds proved some of the proposed fragmentation pathways. Results obtained are very useful in the process of detection and characterisation of 4-hydroxycoumarins, as well as for structural elucidation of their more complex derivatives.
