Quantitative structure-activity relationship of coumarin derivatives : Involvement of partition between aqueous and membrane phase

Abstract

In order to understand the substrate behaviour of several 7-alkoxycoumarins and 7-alkoxy-4-alkylcoumarins towards the liver microsomal monooxygenase system, their lipophilic properties have been examined. As a model for the lipophilicity the reversed-phase liquid chromatographic retention parameter log k w has been used. In a system with methanol-water as the mobile and RP-18 (octadecylsilica) as the stationary phase, we found a quadratic relationship between the volume fraction of the organic solvent and the logarithm of the capacity factor (log k′). The extrapolation to a pure aqueous phase reveals a linear relationship of the theoretical capacity factor log k w with the chain length. This holds for 1–12 carbon atoms in the alkoxy chain and for zero to three carbon atoms in the alkyl chain. Moreover, the incremental effect of the methylene residues on the lipophilicity of the compounds (Δlog k w/ΔCH 2) is found to be 0.60 ± 0.01. If the coumarin derivatives are used as substrates for the liver microsomal monooxygenase system, no systematic dependence of the enzymic data (Michaelis-Menten constant K m) on the lipophilic data (log k w) can be demonstrated. The metabolism of these compounds by the microsomal monooxygenase system seems to be limited by the partition between the membrane and the aqueous phase. Whether other factors, e.g. the lateral diffusion of the substrates versus the membrane-bound enzyme system or enzyme active-site characteristics, govern the metabolism remains to be investigated.