Chromatographic lipophilicity and pharmacokinetic behavior of some newly synthesized styryl lactonestereoisomers

Abstract

The RP-HPLC retention constants of several newly synthesized cytotoxic styryl lactone stereoisomers were determined as parameters of their lipophilicity. Stereochemistry of the compounds has an effect on the retention behavior of only tricyclic isomers. For them, the difference in retention and chromatographic lipophilic parameters are significant. The chromatographic lipophilic parameters of all compounds were correlated with a fourteen computer calculated lipophilic parameters, log P, and pharmacokinetic parameters. Significant linear correlations (R2adj>0.90) were obtained between MLog P and affinity for plasma proteins binding. The correrelations for the other pharmacokinetic parameters were improved by introducing some more molecular descriptors. Multiple linear regression analysis suggested that the volume of distribution depended on the lipopholicity and KaHSA (HSA-human serum albumin) and the absorption through membrane and permeability in the jejunum depend on the lipophilicity and hydrogen bond donors. The tested compounds showed a potent to moderate cytotoxic activity toward several human cancer cells and poor permeation through the blood brain barrier.