Structure-specific inhibition of cholesteryl ester transfer protein by azaphilones.

The effect of thirteen different fungal azaphilones, which have a common 6-isochromane-like ring, was tested on cholesteryl ester transfer protein (CETP) activity in vitro. Chaetoviridin B showed the most potent inhibitory activity with an IC50 value of <6.2 μM, followed by sclerotiorin with an IC50 value of 19.4 μM. Rotiorin, chaetoviridin A and rubrorotiorin had moderate inhibitory activity (IC50; 30-40 μM), but others showed very weak or no inhibitory activity. The relationship between the structures and their inhibitory activity indicated that the presence of an electrophilic ketone(s) and/or enone(s) at both C-6 and C-8 positions in the isochromane-like ring is essential for eliciting CETP inhibitory activity. The transfer activity of both CE and TG was inhibited by sclerotiorin to approximately the same extent (IC50: 14.4 and 10.3 μM, respectively). A model of the reaction suggested that sclerotiorin reacts with a primary amine of amino acids such as lysine in the protein to form a covalent bond.