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 (CE TP) activity bi vitro. Chaetoviridin B showed the most potent inhibitory ac tivity with an TC,, value of < 6.2 mu M, followed by sclerotiorin with an I C50 value of 19.4 mu M. Rotiorin, chaetoviridin A and rubrorotiorin had mod erate inhibitory activity (IC50; 30 similar to 40 mu M), but others showed very weak or no inhibitory activity. The relationship between the structure s and their inhibitory activity indicated that the presence of an electroph ilic ketone(s) and/or enone(s) at both C-6 and C-8 positions in the isochro mane-like ring is essential for eliciting CETP inhibitory activity. The tra nsfer activity of both CE and TG was inhibited by sclerotiorin to approxima tely the same extent (IC50: 14.4 and 10.3 mu M, respectively). A model of t he reaction suggested that sclerotiorin reacts with a primary amine of amin o acids such as lysine in the protein to form a covalent bond.