Fungal azaphilones inhibit CETP by forming a covalent bond with a lysine amine, with potency tracking ketone placement on the isochromane ring (J Antibiot (Tokyo) 1999)

Original title: Structure-specific inhibition of cholesteryl ester transfer protein by azaphilones

J Antibiot (Tokyo) · 1 February 1999 · 5

Tomoda H, Matsushima C, Tabata N, Namatame I, Tanaka H, Bamberger MJ, Arai H, Fukazawa M, Inoue K, Omura S

Testing thirteen fungal azaphilones sharing a common 6-iso-chromane-like ring against CETP activity in vitro, researchers found chaetoviridin B most potent (IC50 below 6.2 micromolar), followed by sclerotiorin (IC50 19.4 micromolar), with rotiorin, chaetoviridin A, and rubrorotiorin showing moderate activity (IC50 roughly 30 to 40 micromolar) and others weak or no activity. Structure-activity analysis showed that electrophilic ketones or enones at both the C-6 and C-8 positions of the isochromane-like ring were essential for CETP inhibition. Sclerotiorin inhibited both cholesteryl ester and triglyceride transfer to a similar degree (IC50 14.4 and 10.3 micromolar respectively), and modeling suggested it reacts with a primary amine, such as a lysine side chain, on the protein to form a covalent bond.

Original abstract

The effect of thirteen different fungal azaphilones, which have a common 6-iso-chromane-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 microM, followed by sclerotiorin with an IC50 value of 19.4 microM. Rotiorin, chaetoviridin A and rubrorotiorin had moderate inhibitory activity (IC50 ; 30 approximately 40 microM), 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 microM, 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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.