title: Structure-specific inhibition of cholesteryl ester transfer protein by azaphilones.
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.
authors.affiliation: Research Center for Biological Function, The Kitasato Institute, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tomoda
authors.forename: C
authors.initials: C
authors.lastname: Matsushima
authors.forename: N
authors.initials: N
authors.lastname: Tabata
authors.forename: I
authors.initials: I
authors.lastname: Namatame
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: M J
authors.initials: MJ
authors.lastname: Bamberger
authors.forename: H
authors.initials: H
authors.lastname: Arai
authors.forename: M
authors.initials: M
authors.lastname: Fukazawa
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: S
authors.initials: S
authors.lastname: Omura
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002021:Buffers; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D013329:Structure-Activity Relationship
chemical_list: D016632:Apolipoprotein A-I; D001578:Benzopyrans; D002021:Buffers; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006023:Glycoproteins; C101449:sclerotiorin; D008239:Lysine