Microbial Source Of Cetp Inhibition And Macrophage Foam Inhibitors

Atherosclerosis, the principal contributor to the pathogenesis of myocardial and cerebral infarction which are responsible for the mortality in developed countries and in China, is the pathogenesis process induced by various factors such as hyperlipidemia, dyslipoprotein, etc.The cholesterol ester transfer protein (CETP) promotes exchange and transfer of neutral lipids such as cholesterol ester (CE) and triacylglycerol (TG) between plasma lipoproteins with secondary decrease in HDL size and protein content. CETP expression may be positive correlated with development of atherosclerosis.The lipoprotein changes of CETP deficiency (increased HDL and decreased CE in VLDL and IDL) are usually associated with resistance to atherosclerosis, therefore, it is reasonable to expect that in vivo an inhibitor of CETP with retard the progression of atherosclerosis is an possible therapeutic agent.In the early lesions of atherosclerosis, macrophages penetrated into the intima and take up effectively modified low density lipoprotein (LDL) such as oxidized LDL by the scavenger receptor, resulting in foam cell formation in the lesions with accumulated by massive oil droplets consisting of neutral lipids such as cholesterol ester (CE) and triacylglycerol (TG) in the cytoplasin.The process of the macrophage-derived foam cell formation is a novel target of inhibition for antiatherosclerosis. During our screening of microbial fermentation for CETP inhibitor, FO-5637 was found to produce a number of the inhibitors of CETP activity. Two new phenalenone compounds FO-5637 D5N, FO-5637 MN5 and a known compound scleroderolide were isolated from the fermentation broth of SP. FO-5637 by solvent extraction, ODS column chromatography and HPLC. Based on the data of UV, IR, MS and various NMR data, the structures of FO-5637 D5N and FO-5637 MN5 are elucidated as follows:...