Related compounds were 13 each NONS cyclic skeleton of two L-amino acids, D-amino acids Hydroxyfetts and a 3 Acid, composed been reported, but their biological activity Th are not clearly defined. Zun Highest was found that beauveriolides I and III show very potent activity in inhibiting Anh Ufung of Lipidtr Droplets in macrophages. In addition, our recent study showed on the structure-activity ZD4054 ETA-receptor inhibitor Ts relationship that these T Activity limited to two connections and au Addition to DDL allo Ile Leu and Phe in molecules important for inhibitory activity of t. These results led us to the molecular target beauveriolides to investigate in macrophages. Several types of inhibitors of lipid accumulation in tears pfchens macrophages were reported.
Sterol derivatives as U18666A, progesterone and pregnenolone prevent the movement of cholesterol from the lysosome or inhibit the activity t of multidrug resistance P-glycoproteins In the plasma membrane, and is large number of ACAT inhibitors block cholesterol esterification in the endoplasmic reticulum. These compounds are known to specifically inhibit CE synthesis in AS-605240 macrophages. On the other hand, triacsins, inhibitors of acyl-CoA synthetase to block the accumulation of droplets also Lipidtr But the compounds inhibit both EC and TG synthesis by depletion of acyl-CoA. Beauveriolides specifically inhibit the synthesis of CE, and the site of inhibition is located inside lysosomes l Sst some steps to cholesterol. Therefore, ACAT, an enzyme ER, tested as a target beauveriolide.
Finally, we have shown to inhibit the activity of I and III beauveriolides t ACAT inmicrosomes from mouse macrophages, with IC50 values of 6.0 and 5.5 million, respectively, prepared as liver of M Usen with IC50 values of 1.5 M for both connections. Recent molecular studies, the presence of two isoforms of ACAT 1 and ACAT 2 have revealed. ACAT 1 is ubiquitous R and expressed a high degree of expression in the sebaceous glands, tissues stero DOGenes and macrophages was observed. In rodents, ACAT is 2 Haupt Chlich expressed in the liver and intestines of humans, and it is in the intestines. Therefore, it is strongly recommended that beauveriolides I and III both ACAT 1 and 2 inhibit ACAT in Hnlichen proportions or inhibit ACAT 2, a little st Stronger than ACAT first from the structure-activity ts relationship, the result of the inhibition of ACAT analogues beauveriolide essentially are similar to the results of inhibition of Anh ufung Lipidtr from droplets in macrophages.
In microsomes from mouse macrophages beauvericin has a cyclic structure more inhibited ACAT activity T st Stronger than beauveriolides, but the connection does not show a specific inhibition of the synthesis of EC and had a cytotoxic effect on macrophages. Thus, 13 to 18 is more cha NONS cyclodepsipeptides tested beauveriolides I and III are the only compounds which t and ACAT activity Inhibit and CE synthesis in macrophages, which droplets in a decrease in the accumulation of Lipidtr. Consequently, the anti-atherogenic effect was investigated in vivo beauveriolides in two mouse models. Beauveriolide III proved to be orally active in M Usen knockout and apoE knockout M Usen LDL-R. After oral administration of 25 mg at least 1 Day 1 kg for 2 months at ApoE knockout Mice, atherosclerotic L versions Aorta and