Lipid droplets accumulation in macrophages is one of the central stages of foam cells formation leading to the development of atherosclerosis in the arterial wall. Inhibition of lipid droplets accumulation in macrophages may control atherosclerogenesis. Beauveriolide III (1), isolated from the culture broth of Beauveria sp. FO-6979, is a 13 membered cyclic depsipeptide and leads to reduction of the number and size of lipid droplets in macrophages without any cytotoxic effect on macrophages. Its in vivo efficacy was shown in LDL receptor knockout mice, reducing the atherogenic lesion in aortas and hearts. Although 1 was expected as a potential lead compound for the treatment and the prevention of atherosclerosis, its structure-activity relationships have not been clearly elucidated. Herein we report an efficient route to synthesize a library of beauveriolide analogues using solid support and their biological evaluation Our synthetic strategy involves solid phase assembly of linear depsipeptide followed by solution phase macrolactamization as shown in Scheme 4. Loading of Fmoc alanine A onto 2-chlorotrityl chloride resin 23, condensation with Fmoc phenylanine B followed by coupling with ester unit C using PyBrop gave 25. Deprotection and cleavage from the resin under acid condition released linear depsipeptide 22 in 93% purity and 98% crude yield. Finally, the cyclization of 22 with EDCI and i-Pr_2NEt under high dilution condition was attained to provide beauveriolide III (1) in 51% yield. Based on this strategy, a library synthesis of beauveriolide analogues composing building blocks A, B and C was achieved by split & pool method using AccuTag^<TM> System yielding 202 member beauveriolide analogues. Inhibitory activity of the beauveriolide analogues against CE synthesis by macrophages was evaluated (Figure 2). Linear depsipeptides including NBV113 were found to spoil activity. It appears that the ring construction plays a crucial role in inhibitory of CE synthesis. The S configuration of 3-hydroxy ester moiety is important to maintain the activity. It is interesting to note that NBV248 having 4-chlorophenylalanine is 5 times as potent as beauveriolide III (1).
