Abstract
5-Methoxyleoligin and leoligin are natural occurring lignans derived from Edelweiss (Leontopodium nivale ssp. alpinum), displaying potent pro-angiogenic and pro-arteriogenic activity. Cholesterol efflux from macrophages is associated with reverse cholesterol transport which inhibits the development of cardiovascular disease. Within this study, we developed a modular and stereoselective total synthesis of 5-methoxyleoligin which can be readily used to prepare a novel compound library of related analogs. The target 5-methoxyleoligin was synthesized exploiting a recently disclosed modular route, which allows also rapid synthesis of analogous compounds. All obtained products were tested towards macrophage cholesterol efflux enhancement and the performance was compared to the parent compound leoligin. It was found that variation on the aryl moiety in 2-position of the furan ring allows optimization of the activity profile, whereas the ester-functionality does not tolerate significant alterations.
Highlights
According to the World Health Organization the number one cause of death results from ischemic heart disease, followed by stroke [1]
A number of leoligin derivatives has been synthesized and subjected to a macrophage cholesterol efflux assay to test whether they promote the efflux of cholesterol out of macrophages as previously shown for leoligin [10]. Furan type lignans such as (−)-dihydrosesamin 5 and (−)-acuminatin 6 have been synthesized by the group of Roy [16], involving a kinetic resolution by a Sharpless asymmetric epoxidation, a Williamson ether synthesis and a radical cyclization reaction according to a protocol developed by RajanBabu and Nugent (Scheme 1) [17]
Since we are aiming for a modular synthesis, we envisioned a common cyclized intermediate, which can be decorated with different Ar2 substituents in an efficient and simple procedure reducing the overall number of reaction steps for the synthesis of focused lignan libraries
Summary
According to the World Health Organization the number one cause of death results from ischemic heart disease, followed by stroke [1]. Both are examples of cardiovascular diseases (CVD), which is overall the leading cause of mortality and morbidity worldwide [2]. One key determinant within prevention is the lowering of cholesterol, especially low-density lipoprotein (LDL) cholesterol, in the body [3]. Molecules 2020, 25, 662 to foam cell formation in the arterial intima reflecting an early stage of atherosclerosis, which is the pathological basis of most CVD [4]. Macrophages contribute to foam cell formation via uptake of ox-LDL, cleavage of cholesterol esters, cholesterol re-esterification and accumulation
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