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. 2020 Feb 4;25(3):662.
doi: 10.3390/molecules25030662.

Design and Synthesis of a Compound Library Exploiting 5-Methoxyleoligin as Potential Cholesterol Efflux Promoter

Thomas Linder  1 , Sophie Geyrhofer  1 , Eleni Papaplioura  1 , Limei Wang  2 , Atanas G Atanasov  3   4   5   6 , Hermann Stuppner  7 , Verena M Dirsch  3 , Michael Schnürch  1 , Marko D Mihovilovic  1
Affiliations

Design and Synthesis of a Compound Library Exploiting 5-Methoxyleoligin as Potential Cholesterol Efflux Promoter

Thomas Linder et al. Molecules. .

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.

Keywords: cardiovascular diseases; lignans; macrophage cholesterol efflux; natural product synthesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of leoligin 18, 5-methoxyleoligin 1 and general structure of derivatives 19–40.
Scheme 1
Scheme 1
Synthesis of furan lignans (−)-dihydrosesamin 5 and (−)-acuminatin 6 by Roy, RajanBabu and Nugent.
Scheme 2
Scheme 2
Synthesis of epoxy alcohol 9.
Figure 2
Figure 2
From left to right structures of diethyl azodicarboxylate (DEAD) and its reaction product 15 as well as 1,1′-(azodicarbonyl)dipiperidine 16 (ADD) and its reaction product 17.
Scheme 3
Scheme 3
Synthesis of 5-methoxyleoligin 1.
Figure 3
Figure 3
Results of leoligin 29 and 5-methoxyleologin 1 tested in a macrophage cholesterol efflux activation assay in THP-1 cells. The bars represent means ± SD of three independent experiments. *** p < 0.001, * p < 0.05 vs. the solvent vehicle control (n = 3, ANOVA/Bonferroni).
Scheme 4
Scheme 4
Synthesis of leoligin derivatives 19–40.
Figure 4
Figure 4
Structures of leoligin 29 and analog compounds tested in a macrophage cholesterol efflux activation assay.
See this image and copyright information in PMC

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