Leoligin-inspired synthetic lignans with selectivity for cell-type and bioactivity relevant for cardiovascular disease

Abstract

Recently, a natural compound leoligin, a furan-type lignan, was discovered as an interesting hit compound with an anti-inflammatory pharmacological activity profile. We developed a modular and stereoselective approach for the synthesis of the edelweiss-derived lignan leoligin and used the synthetic route to rapidly prepare leoligin analogs even on the gram scale. Proof of concept of this approach together with cell-based bio-assays gained structural analogs with increased selectivity towards vascular smooth muscle versus endothelial cell proliferation inhibition, a major benefit in fighting vascular neointima formation. In addition, we identified the structural features of leoligin analogs that define their ability to inhibit the pro-inflammatory NF-κB pathway. Results are discussed in the context of structural modification of these novel synthetic lignans.

Fig. 1. Leoligin, the major lignan isolated from L. nivale ssp. alpinum.

Scheme 1. Synthesis of a library of furan-type lignans based on the leoligin hit-structure.

Fig. 2. Development of leoligin analogs as NF-κB inhibitors. NF-κB inhibition is expressed by their IC₅₀ values. Inhibition of EC proliferation is given as the reduction in cell number ± standard error of the mean at 30 μM concentration with respect to the negative control (100%).

Fig. 3. Development of leoligin analogs as inhibitors of VSMC proliferation. Inhibition of VSMC proliferation is expressed by their IC₅₀ values. Inhibition of EC proliferation is given as the reduction in the number of cells ± standard error of the mean at 30 μM concentration with respect to the negative control (100%). VSMC toxicity was also tested (via LDH release) at 30 μM concentration; for simplicity, significant positive toxicity (p < 0.1 in one-tailed t-test) is described qualitatively with respect to the negative control.

Fig. 4. Further development of NF-κB- and VSMC-selective inhibitors.