Abstract
The transcription factor NF-κB is an essential mediator of inflammation; thus, the identification of compounds that interfere with the NF-κB signaling pathway is an important topic. The natural products leoligin and 5-methoxyleoligin have served as a starting point for the development of NF-κB inhibitors. Using our modular total synthesis method of leoligin, modifications at two positions were undertaken and the effects of these modifications on the biological activity were investigated. The first modification concerned the ester functionality, where it was found that variations in this position have a significant influence, with bulky esters lacking Michael-acceptor properties being favored. Additionally, the substituents on the aryl group in position 2 of the tetrahydrofuran scaffold can vary to some extent, where it was found that a 3,4-dimethoxy and a 4-fluoro substitution pattern show comparable inhibitory efficiency.
Highlights
Leoligin [1] (Figure 1), a naturally occurring furan-type lignan, found in the roots of Edelweiss (Leontopodium nivale ssp. alpinum), was shown to display a pharmacological profile that suggests an overall anti-inflammatory activity
Reisinger et al demonstrated that leoligin is able to reduce intimal hyperplasia and to decrease TNF-α-induced vascular cell adhesion molecule (VCAM)-1 expression in primary human endothelial cells [2], which is highly regulated by the nuclear factor kappa-light-chainenhancer of activated B-cells (NF-κB) [3]
In the context of a multi-disciplinary project on the synthesis of furan-type lignans with anti-inflammatory activity, several leoligin analogs were synthesized in our group and subjected to cell-based assays, which led to analogs that selectively inhibited VSMC versus EC proliferation, which is advantageous in the treatment of vascular neointima formation [5]
Summary
Leoligin [1] (Figure 1), a naturally occurring furan-type lignan, found in the roots of Edelweiss (Leontopodium nivale ssp. alpinum), was shown to display a pharmacological profile that suggests an overall anti-inflammatory activity. In the context of a multi-disciplinary project on the synthesis of furan-type lignans with anti-inflammatory activity, several leoligin analogs were synthesized in our group and subjected to cell-based assays, which led to analogs that selectively inhibited VSMC (vascular smooth muscle cell) versus EC (endothelial cell) proliferation, which is advantageous in the treatment of vascular neointima formation [5]. Based on this finding and taking into account that drug-eluting stents releasing immunosuppressant drugs are able to reduce local VSMC proliferation, leoligin and derivatives thereof were exploited in drug-releasing experiments using an inexpensive stent model, aiming to determine their relative releasing 4.0/).
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