Lepidotols and lepidotins: new phenylcoumarins from Mesua lepidota as promising inhibitors of endothelial immune responses and dysfunction

During organ transplantation, graft endothelium is the first barrier encountered by immune cells of the recipient. Endothelial cells surface presents inflammatory and immune proteins which are over-expressed after activation by pro-inflammatory cytokines, Damage Associated Molecular Patterns (DAMPs) or Advanced Glycation End Products (AGEs) [1]. Among natural products, several polyprenylated polyphenols have shown anti-inflammatory, immunomodulatory and anti-AGEs properties [2 – 3]. Such secondary metabolites are biosynthesized by Calophyllaceae species such as Calophyllum or Mesua species. In order to identify natural products able to prevent endothelial dysfunction, a dereplication analysis was conducted on various extracts from Calophyllum and Mesua species native to Malaysia. It appeared that the fruits of Mesua lepidota T. Anderson are a rich source of original phenylcoumarins named as lepidotols and lepidotins. The main compound, lepidotol A, was evaluated for its anti-inflammatory, immunomodulatory and anti-AGEs potential. Beside a potent inhibitory effect of the VCAM-1, class II HLA and HLA-E induced surface-expressions on human endothelial cells (52%, 97% and 66%, respectively), lepidotol A exhibited an inhibition of AGEs formation five to thirty times higher than aminoguanidine (positive control). These results are consistent with the marked pharmacological activities of prenylated aromatic metabolites [4], and highlight a new approach to discover protective compounds against graft rejection