The steroidal alkaloid cyclovirobuxine D(Cvb-D)is the active principle of the oral drug huangyangning used for many years in China for the treatment of cardiovascular and cerebrovascular diseases.The drug is listed in the Chinese pharmacopeia.Recent studies have revealed that this unsung alkaloid also dis-plays anticancer properties in vitro and in vivo.The drug activates several signaling pathways,and notably represses phosphorylation of proteins EGFR,ERK,Akt,mTOR.Thereby,Cvb-D exerts anti-proliferative and antimetastatic activities.In the present review,the anticancer effects of Cvb-D and related natural products isolated from Buxus species have been analyzed.The molecular targets of Cvb-D are unknown at present,but hypotheses are formulated based on the signaling pathways modulated by the drug and the analogy with other compounds.Proteins EGFR and CTHRC1,implicated in the anti-proliferative action of Cvb-D,could be considered as upstream targets.A bolder assumption is also formulated with the metastasis-associated protein S100A4 as a potential co-target for Cvb-D.This review aims to shed light on the anticancer properties of Cvb-D and to encourage further mechanistic studies with this drug with a good safety profile and a recognized anti-cardiovascular efficacy.

Objective The mangrove tree Xylocarpus granatum J. Koenig (X. granatum) is a medicinal plant used to treat various diseases in several Asian countries. Many bioactive natural products have been isolated from the plants, particularly several groups of limonoids, including 18 xylogranatins (Xyl-A to R), all of which bear a furyl-δ-lactone core commonly found in limonoids. Based on a structural analogy with the limonoids obacunone and gedunin, we hypothesized that xylogranatins could target the enzyme glycogen synthase kinase-3β (GSK-3β), a major target for the treatment of neurodegenerative pathologies, viral infections, and cancers. Methods We investigated the binding of the 18 xylogranatins to GSK-3β using molecular docking in comparison with two known reference GSK-3β ATP-competitive inhibitors, LY2090314 and AR-A014418. For each compound bound to GSK-3β, the empirical energy of interaction (ΔE) was calculated and compared to that obtained with known GSK-3β inhibitors and limonoid triterpenes that target this enzyme. Results Five compounds were identified as potential GSK-3β binders, Xyl-A, -C, -J, -N, and -O, for which the calculated empirical ΔE was equivalent to that calculated using the best reference molecule AR-A014418. The best ligand is Xyl-C, which is known to have marked anticancer properties. Binding of Xyl-C to the ATP-binding pocket of GSK-3β positions the furyl-δ-lactone unit deep into the binding-site cavity. Other xylogranatin derivatives bearing a central pyridine ring or a compact polycyclic structure are much less adapted for GSK-3β binding. Structure-binding relationships are discussed. Conclusion GSK-3β may contribute to the anticancer effects of X. granatum extract. This study paves the way for the identification of other furyl-δ-lactone-containing limonoids as GSK-3β modulators.