Kingianins O-Q: Pentacyclic polyketides from Endiandra kingiana as inhibitor of Mcl-1/Bid interaction.

A phytochemical study of the EtOAc-soluble part of the methanolic extract of the bark of Endiandra kingiana led to the isolation of three new pentacyclic kingianins as racemic mixtures, kingianins O–Q (1–3), together with the known kingianins A, F, K, L, M and N (4–9), respectively. The structures of the new kingianins 1–3 were determined by 1D and 2D NMR analysis in combination with HRESIMS experiments. Kingianins A–Q were assayed for Mcl-1 binding affinity. Kingianins G and H were found to be potent inhibitors of Mcl-1/Bid interaction. A structure–activity relationship study showed that potency is very sensitive to the substitution pattern on the pentacyclic core. In addition, in contrast with the binding affinity for Bcl-xL, the levorotatory enantiomers of kingianins G, H and J exhibited similar binding affinities for Mcl-1 than their dextrorotatory counterparts, indicating that the two anti-apoptotic proteins have slightly different binding profiles.