Targeted isolation of antiviral cinnamoylphloroglucinol-terpene adducts from Cleistocalyx operculatus by building blocks-based molecular networking approach

The building blocks-based molecular network(BBMN)strategy was applied to the phytochemical investigation of Cleistocalyx operculatus,leading to the targeted isolation of eighteen novel cinnamoylphloroglucinol-terpene adducts(CPTAs)with diverse skeleton types(cleistoperones A-R,1-18).Their structures including absolute configurations were determined by extensive spectroscopic methods,quantum chemical calculations,and single-crystal X-ray crystallographic experiments.Cleistoperone A(1),consisting of a cinnamoylphloroglucinol motif and two linear monoterpene moieties,represents an unprecedented macrocyclic CPTA,whose densely functionalized tricyclo[15.3.1.0^(3,8)]heneicosane bridge ring skeleton contains an enolizableβ,β′-triketone system and two different kinds of stereogenic elements(including five point and three planar chiralities).Cleistoperones B and C(2 and 3)are two new skeletal CPTAs with an unusual coupling pattern between the(nor)monoterpene moiety and the cinnamoyl chain of the cinnamoylphloroglucinol unit.Cleistoperone D(4)possesses an unprecedented cage-like 6/6/6/4/6-fused heteropentacyclic scaffold.The plausible biosynthetic pathways for 1-18 were also proposed.Notably,compounds 1,4,7,8,and 18 exhibited significant antiviral activity against respiratory syncytial virus(RSV).The most potent one,cleistoperone A(1)with IC_(50) value of 1.71±0.61μmol/L,could effectively inhibit virus replication via affecting the Akt/mTOR/p70S6K signaling pathway.