Sesquiterpene dimers with a rare skeleton from<i> Chloranthus</i><i> holostegius</i> exhibiting multidrug resistance reversal activity<i> in</i><i> vitro</i> and<i> in</i><i> vivo</i>

초록

Two previously unreported lindenane sesquiterpene dimers (1 and 2) with a rare skeleton containing an oxaspiro [4.5]decane moiety were isolated from the roots of Chloranthus holostegius var. trichoneurus. Their structures were elucidated by HRESIMS, NMR, ECD, and NMR quantum chemical calculations, along with DP4+ probability analysis. In bioassay, compound 1 exhibited significant activity to reverse the multidrug resistance (MDR)in MCF-7/ADR cells, with an IC50 value of 4.4 mu M. Further mechanistic studies revealed that compound 1 combined with doxorubicin could induce apoptosis of MCF-7/ADR cells and block the cell cycle in the G2/M phase. Mechanistically, compound 1 could inhibit the efflux function of P-glycoprotein (P-gp) using the zebrafish model. Finally, the enhanced chemotherapeutic effects of doxorubicin were further confirmed by in vivo zebrafish xenograft experiments.

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