Plant-microbial interactions inspired the discovery of novel sesquiterpenoid dimeric skeletons of hidden natural products from Hibiscus tiliaceus

Hidden natural products are representative of defensive strategies produced in vivoin diseased plants, a process that is induced by the plant immune system. The first transcriptome library of uninfected and pathogen infected Hibiscus tiliaceusstems was constructed by transcriptome sequencing technology, genes related to cadinene-type sesquiterpenoid biosynthesis were screened and combined with ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-QTOF-MS) analysis data, which indicated pathological tissue had potential to produce novel carbon skeletons of cadinane sesquiterpenoid dimers. Successfully, two cadinane-derived sesquiterpenoid dimers with unprecedented carbon skeletons, hibisceusanols A (1) and B (2) were isolated for the first time from the stems of H. tiliaceusinduced by plant-microbial interactions. Their structures and absolute configurations were unambiguously established by spectroscopy, advanced chemistry development (ACD) and electronic circular dichroism (ECD) methods. Compounds 1and 2exhibited significant antitumor activity in vitrowith half maximal inhibitory concentration (IC50) values of 2.3–7.2 µmol/L. The anticancer effect was generated viathe induction of HepG2 cell apoptosis by inhibiting the phosphatidylinositol 3-kinase (PI3K) pathway.