A Unified Total Synthesis of Benzo[d][1,3]dioxole-type Benzylisoquinoline Alkaloids of Aporphines, Coptisines, and Dibenzopyrrocolines

The first total synthesis of (S)-(+)-ovigerine, (S)-(+)-N-formylovigerine, and (6aS,6a'S)-(+)-ovigeridimerine of aporphine alkaloids with benzo[d][1,3]dioxole structure feature was established. The strategy was based upon the well known Pd-catalyzed arylation to set...

Living with a giant, flowering parasite: metabolic differences between Tetrastigma loheri Gagnep. (Vitaceae) shoots uninfected and infected with Rafflesia (Rafflesiaceae) and potential applications for propagation

Main conclusion Metabolites in Rafflesia-infected and non-infected Tetrastigma were compared which may have applications in Rafflesia propagation. Benzylisoquinoline alkaloids, here reported for the first time in Vitaceae, were abundant in non-infected shoots and may be a form of defense. In Rafflesia-infected shoots, oxylipins, which mediate immune response, were elevated. Abstract Endemic to the forests of Southeast Asia, Rafflesia (Rafflesiaceae) is a genus of holoparasitic plants producing the largest flowers in the world, yet completely dependent on its host, the tropical grape vine, Tetrastigma. Rafflesia species are threatened with extinction, making them an iconic symbol of plant conservation. Thus far, propagation has proved challenging, greatly decreasing efficacy of conservation efforts. This study compared the metabolites in the shoots of Rafflesia-infected and non-infected Tetrastigma loheri to examine how Rafflesia infection affects host metabolomics and elucidate the Rafflesia infection process. Results from LC–MS-based untargeted metabolomics analysis showed benzylisoquinoline alkaloids were naturally more abundant in non-infected shoots and are here reported for the first time in the genus Tetrastigma, and in the grape family, Vitaceae. These metabolites have been implicated in plant defense mechanisms and may prevent a Rafflesia infection. In Rafflesia-infected shoots, oxygenated fatty acids, or oxylipins, and a flavonoid, previously shown involved in plant immune response, were significantly elevated. This study provides a preliminary assessment of metabolites that differ between Rafflesia-infected and non-infected Tetrastigma hosts and may have applications in Rafflesia propagation to meet conservation goals.

Benzylisoquinoline alkaloids from Nelumbo nucifera Gaertn. petals with antiausterity activities against the HeLa human cervical cancer cell line

Ethanolic extract of Nelumbo nucifera petals showed preferential cytotoxic activity against HeLa human cervical cancer cell line with a PC50 value of 10.4 μg/mL. This active extract was subjected to a phytochemical investigation study which led to the isolation of nine benzylisoquinoline alkaloids (1–9). The isolated compounds exhibited potent antiausterity activities. Moreover, under nutrient-deprived conditions, (−)-lirinidine (8) induced remarkable alterations in HeLa cell morphology including cell shrinkage and plasma blebbing leading to total cell death within 10 h. Mechanistically, 8 was found to inhibit Akt/mTOR signaling pathway. It also induced apoptosis by promoting caspase-3 activation and inhibiting Bcl-2 expression. Therefore, benzylisoquinoline alkaloids skeleton can be considered as a promising scaffold for the anticancer drug development against cervical cancer.

The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants

DNA replication inhibitors are utilized extensively in studies of molecular biology and as chemotherapy agents in clinical settings. The inhibition of DNA replication often triggers double-stranded DNA breaks (DSBs) at stalled DNA replication sites, resulting in cytotoxicity. In East Asia, some traditional medicines are administered as anticancer drugs, although the mechanisms underlying their pharmacological effects are not entirely understood. In this study, we screened Japanese herbal medicines and identified two benzylisoquinoline alkaloids (BIAs), berberine and coptisine. These alkaloids mildly induced DSBs, and this effect was dependent on the function of topoisomerase I (Topo I) and MUS81-EME1 structure-specific endonuclease. Biochemical analysis revealed that the action of BIAs involves inhibiting the catalytic activity of Topo I rather than inducing the accumulation of the Topo I-DNA complex, which is different from the action of camptothecin (CPT). Furthermore, the results showed that BIAs can act as inhibitors of Topo I, even against CPT-resistant mutants, and that the action of these BIAs was independent of CPT. These results suggest that using a combination of BIAs and CPT might increase their efficiency in eliminating cancer cells.