Abstract
The chemical investigation of the culture filtrate of endophyte Alternaria sp. W-1 associated with Laminaria japonica provided a new tricycloalternarene compound, 2H-(2E)-tricycloalternarene 12a (1), together with five known analogs: (2E)-tricycloalternarene 12a (2), tricycloalternarene 3a (3), tricycloalternarene F (4), 15-hydroxyl tricycloalternarene 5b (5), and ACTG-Toxin D (6). In vitro cytotoxicity against the human hepatocellular carcinoma cell line SMMC-7721 and the human gastric carcinoma cell line SGC-7901 was evaluated by the MTT method. Compounds 1, 3, and 4 inhibited the growth of SMMC-7721 cells with IC50 values of 49.7 ± 1.1, 45.8 ± 4.6, and 80.3 ± 3.8 μg/mL, respectively, while the IC50 value of the positive control cisplatin was 6.5 ± 0.5 μg/mL. Compounds 3 and 6 also showed moderate anti-proliferation activity against SGC-7901 cells with IC50 values of 53.2 ± 2.9 and 35.1 ± 0.8 μg/mL, respectively, while the IC50 value of cisplatin was 4.5 ± 0.6 μg/mL. Further studies revealed that the in vitro anticancer activity of compound 3 to SMMC-7721 cells was related to G1 phase cell cycle arrest and cell apoptosis, and the induced apoptosis was involved in both the mitochondrial pathway and the death receptor pathway. This is the first report on the anticancer mechanism of tricycloalternarene compounds.
Highlights
Marine microorganisms survive under extreme conditions, including the absence of light, low level of oxygen, and intensely high pressure, which often leads to modifications of primary and secondary metabolic pathways and an increased likelihood of producing natural products with unique structures and/or significant activities that differ from those produced by terrestrial microorganisms
The results show that, compared to the negative control (NC), the percentages of treated SMMC-7721 cells in G1 phase were increased from 65.71% to 69.49%, 69.68%, 70.63%, 70.79%, and 78.44% (Figure 4), which implied that compound 3 could induce cell cycle arrest in SMMC-7721 cells in G1 phase
The upregulation of p27 in the present study demonstrated that the anti-proliferation effect of tricycloalternarene 3a against SMMC-7721 cells might be achieved by p27-mediated G1 phase cell cycle arrest to some extent
Summary
Marine microorganisms survive under extreme conditions, including the absence of light, low level of oxygen, and intensely high pressure, which often leads to modifications of primary and secondary metabolic pathways and an increased likelihood of producing natural products with unique structures and/or significant activities that differ from those produced by terrestrial microorganisms. The seabed sediment, mangrove plants, sponges, and algae with relatively rich nutrition are the main habitats or hosts for marine microorganisms that produce new and/or bioactive compounds [3]. Alternaria is a cosmopolitan fungal genus widely distributed in soil and organic matter. It includes saprophytic, endophytic, and pathogenic species. F (4) [7], 15-hydroxyl tricycloalternarene 5b (5) [8], and ACTG-Toxin D (6) [9] (Figure 1)—were isolated from the liquid culture of Alternaria sp. Tricycloalternarenes, related to ACTG-toxins, are a kind of meroterpene found in Alternaria sp. The in vitro cytotoxicity of six tricycloalternarene compounds (1–6) are reported, and the details of their isolation and structure are elucidated
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