Three new 21-membered macrocyclic benzenoid ansamycins, trienomycins J-L (1-3), together with seven known analogues, trienomycins A-G (4-10), were isolated from liquid culture of the moss soil-derived actinomycete Streptomyces cacaoi subsp. asoensis H2S5. The structures of the new compounds were elucidated by extensive NMR spectroscopic analysis and HRESIMS data. The absolute configurations of trienomycins were established by Marfey's method. Antiproliferative assays showed that compound 1 had the greatest activity against HepG2 cells, with an IC value of 0.1 μM. The induction of apoptosis of HepG2 cells by 1 was investigated by flow cytometry and evaluation of nuclear morphology. In addition, all of the compounds inhibited nitric oxide production with IC values of 0.02 to 8.3 μM, and compounds 1, 4, and 7 were the most potent inhibitors. These findings will facilitate the development of new antineuroinflammatory agents.

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Background and Purpose: Pancreatic cancer is an exceptionally fatal disease. However, therapeutic drugs for pancreatic cancer have presented a serious shortage over the past few decades. Signal transducer and activator of transcription-3 (STAT3) is persistently activated in many human cancers where it promotes tumour development and progression. Natural products serve as an inexhaustible source of anticancer drugs. Here, we identified the natural product trienomycin A (TA), an ansamycin antibiotic, as a potential inhibitor of the STAT3 pathway with potent activity against pancreatic cancer. Experimental Approach: Effects of trienomycin A on transcriptional activity of STAT3 were assessed by the STAT3-luciferase (STAT3-luc) reporter system. In vitro and in vivo inhibitory activity of TA against pancreatic cancer made use of molecular docking, surface plasmon resonance (SPR) assay, MTS assay, colony formation assay, transwell migration/invasion assay, flow cytometric analysis, immunofluorescence staining, quantitative real-time polymerase chain reaction (PCR), western blotting, tumour xenograft model, haematoxylin and eosin (H&E) staining and immunohistochemistry. Key Results: Trienomycin A directly bound to STAT3 and inhibited STAT3 (Tyr705) phosphorylation, thus inhibiting the STAT3 pathway. Trienomycin A also inhibited colony formation, proliferation, migration and invasion of pancreatic cancer cell lines.Trienomycin A also markedly blocked pancreatic tumour growth in vivo. More importantly, trienomycin A did not show obvious toxicity at the effective dose in mice. Conclusions and Implications:Trienomycin A exerted anti-neoplastic activity by suppressing STAT3 activation in pancreatic cancer. This natural product could be a novel therapeutic candidate for pancreatic cancer.

Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of cis-olefin and poor metabolic stability, structure modifications on cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its cis-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound 6b, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC50 values of less than 0.5 μM. The two isomers of 6b induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover, 6b-(E) displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of 6b could bind efficiently at colchicine binding site of tubulin similar to CA-4.

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