•Anti-hepatoma effect of andrographolide (AD) derivative ADN-9 is more potent than AD.•Inhibition of liver tumor growth and metastasis in an orthotopic mouse xenograft model.•ADN-9 showed stronger anti-angiogenic activity than AD in vivo and in vitro.•Attentuating VEGF/VEGFR2/Akt pathway is involved in the related mechanisms.It is well known that liver cancer is a highly aggressive malignancy with poor prognosis. Andrographolide (AD), a major bioactive component of Andrographis paniculata (Burm. F.), is a potential anti-cancer pharmacophore and the synthesis of AD derivatives with better cytotoxicity to cancer cells has attracted considerable attentions. In the present study, we evaluated the in vivo inhibitory effects of ADN-9, a 15-benzylidene substituted derivative of AD, on the growth and metastasis of murine hepatoma H22 using an orthotopic xenograft model and a subcutaneous xenograft model, and we further studied the anti-angiogenic action and the related mechanisms of ADN-9 in vivo and in vitro. Importantly, ADN-9 remarkably suppressed the growth and metastasis of both orthotopic and subcutaneous xenograft tumors, and the serum AFP level in orthotopic hepatoma-bearing mice treated with 100 mg/kg ADN-9 (ig.) was decreased to the normal level. We also found that ADN-9 showed stronger abilities than AD in shrinking tumors, suppressing the invasion and metastasis of H22 cells, decreasing the MVD and promoting tumor cell apoptosis in subcutaneous xenograft of mice. Additionally, ADN-9 exhibited stronger inhibitory activity than AD against the migration and VEGF-induced capillary-like tube formation in HUVECs, which was further proved to be associated with attenuating VEGF/VEGFR2/AKT signaling pathway. The present research provides the first evidence that a 15-substituted AD derivative is more promising than the parent compound in therapeutic treatment of liver cancer.

A series of novel pyrazole fused heterocyclic derivatives were synthesized via a two-step procedure or a one-pot two step method, and their catalytic DNA cleavage abilities and anti-BVDV activities were also evaluated. The results obtained indicated that compounds 3b–3c could catalyze the cleavage of supercoiled DNA (pUC 19 plasmid DNA) to nicked DNA under physiological conditions with high yields via a hydrolytic mechanism. The studies on anti-viral activities against bovine viral diarrhea virus (BVDV) demonstrated that some of the pyrazole derivatives showed pronounced anti-BVDV activity with interesting EC50 values and no significant cytotoxicity. Among them, compound 3l showed the highest antiviral activity (EC50 = 0.12 μmol/L) and was 10 fold more than that of the positive control ribavirin (EC50 = 1.3 μmol/L), which provided a potential candidate for the development of anti-BVDV agents.We have synthesized some novel pyrazoles fused heterocyclic derivatives. With 3b-Cu2+ and 3c-Cu2+, the plasmid DNA could be cleaved completely. Meanwhile, Compound 3l showed the highest antiviral activity (EC50 = 0.12 μmol/L).

In this study we report the synthesis and activity against bovine viral diarrhea virus (BVDV) of a novel series of bicycle δ-sultones containing γ-lactones. BVDV is responsible for major losses in cattle. Some of the synthesized δ-sultones showed pronounced anti-BVDV activity with EC50 values of 0.12–1.0 μM and no significant cytotoxicity. Among them, the ortho bromosubstituted derivative 4f (EC50 = 0.12 μM) showed better antiviral activity than other derivatives and was 10 fold more that of than positive control ribavirin (EC50 = 1.3 μM). BVDV is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug studies. The above results provided a novel candidate for the development of anti-HCV agents.

In the present study, andrographolide (Andro, 1) derivatives were screened to identify potent inhibitors against tumor-cell migration and invasion, and associated structure–activity relationships were studied. Compared to 1, compounds 8a–8d exhibited more potent activities against migration in SGC-7901, PC-3, A549, HT-29 and Ec109 cell lines. Improved activities against tumor-cell migration and invasion were proved to be associated with the down-regulation of MMPs.Inhibition of tumor cell migration and invasion of andrographolide derivatives were reported and the structure–activity relationships were analyzed.

Andrographolide (1) is a major diterpene lactone exhibiting anti-inflammatory effects and is found in the plant Andrographis paniculata (Burm. f) Nees, which is widely used in Traditional Chinese Medicine. Synthesis of more effective drugs from andrographolide is very interesting and can prove to be highly useful. In this study, we investigated the anti-inflammatory effects of andrographolide and its derivatives (compounds 2–6) through dimethylbenzene-induced ear edema in mice. Substances under study were administrated intragastrically and the structure–activity relationship was analyzed. Results showed that compounds 5 and 6 significantly inhibited ear edema compared with compound 1 (p < 0.05), indicating that the introduction of p-Chlorobenzylidene to C-15 of compound 2 enhances the anti-inflammatory effect. Moreover, compound 6 exhibited the strongest anti-inflammatory effect against ear edema in mice (79.4%; 1.35 mmol/kg, ig) and paw edema in rats (50.4%; 0.90 mmol/kg, ig). In addition, compound 6 significantly (p < 0.05) inhibited granuloma formation and reduced the increase in vascular permeability induced by peritoneal injection of 0.6% acetic acid solution in mice. Findings indicate that compound 6 exerts its enhanced anti-inflammatory effects by decreasing serum iNOS activity, NO production, and PGE2 production.Highlights► Introducing 15-p-Chlorobenzylidene significantly enhances anti-inflammatory effect. ► Compound 6, the most potent one, inhibits ear edema by 79.4% at 1.35 mmol/kg (ig). ► Improved activity (6) is owing to inhibition of iNOS activity and NO production. ► Compound 5 exerts the enhanced activity through inhibition of PGE2 production.