Andrographolide derivatives or analogs exhibit potent anti-inflammatory effects in several disease models through NF-κB activity. In this study, we synthesized different andrographolide derivatives and investigated their effects on the toll-like receptor (TLR)-induced production of pro-inflammatory cytokines. Among these compounds, 3b, 5a, and 5b inhibited both TNF-α/NF-κB and TLR4/NF-κB signaling pathways. Treatment with compounds 3b, 5a, and 5b and their structural analogs, 3a and 6b, suppressed the expression of pro-inflammatory cytokines upon the activation of TLR3 and TLR4 ligands. Compounds 3b and 5a, but not 3a, 5b, or 6b, inhibited the nuclear translocation of the NF-κB p65 subunit. Treatment with compounds 3b, 5a, 3a, 5b, and 6b attenuated the phosphorylation of p65 and IκBα. Compounds 6b suppressed the expression of the NF-κB p65 subunit. However, these compounds, except for 5b, did not affect the TLR9-induced NF-κB-independent production of the pro-inflammatory cytokines, TNF-α, and IFN-β. Compound 3b potentially protected mice from LPS-induced acute pulmonary inflammation through the inhibition of p65 phosphorylation and the decrease of serum pro-inflammatory cytokines and chemokine. Our study revealed a functional structure–activity relationship between andrographolide derivatives and innate immunity. We identified compound 3b as a potent immune suppressive agent with the potential to protect acute pulmonary infection.

Andrographolide is bestowed with an interesting pharmacophore and has attracted numerous studies on the design and synthesis of andrographolide derivatives.

The aim of this study is to investigate the anti-angiogenic properties of andrographolide derivatives AGP-26a (12β-isomer), AGP-26b (12α-isomer) and AGP-26 (4 : 1 mixture of AGP-26a and AGP-26b) in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) and the Tg(fli-1a:EGFP)y1 zebrafish model were used to identify the anti-angiogenic activities of AGP-26, AGP-26a, and AGP-26b. The results showed that AGP-26b exhibits the strongest inhibitory effect on VEGF-induced proliferation, migration, invasion and formation of capillary-like structures in HUVECs. In the zebrafish model, AGP-26b also showed the strongest suppression of ISV development. Further studies showed that the underlying mechanism of the anti-angiogenic effects of AGP-26b was at least partly through the blockage of the VEGF/VEGFR2 signaling pathways. AGP-26b blocked the activation of VEGFR2. Consequently, the phosphorylation of key intracellular proangiogenic kinases such as Src family kinase (Src), focal adhesion kinase (Fak), mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase 1 and 2 (Erk1/2) and Akt induced by VEGF was suppressed by treatment with AGP-26b. Moreover, AGP-26b reduced the protein expression of matrix metalloproteinases (MMP-9 but not MMP-2) in HUVECs. These results provide evidence supporting the notion that AGP-26b may serve as a potential therapeutic anti-angiogenic agent.

In the title compound, C11H8Cl2N2O2·H2O, the dihedral angle between the benzene and isoxazole rings is 59.10 (7)°. In the crystal, the components are linked by N—H⋯O and O—H⋯O hydrogen bonds into a three-dimensional network. The crystal structure is further stabilized by π–π stacking inter­actions [centroid–centroid distance = 3.804 (2) Å].

As one of the major active constituents in Andrographis panniculata (Burm. f.) Nees of Acanthaceae family, andrographolide is proved to possess a wide range of biological activities. In recent years, numerous studies show that the structural modification of andrographolide could enhance its anti-tumor activities. Therefore, according to the structural properties of andrographolide derivatives, five types of derivatives classified by different basic skeletons are denoted as the skeleton of andrographolide derivatives, the skeleton of 14-deoxyandrographolide derivatives, the skeleton of dehydroandrographolide derivatives, the skeleton of isoandrographolide derivatives and the skeleton of 12-ring replaced andrographolide derivatives. On this basis, the synthesis and anti-tumor activities of andrographolide derivatives are reviewed, and the structure activity relationship are also summarized preliminarily. The future trends of the derivatives research are discussed in the end.