Design, Synthesis, and Anticancer Activity of Cinnamoylated Barbituric Acid Derivatives.

This work deals with the design and synthesis of 18 barbituric acid derivatives bearing 1,3-dimethylbarbituric acid and cinnamic acid scaffolds to find potent anticancer agents. The target molecules were obtained through Knoevenagel condensation and acylation reaction. The cytotoxicity was assessed by the MTT assay. Flowcytometry was performed to determine the cell cycle arrest, apoptosis, ROS levels and the loss of MMP. The ratios of GSH/GSSG and the MDA levels were determined by using UV spectrophotometry. The results revealed that introducing substitutions (CF3 , OCF3 , F) on the meta- of the benzyl ring of barbituric acid derivatives led to a considerable increase in the antiproliferative activities compared with that of corresponding ortho- and para-substituted barbituric acid derivatives. Mechanism investigation implied that the 1c could increase the ROS and MDA level, decrease the ratio of GSH/GSSG and MMP, and lead to cell cycle arrest. Further research is needed for structural optimization to enhance hydrophilicity, thereby improve the biological activity of these compounds.

Hepatoprotective Effects of Albumin-Encapsulated Nanoparticles of a Curcumin Derivative COP-22 against Lipopolysaccharide/D-Galactosamine-Induced Acute Liver Injury in Mice.

Acute liver injury (ALI) is a severe syndrome and can further develop into acute liver failure (ALF) which can lead to high mortality and cause irreversible liver injuries in the clinic. Liver transplantation is the most common treatment; however, liver donors are lacking, and the progression of ALF is rapid. Nanoparticles can increase the bioavailability and the targeted accumulation of drugs in the liver, so as to significantly improve the therapeutic effect of ALI. Curcumin derivative COP-22 exhibits low cytotoxicity and effective anti-inflammatory activity; however, it has poor water solubility. In this study, COP-22-loaded bovine serum albumin (BSA) nanoparticles (22 NPs) were prepared and characterized. They exhibit effective hepatoprotective effects by inhibiting inflammation, oxidative stress, and apoptosis on Lipopolysaccharide/D-Galactosamine-induced acute liver injury of mice. The anti-inflammatory activity of 22 NPs is related to the regulation of the NF-κB signaling pathways; the antioxidant activity is related to the regulation of the Nrf2 signaling pathways; and the apoptosis activity is related to mitochondrial pathways, involving Bcl-2 family and Caspase-3 protein. These three cellular pathways are interrelated and affected each other. Moreover, 22 NPs could be passively targeted to accumulate in the liver through the retention effect and are more easily absorbed than 22.HCl salt in the liver.

Meta-substituted piperlongumine derivatives attenuate inflammation in both RAW264.7 macrophages and a mouse model of colitis.

Piperlongumine (PL) has been showed to have multiple pharmacological activities. In this study, we reported the synthesis of three series of PL derivatives, and evaluation of their anti-inflammatory effects in both lipopolysaccharide (LPS)-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. Our results presented that two meta-substituent containing derivatives 1-3 and 1-6, in which γ-butyrolactam replaced α,ß-unsaturated δ-valerolactam ring of PL, displayed low cytotoxicity and effective anti-inflammatory activity. Molecular docking also showed that the meta-substituted derivative, compared with the corresponding ortho- or para-substituted derivative, had significant interactions with the amino acid residues of CD14, which was the core receptors recognizing LPS. In vitro and in vivo studies, 1-3 and 1-6 could inhibit the expression of pro-inflammatory cytokines, and the excessive production of reactive nitrogen species and reactive oxygen species. Oral administration of 100 mg/kg/day of 1-3 or 1-6 alleviated the severity of clinical symptoms of colitis in mice, and significantly reduced the colonic tissue damage to protect the colonic tissue from the DSS-induced colitis. These results suggested that meta-substituted derivatives 1-3 and 1-6 were potential anti-inflammatory agents, which may lead to future pharmaceutical development.

Piperlongumine Analogs Promote A549 Cell Apoptosis through Enhancing ROS Generation.

Chemotherapeutic agents, which contain the Michael acceptor, are potent anticancer molecules by promoting intracellular reactive oxygen species (ROS) generation. In this study, we synthesized a panel of PL (piperlongumine) analogs with chlorine attaching at C2 and an electron-withdrawing/electron-donating group attaching to the aromatic ring. The results displayed that the strong electrophilicity group at the C2-C3 double bond of PL analogs plays an important role in the cytotoxicity whereas the electric effect of substituents, which attached to the aromatic ring, partly contributed to the anticancer activity. Moreover, the protein containing sulfydryl or seleno, such as TrxR, could be irreversibly inhibited by the C2-C3 double bond of PL analogs, and boost intracellular ROS generation. Then, the ROS accumulation could disrupt the redox balance, induce lipid peroxidation, lead to the loss of MMP (Mitochondrial Membrane Potential), and ultimately result in cell cycle arrest and A549 cell line death. In conclusion, PL analogs could induce in vitro cancer apoptosis through the inhibition of TrxR and ROS accumulation.

Synthesis and biological evaluation of ß-ionone oriented proapoptosis agents by enhancing the ROS generation.

ß-ionone, a cyclic terpenoid compound present in many fruits, has been showed a broad spectrum of biological activities. In this paper, we synthesized a panel of ß-ionone derivatives and tested their anti-proliferation activity on cancer cell by the MTT assay. The results showed that most of the ß-ionone derivatives were more active than ß-ionone and curcumin. Particularly, the ß-ionone derivatives (1a, 1d and 1g) with ortho-substituents on the aromatic ring exhibited much stronger cytotoxicity than their corresponding meta- and para-substituted compounds. Importantly, the cytotoxicity of the ß-ionone derivatives (1a, 1d and 1g) were relationship with their reactive oxygen species (ROS)-generation abilities, which could lead to the redox imbalance, lipid peroxidation, the loss of mitochondrial membrane potential (MMP), the activation of Bax and Caspase 3, followed by cell apoptosis. This work suggest that the "ortho effect", the ROS-generation ability and drawing fluorine atom into drugs may play a potent role in enhancing the anticancer activity of ß-ionone derivatives.

Anti-inflammatory activity of ortho-trifluoromethoxy-substituted 4-piperidione-containing mono-carbonyl curcumin derivatives in vitro and in vivo.

Curcumin was reported as an anti-inflammatory agent. However, curcumin's poor bioavailability limited its clinical utility. Here, thirty ortho-substituted mono-carbonyl curcumin derivatives, containing acetone, cyclopentanone, cyclohexanone or 4-piperidione (NH, N-methyl or N-acrylyl) moieties replacing ß-diketone moiety of curcumin, were investigated for anti-inflammatory activity. Two active ortho-trifluoromethoxy-substituted 4-piperidione-containing derivatives 22 and 24 owned good cell uptake ability, and displayed excellent anti-inflammatory activity in both lipopolysaccharide-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. They inhibited the production of nitric oxide, reactive oxygen species, malonic dialdehyde and cyclooxygenase-2; and the expression of pro-inflammatory cytokines interleukin-1ß, tumor necrosis factor-α and myeloperoxidase; the phosphorylation of mitogen-activated protein kinases; and the nucleus translocation of p65. What's more, 22 or 24 oral administered reduced the severity of clinical symptoms of ulcerative colitis (body weight and disease activity index), and reduced obviously DSS-induced colonic pathological damage (the colon length and histopathology analysis). These results suggested that ortho-trifluoromethoxy-substituted 4-piperidione-containing mono-carbonyl curcumin derivatives 22 and 24 were potential anti-inflammatory agents; and offered the important information for design and discovery of more potent anti-inflammatory drug candidates.

Synthesis and evaluation of the anticancer activity of bischalcone analogs in human lung carcinoma (A549) cell line.

Bischalcone has gained much attention because of its wide range of application in pharmaceutical chemistry. This work aims to evaluate the antiproliferation effects and explore the anticancer mechanism of bischalcone analogs on human lung cancer A549 cells. In this study, we synthesized a series of bischalcone analogs via Aldol condensation reaction; MTT method was used to evaluate the antiproliferation effects; the 2',7'-dichlorofluorescein fluorescence assay was used to determine the intracellular reactive oxygen species levels; the glutathione reductase-DTNB recycling assay was used to detect the redox imbalance; determination of thiobarbituric acid-reactive substance was used to evaluate the lipid peroxidation; Rhodamine 123 was used to test the mitochondrial membrane potential (MMP); the FITC/PI kit was used to detect the apoptosis; Western blotting was used to detect the expression of Bax and Caspase 3. After treatment with curcumin and bischalcone analogs, compounds 1d and 1g, the more stabilities compounds than curcumin, exhibited much higher potency in A549 cells than curcumin and other bischalcone analogs. Further mechanism of action studies revealed that 1d and 1g exhibited more stronger reactive oxygen species production abilities than curcumin and accompanied by the redox imbalance, lipid peroxidation, the loss of MMP, the activition of Bax and Caspase 3, and ultimately resulted in apoptosis of A549 cell. These data suggest that enhancing the reactive oxygen species generation ability of bischalcone analogs may be a promising strategy for the treatment of human lung cancer.

The potential role of the 5,6-dihydropyridin-2(1H)-one unit of piperlongumine on the anticancer activity.

Piperlongumine (PL), a potent anticancer agent from the plant long pepper (Piper longum), contains the 5,6-dihydropyridin-2(1H)-one heterocyclic scaffold and cinnamoyl unit. In this paper, we synthesized a series of PL analogs and evaluated their cytotoxicity against cancer cells for the sake of exploring which pharmacophore plays a more potent role in enhancing the anticancer activities of PL. These results illustrated that the position effect, not the electronic effect, of substituents plays a certain role in the cytotoxicity of PL and its analogs. More important, the 5,6-dihydropyridin-2(1H)-one unit, a potent pharmacophore in enhancing the antiproliferative activities of PL, could react with cysteamine and lead to ROS generation, and then bring about the occurrence of ROS-induced downstream events, followed by cell cycle arrest and apoptosis. This work suggests that introducing a lactam unit containing Michael acceptors may be a potent strategy to enhancing the anticancer activity of drugs.