Anti-inflammatory activity of fluorine-substituted benzo[h]quinazoline-2-amine derivatives as NF-κB inhibitors.

Excessive inflammation can cause loss of tissue or organ function, leading to a number of chronic diseases and sometimes even death. Traditional treatment strategies for inflammation have mainly involved steroidal and non-steroidal anti-inflammatory drugs, but both have increasingly prominent side effects. Nuclear factor kappa B (NF-κB) inhibitors with anti-inflammatory properties and low toxicity are a new therapeutic strategy for the treatment of inflammatory diseases. To obtain novel NF-κB inhibitors, a series of 3,4-dihydronaphthalen-1(2H)-one derivatives (DHNs 6a-s), 1,4,5,6-tetrahydrobenzo[h]quinazolin-2-amine derivatives (BQAs 7a-c) and 5,6-dihydrobenzo[h]quinazolin-2-amine derivatives (BQAs 8a-p) were designed and synthesized, and characterized by NMR and HRMS. By evaluating toxicity and anti-inflammatory properties, fluorine-substituted 8c showed more potential anti-inflammatory activity and lower toxicity. 8c significantly reduced the phosphorylation of IκBα and p65, thereby inhibiting the NF-κB signaling pathway. In addition, 8c markedly decreased reactive oxygen species (ROS) production and downregulated the expression of NOD-like receptor pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC) and cysteine aspartate protein hydrolase-1 (caspase-1). Therefore, compound 8c is expected to be a candidate compound for NF-κB inhibition and deserves further research and development.

Synthesis, biological evaluation and molecular docking studies of novel diosgenin derivatives as anti-inflammatory agents.

Thirty-two novel DG F-spiroacetal ring-opening derivatives, including 24 acetylated derivatives and 8 nitrogenous derivatives, were designed and synthesized from diosgenin (DG). The cytotoxicity of the novel derivatives was evaluated by MTT assay, except for compounds 4a, 4e, 4i, 4 l, 5a and 5 h, which were potentially cytotoxic to RAW264.7 cells, all the other derivatives had no significant cytotoxicity. The NO release inhibitory activities of novel derivatives were screened by Griess method. The results showed that the anti-inflammatory activity of the DG acetylated derivatives was stronger than the nitrogenous derivatives, and 4a-4 m containing acetyl groups at the 3-position may have better anti-inflammatory effects than 5a-5 k containing free hydroxyl groups. In ELISA assay, compound 4 m exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by LPS with IC50 values 0.449 ± 0.050 µM. The results of docking experiments showed that 4 m has a good affinity for p65 protein.

Synthesis and in vitro Anti-proliferative Activities on LNCaP, LS180 and MKN45 of Novel 20(R)-Panaxadiol Derivatives.

BACKGROUND: 20(R)-PD, a tetracyclic triterpenoid, is a non-natural saponin present in the form of protopanaxadiol. Because of its essential biological activities, especially anti-tumor activity, structural modification of 20(R)-PD and the development of innovative and novel 20(R)-PD derivatives with better anti-tumor activity are increasingly relevant. AIMS: 20(R)-Panaxadiol (20(R)-PD) can inhibit tumor proliferation. Three series of novel 20(R-PD derivatives were synthesized by modifying the A-ring. OBJECTIVE: The objective of this work was to synthesize and evaluate the in vitro anti-proliferative activities of 20(R)- PD derivatives in LNCaP, LS180, and MKN45 cancer cells. Structural modifications were performed at the C-3 position and A-ring. METHODS: The in vitro anti-proliferative activities of novel derivatives in LNCaP, LS180, and MKN45 cells were evaluated by the MTT assay. The effects of compounds 5 and C9 on apoptosis were determined by flow cytometry. RESULTS: Compounds 5, B2, C2, C4, C7, C8, C9, C10, and C11 exhibited good anti-proliferative activities in LNCaP, LS180, and MKN45 cells in vitro. The best anti-proliferative activity was observed for the C-series derivatives with the introduction of amino acids at the C-3 position. C9 exhibited good potent activity with an IC50 of 2.89 µM. CONCLUSION: Compound C9 is a potential candidate with potent anti-proliferative activity.

Advances in Anti-inflammatory Activity, Mechanism and Therapeutic Application of Ursolic Acid.

In vivo and in vitro studies reveal that Ursolic Acid (UA) is able to counteract endogenous and exogenous inflammatory stimuli and has favorable anti-inflammatory effects. The antiinflammatory mechanisms mainly include decreasing the release of histamine in mast cells, suppressing the activities of lipoxygenase, cyclooxygenase and phospholipase, and reducing the production of nitric oxide and reactive oxygen species, blocking the activation of the signal pathway, downregulating the expression of inflammatory factors, and inhibiting the activities of elastase and complement. These mechanisms can open up new avenues for the scientific community to develop or improve novel therapeutic approaches to tackle inflammatory diseases, such as arthritis, atherosclerosis, neuroinflammation, liver diseases, kidney diseases, diabetes, dermatitis, bowel diseases, cancer. The anti-inflammatory activity, the anti-inflammatory mechanism of ursolic acid and its therapeutic applications are reviewed in this paper.

Anti-neuroinflammatory effects of novel 5,6-dihydrobenzo[h]quinazolin-2-amine derivatives in lipopolysaccharide-stimulated BV2 microglial cells.

Neuroinflammation is an intricate process that is associated with both normal and pathological conditions. Microglia-mediated neuroinflammation is known to lead to various neurodegenerative and neurological disorders. A series of 3,4-dihydronaphthalen-1(2H)-one derivatives (1-15) and novel 5,6-dihydrobenzo[h]quinazolin-2-amine derivatives (16-30) were synthesized and characterized by various analytical methods, such as NMR and HRMS. All compounds were evaluated for toxicity, screened for their anti-neuroinflammatory properties, and investigated for the potential molecular mechanism of lipopolysaccharide (LPS) induction in BV2 microglia. Structure activity relationship analysis showed that compound 17 substituted by the 7-fluorine atom on the A-ring and the 3-methoxy on the D-ring had more potential anti-neuroinflammatory activity by inhibiting the secretion of cytokines TNF-α and IL-6. The results of western blotting assay showed that 17 significantly blocked the activation and phosphorylation of IκBα, significantly reduce the expression of NLRP3 inflammatory vesicle-associated proteins, and thus inhibit the activation of NF-κB pathway. Thus, compound 17 was demonstrated to be an excellent potential therapeutic agent for the treatment of neuroinflammation-related diseases.

Design and synthesis of novel aza-ursolic acid derivatives: in vitro cytotoxicity and nitric oxide release inhibitory activity.

Aim: Inducible nitric oxide synthase (iNOS) is a validated target for anti-inflammatory treatment. Based on the authors' previous work, novel aza-ursolic acid derivatives were designed and synthesized and their inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) release from RAW264.7 cells was evaluated. Materials & results: 16 novel derivatives were screened for their in vitro inhibitory activity against NO release using Griess assays and the cytotoxicity was evaluated using MTT assays. The presence of furoxan joined to the A-ring of ursolic acid and N-methylpiperazine groups in the lead compound was identified for anti-inflammatory activity, and compound 21b showed 94.96% inhibition of NO release at 100 µM with an IC50 value of 8.58 µM. Conclusion: Compound 21b has potential anti-inflammatory activity with low cytotoxicity that warrants further preclinical study and evaluation.

Advances on the Anti-Inflammatory Activity of Oleanolic Acid and Derivatives.

Oleanolic acid can inhibit edema and exhibit obvious inhibitory activity to inflammatory by activating of the pituitary-adrenal cortical system, inhibiting the synthesis or release of PGs, inhibiting endotoxin-mediated release of HMGB1 by endothelial cells or regulating MAPK, PI3K/Akt/NF- κB/ICAM-1/JAK/STAT signaling pathways, etc. In recent years, an increased number of interesting research work has been carried out on the anti-inflammatory activity and mechanisms of OA derivatives, such as acyloxyimino derivative, 3-acetylated derivatives, novel 3,5-disubstituted isoxazoles derivatives, acetate, ester derivatives and oximes derivatives. The review summaries and highlights the updated advances on the anti-inflammatory activity and mechanism of OA and its derivatives.

The Advances on the Protective Effects of Ginsenosides on Myocardial Ischemia and Ischemia-Reperfusion Injury.

Ginseng is a traditional medicine with a complex chemical composition, wide bioactivity and unique pharmacological action. Many studies have confirmed that ginsenosides are the active ingredients of ginseng, and ginsenosides have always been the focus of different researchers. With the development of modern separation and analysis technology, more than 150 kinds of ginsenosides have been isolated. The ginsenosides Rb1, Rb2, Rc, Rg1 and Re account for more than 80% of total ginsenosides, and other saponins, such as Rd, Rg3 and Rh2, which are minor constituents, accounting for only a small portion of the total amount. In recent years, ginsenosides have been found to possess strong pharmacological activities, such as antioxidation, clearing of oxygen free radicals, reducing calcium overload and anti-apoptosis. Ginsenosides play a protective role in ischemia-reperfusion injury. This paper reviews the protective effects of ginsenosides on myocardial ischemia and ischemiareperfusion injury.