Coumarins and flavones with anti-inflammatory activity isolated from the branches and leaves of Daphne retusa.

In this study, two new (1, 13) and fourteen known (2-12, 14-16) compounds were isolated from the branches and leaves of Daphne retusa. On the basis of chemical evidence and spectral data analysis (UV, ECD NMR, and HR-ESI-MS), the structures of new compounds were elucidated. Furthermore, all compounds have been tested for their inhibitory effects on NO production in LPS-induced RAW 264.7 cells, and compound 3 showed obvious inhibitory effect. Through target screening and molecular docking technology, potential binding targets for compound 3 to exert anti-inflammatory effects have been predicted.

A potent GPX4 degrader to induce ferroptosis in HT1080 cells.

Glutathione peroxidase 4 (GPX4) is the most promising target for inducing ferroptosis. GPX4-targeting strategies primarily focus on inhibiting its activity or adjusting its cellular level. However, small inhibitors have limitations due to the covalent reactive alkyl chloride moiety, which could lead to poor selectivity and suboptimal pharmacokinetic properties. Herein, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) by connecting RSL3, a small molecule inhibitor of GPX4, with six different ubiquitin ligase ligands. As a highly effective degrader, compound 18a is a potent degrader (DC50, 48h = 1.68 µM, Dmax, 48h = 85 %). It also showed an obvious anti-proliferative effect with the IC50 value of 2.37 ± 0.17 µM in HT1080. Mechanism research showed that compound 18a formed a ternary complex with GPX4 and cIAP and induced the degradation of GPX4 through the ubiquitin-proteasome system pathway. Furthermore, compound 18a also induced the accumulation of lipid peroxides and mitochondrial depolarization, subsequently triggering ferroptosis. Our work demonstrated the practicality and efficiency of the PROTAC strategy and offered a promising avenue for designing degraders to induce ferroptosis in cancer cells.

Alkaloids from the roots of Sophora flavescens and their anti-tumor activity.

Sophora flavescens belongs to Sophora genus of Leguminosae. Its roots are used as a traditional Chinese medicine. In our study on Sophora flavescens roots, 3 new and 19 known alkaloids have been found, including 8 aloperine-type and 14 matrine-type alkaloids. The planar configurations of these compounds were determined by the spectral data, and the absolute configurations of new compounds 1, 2 and 4 were determined by pyridine solvent effect, ECD and snatzke methods, respectively. All compounds were tested for their inhibitory activity on MCF-7 cell growth, and compound 12 exhibited certain inhibitory effects on the growth of MCF-7 cells after 24 h of treatment at a concentration of 20 µM, with inhibition rates of 31.28%. Through target screening and molecular docking, human Rho GTPase activating protein 5 variant and human arachidonate 12-lipoxygenase (12S-type) might be important targets for compound 12 to exert anti-tumor activity.

Research progress of plant-derived natural alkaloids in central nervous system diseases.

Central nervous system (CNS) disease is one of the most important causes of human death. Because of their complex pathogenesis, more and more attention has been paid to them. At present, drug treatment of the CNS is the main means; however, most drugs only relieve symptoms, and some have certain toxicity and side effects. Natural compounds derived from plants can provide safer and more effective alternatives. Alkaloids are common nitrogenous basic organic compounds found in nature, which exist widely in many kinds of plants and have unique application value in modern medicine. For example, Galantamine and Huperzine A from medicinal plants are widely used drugs on the market to treat Alzheimer's disease. Therefore, the main purpose of this review is to provide the available information on natural alkaloids with the activity of treating central nervous system diseases in order to explore the trends and perspectives for the further study of central nervous system drugs. In this paper, 120 alkaloids with the potential effect of treating central nervous system diseases are summarized from the aspects of sources, structure types, mechanism of action and structure-activity relationship.

Structure-Based Drug Design and Synthesis of Pyrrolidine-2,5-diones as Novel TNF-α Inhibitors.

Tumor necrosis factor α (TNF-α) inhibitors are the treatment of choice for autoimmune diseases including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and Crohn's disease. Herein, some Benpyrine derivatives with stronger binding affinity, better activity, better solubility, and higher synthetic efficiency were identified using structure-based drug design and optimization strategies. Among the synthesized series of compounds, 10 directly binds to TNF-α and blocks the activation of TNF-α-trigged caspase and NF-κB signaling pathway. Compound 10 represents a promising scaffold for the further development of TNF-α inhibitors. Drug development based on compound 10 may provide a new strategy for the treatment of TNF-α-mediated autoimmune diseases.

Xanthones and Phenylpropanoids from the Whole Herb of Swertia pseudochinensis and Their Anti-Inflammatory Activity.

An undescribed xanthone dimer, 1,3,5,8-tetrahydroxy-7-(1',5',8'-trihydroxy-3'-methoxy-2'-xanthonyl)xanthone (1) was separated together with eleven known compounds (2-12) from the dried whole herb of Swertia pseudochinensis. It was the first time that the compounds 8-12 were isolated from the Swertia genus. The structure of compound 1 was illuminated based on chemical evidence and spectral data analysis (UV, 1D and 2D-NMR, HR-ESI-MS). Moreover, the inhibitory effects of all compounds on NO production in LPS-induced RAW 264.7 cells were tested, compounds 8, 9, 10, 11 and 12 showing significant inhibition. The IC50 value of compound 12 was 3.05±1.10 µM. Using target screening and molecular docking, we hypothesized that compound 12 may bind neutrophil elastase to exert its anti-inflammatory effects.

Terpenoids and Phenylpropanoids Isolated from the Twigs and Leaves of Abelia macrotera and Their Anti-Inflammatory Activities.

A new triterpenoid, 3ß-hydroxyurs-12-en-28,20ß-olide (1), as well as thirteen known terpenoids (2-14) and three known phenylpropanoids (15-17), were isolated from the twigs and leaves of Abelia macrotera. Compounds 2, 5-17 were isolated for the first time from the Abelia genus. The structure of compound 1 was determined using the characteristic spectral data (HR-ESI-MS, UV, 1D and 2D-NMR, and X-ray single-crystal diffraction. Furthermore, the inhibitory effects of all compounds on NO production in LPS-induced RAW 264.7 cells were tested, and compound 15 showed obvious inhibitory effect, with IC50 values of 23.77±1.61 µM. Through target screening and molecular docking technology, it can be speculated that compound 15 may play an anti-inflammatory role by combining with Cathepsin G & Chymase and HPG D.