A novel structural class of coumarin-chalcone fibrates as PPARα/γ agonists with potent antioxidant activities: Design, synthesis, biological evaluation and molecular docking studies.

A series of structurally interesting coumarin-chalcone fibrates were synthesized and evaluated for their PPARα/γ agonist activities and antioxidant activities. Among these compounds, compounds 5a, 5d, and 7a were identified as potent PPARα and γ dual agonists, and their PPARα agonist activities were found to be more potent than that of Fenofibrate. Furthermore, the results of antioxidant investigations revealed that compounds 5d and 6a-6d had greater potency than Trolox with IC50 values ranging from 9.40 µM to 18.63 µM. The structure-activity relationship revealed that the electron-withdrawing nitro group substituted at the C6' position of the benzopyran moiety increased the PPARα and γ agonist efficacy. Moreover, the presence of a double bond on the benzopyran moiety was essential for PPARα and γ agonist efficacy. The agonist activity of PPARα exhibited by compound 5d was examined by molecular docking studies. Taken together, the results we obtained showed that compound 5d had the potential to be a lead compound for further research.

Synthesis and evaluation of 1-hydroxy/methoxy-4-methyl-2-phenyl-1H-imidazole-5-carboxylic acid derivatives as non-purine xanthine oxidase inhibitors.

Xanthine oxidase is a key enzyme that catalyses hypoxanthine and xanthine to uric acid, whose overproduction leads to the gout-causing hyperuricemia. In this study, a series of 1-hydroxy/methoxy-4-methyl-2-phenyl-1H-imidazole-5-carboxylic acid derivatives (4a-4k and 6a-6k) was synthesized and evaluated for their inhibitory potency against xanthine oxidase. The 1-hydroxyl substituted derivatives 4a-4k showed excellent inhibitory potency with IC50 values ranging from 0.003 µM to 1.2 µM, with compounds 4d (IC50 = 0.003 µM), 4e (IC50 = 0.003 µM), and 4f (IC50 = 0.006 µM) manifesting the most potent xanthine oxidase inhibitory potency that were comparable with that of Febuxostat (IC50 = 0.01 µM). Lineweaver-Burk plot analysis revealed that representative compound 4f acted as a mixed-type inhibitor for xanthine oxidase. The basis of significant inhibition of xanthine oxidase by 4f was rationalized by its molecular docking into the active site of xanthine dehydrogenase.

Star-shape redox-responsive PEG-sheddable copolymer of disulfide-linked polyethylene glycol-lysine-di-tocopherol succinate for tumor-triggering intracellular doxorubicin rapid release: head-to-head comparison.

A redox-responsive poly(ethylene glycol) (PEG)-sheddable copolymer of disulfide-linked PEG 5000-lysine-di-tocopherol succinate (P(5k)SSLV) is developed which can self-assemble into nanomicelles in aqueous condition and trigger the rapid release of encapsulated drugs within tumor cells. The reduction-insensitive doxorubicin (DOX)-loaded P(5k)LV (P(5k)LV-DOX) nanomicelles are further prepared. Then head-to-head comparison of P(5k)SSLV-DOX, P(5k)LV-DOX and DOX-Sol is performed concerning in vitro release, cytotoxicity, cellular uptake and apoptosis. Results show that P(5k)SSLV-DOX nanomicelles have a faster DOX release, a higher anti-tumor activity and more DOX concentrating in the nucleus than P(5k)LV-DOX nanomicelles. In conclusion, the redox-responsive P(5k)SSLV nanomicelles might hold a great potential to improve chemotherapy by tumor-triggering intracellular rapid release. The outcomes of this study also address the significance of such head-to-head comparison studies in translational research of nanomedicine.