Pyranochromones with Anti-Inflammatory Activities in Arthritis from Calophyllum membranaceum
- J Nat Prod. 2022 May 27;85(5):1374-1387. doi: 10.1021/acs.jnatprod.2c00157.
- 1. State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
- 2. Instrumental Analysis Center, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
- 3. Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632, People's Republic of China.
Eleven new pyranochromones, calomembranone A-K (1-11), two new pyranocoumarins, calopolyanolide E and F (12 and 13), together with six known analogues (14-19) were isolated from the leaves of Calophyllum membranaceum. Their structures and absolute configurations were elucidated by analysis of spectroscopic data, computational calculations, as well as X-ray crystallography of 4 and 9. The anti-inflammatory activities of all the isolates were evaluated by measuring their NO inhibitory effects in LPS-stimulated RAW 264.7 cells. Structure-activity relationships are also discussed. Compound 7 showed the strongest NO inhibition (IC50 = 0.92 μM). Oral administration of 7 dose-dependently reduced the paw swelling and downregulated neutrophil-to-lymphocyte ratio in the carrageenan-induced acute Arthritis mice model. Molecular dynamics simulation and cellular thermal shift assay results indicated that 7 participated in a robust and stable interaction with the active site of TLR4. Compound 7 also suppressed the inflammation in Arthritis through the regulation of TLR4 mediated signal transduction via IKK/NF-κB signaling pathway and the consequent reduction of IL-2, IL-4, and IL-5.