摘要
To identify small molecule inhibitors of TNF-alpha, bioassay- and LC-MS-guided chemical investigation on EtOAc extract of Pseudomonas aeruginosa ABS-36 culture broth (EEPA) was performed, which yielded four proline-based cyclic dipeptides, cyclo(Gly-L-Pro) (1), cyclo(L-Pro-L-Phe) (2), cyclo(trans-4-hydroxy-L-Pro-L-Phe) (3) and cyclo(trans-4-hydroxy-L-Pro-L-Leu) (4). Compounds 1 and 3 exhibited potent inhibition of TNF-alpha release with IC50 values of 4.5 and 14.2 mu g/mL, respectively, while EEPA showed IC50 of 38.8 mu g/mL under lipopolysaccharide treated RAW 264.7 cell ELISA assay. Also, marked attenuation of mRNA-expression of TNF-alpha was shown by all compounds. In vivo testing in rats of EEPA and chemically synthesized 4 validated significant TNF-alpha reduction with 51% (500 mg/kg) and 79% (50 mg/kg), respectively. In addition, all compounds exhibited significant diminution of IL-1 beta and IL-6 mRNA-expression levels and NO production. All samples displayed only weak toxicity to lipopolysaccharide-induced RAW 264.7 cells.
- 出版日期2015-12-15