发现苯并[f]吲哚-4,9-二酮衍生物作为新型抗炎剂
Discovery of benzo[f]indole-4,9-dione derivatives as new types of anti-inflammatory agents.
作者信息
Chen You-Ren, Tseng Chih-Hua, Chen Yeh-Long, Hwang Tsong-Long, Tzeng Cherng-Chyi
机构信息
Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
出版信息
Int J Mol Sci. 2015 Mar 23;16(3):6532-44. doi: 10.3390/ijms16036532.
Certain benzo[f]indole-4,9-dione derivatives were synthesized and evaluated for their inhibitory effects on superoxide anion generation and neutrophil elastase (NE) release in formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils. Results indicated that (Z)-1-benzyl-4-(hydroxyimino)-1H-benzo[f]indol-9(4H)-one (10) showed a potent dual inhibitory effect on NE release and superoxide anion generation with IC50 value of 2.78 and 2.74 μM respectively. The action mechanisms of 10 in human neutrophils were further investigated. Our results showed that compound 10 did not alter fMLF-induced phosphorylation of Src (Src family Y416). Notably, phosphorylation of Akt (S473) and mobilization of [Ca2+]i caused by fMLF was inhibited by compound 10. Further structural optimization of 10 is ongoing.
合成了某些苯并[f]吲哚-4,9-二酮衍生物，并评估了它们对甲酰-l-甲硫氨酰-l-亮氨酰-l-苯丙氨酸（fMLF）激活的人中性粒细胞中超氧阴离子生成和中性粒细胞弹性蛋白酶（NE）释放的抑制作用。结果表明，（Z）-1-苄基-4-（羟基亚氨基）-1H-苯并[f]吲哚-9（4H）-酮（10）对NE释放和超氧阴离子生成具有强大的双重抑制作用，IC50值分别为2.78和2.74μM。进一步研究了10在人中性粒细胞中的作用机制。我们的结果表明，化合物10不会改变fMLF诱导的Src（Src家族Y416）磷酸化。值得注意的是，化合物10抑制了fMLF引起的Akt（S473）磷酸化和[Ca2+]i动员。正在对10进行进一步的结构优化。
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