探索苯并[f]吲哚-4,9-二酮衍生物為新型抗發炎藥劑

Discovery of Benzo[f]indole-4,9-dione Derivatives as New Types of Anti-Inflammatory Agents

陳宥任(You-Ren Chen)

指導教授 ： 曾誠齊

共同指導教授 ： 陳義龍(Yeh-Long Chen)

高雄醫學大學/生命科學院/醫藥暨應用化學系博士班/博士(2017年)

摘要

本研究主要探討合成苯并[f]吲哚-4,9-二酮類衍生物，並評估其抗發炎活性，對於formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF)誘導嗜中性白血球過度活化所釋放的超氧陰離子自由基與彈性蛋白酶等之抑制效果。結果顯示化合物15a具有抑制超氧陰離子自由基與抑制彈性蛋白酶釋放的雙重抑制效果，IC50分別為2.78與2.74 μM；在作用機制方面，化合物15a 不具有抑制fMLF誘導Src磷酸化(Y416)的效果；但可顯著地抑制fMLF誘導Akt磷酸化(S473)及調控鈣離子流動。化合物15a的初步性結構修飾也已經完成。

關鍵字

苯并[f]吲哚-4,9-二酮 ； 超氧自由基 ； 彈性蛋白酶抗發炎

並列摘要

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 (15a) 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 15a in human neutrophils were further investigated. Our results showed that compound 15a 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 15a. Preliminary further structural optimization of 15a were completed.

並列關鍵字

benzo[f]indole-4,9-dione ； superoxide anion ； elastase ； anti-inflammatory agents

參考文獻

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