Abstract
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.
Highlights
Human neutrophils play an important role in the defense system against invasion by microorganisms and in the pathogenesis of various diseases such as rheumatoid arthritis, ischemia-reperfusion injury, chronic obstructive pulmonary disease, and asthma [1,2,3,4,5]
We have demonstrated that benzo[a]furo[2,3-c]phenazinecarboxylic acid (3) [20] strongly inhibited superoxide anion generation while 4-(4-methoxyphenoxy)naphthalene-1,2-dione (4) [21] was able to inhibit NO
Phenylalanine-activated human neutrophils and results are shown in Table 1. 1-Benzyl-1H-benzo
Summary
Human neutrophils play an important role in the defense system against invasion by microorganisms and in the pathogenesis of various diseases such as rheumatoid arthritis, ischemia-reperfusion injury, chronic obstructive pulmonary disease, and asthma [1,2,3,4,5]. In order to discover novel drug candidates, we have synthesized certain furo[3',2':3,4]naphtho[1,2-d]imidazole derivatives and evaluated for their anti-inflammatory activities. In continuation of our search for novel type of anti-inflammatory agents, the present study describes preparation and biological evaluation of certain benzo[f]indole-4,9-dione derivatives which belong to a new structural type possessing versatile iminoquinone moiety. Their cytotoxicities were evaluated due to the structural similarity of these tricyclic compounds to the cytotoxic (Z)-4-(hydroxyimino)naphtho[2,3-b]furan-9(4H)-one (5) [22] which exhibited an IC50 value of 0.82 μM against the growth of K562 cell
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