4(1H)-Quinolones as inhibitors of LTB4 formation in vitro

Abstract

Different 2-alkyl-4(1H)-quinolones from the fruits of Euodia rutaecarpa Hook. f. & Thomson (Rutaceae) inhibited leukotriene biosynthesis in previous studies [1]. It was concluded that the characteristic lipophilic side chain might be essential for the observed activities. In order to substantiate this assumption, derivatives of 1-methyl-4(1H)-quinolones with variations of the side chain at C-2 differing in length and unsaturation were synthesised and tested for inhibition of leukotriene B4 formation in an in vitro assay using activated neutrophile granulocytes [2]. A saturated side chain as well as a trans double bond at C-1′ lead only to moderate inhibition at 50µM (15.1–28.3% inhibition of LTB4 formation) whereas compounds with a cis double bond in combination with chain lengths between C-10 and C-14 showed the highest activities (42.1–93.0% inhibition at 50µM). Increasing the chain length to C-20 significantly lowered the activity (9.8% inhibition; positive control zileuton 78.5% inhibition at 10µM). The most active compound revealed no cytotoxicity at 300µM even after 48h incubation time in MRC-5 cells (XTT assay) [3]. It can be concluded that the length and saturation of the lipophilic side chain at C-2 in 1-methyl-4(1H)-quinolones exert a significant influence on leukotriene biosynthesis in neutrophile granulocytes.