Identification of β - carboline and canthinone alkaloids as anti-inflammatory agents but with different inhibitory profile on the expression of iNOS and COX-2 in lipopolysaccharide-activated RAW 264.7 macrophages

A compound library, which consists of 75 natural β-carboline-type or canthinone-type alkaloids from Simaroubaceae plants and their chemical synthetic analogues, was screened for the anti-inflammatory activity by inhibition of the overproduction of inflammatory mediator nitric oxide (NO) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophage cells. Six compounds, namely, benzalharman ( 23 ), kumujian ( 27 ), 1-ethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid ( 37 ), 1-acetophenone-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid ( 42 ), cathin-6-one ( 46 ), and 9-methoxy-cathin-6-one ( 57 ), exhibited significant inhibitory activity on the overproduction of NO with good dose dependency. Further investigation demonstrated that all of the six compounds down-regulated the high expression of inducible nitric oxide synthase (iNOS) protein. Among them, two canthinone-type alkaloids ( 46 and 57 ) potently down-regulated cyclooxygenase-2 (COX-2) protein expression in a dose-dependent manner and also inhibited the overproduction of inflammatory mediator prostaglandin E 2 (PGE 2 ). However, the β-carboline-type alkaloids ( 23 , 27 , 37 , and 42 ) exhibited no obvious inhibition on the overproduction of PGE 2 and the expression of COX-2 protein. The results suggested that β-carboline-type alkaloids and canthinone-type alkaloids may exert an anti-inflammatory effect through different mechanism.