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

Abstract

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. Electronic supplementary material The online version of this article (10.1007/s11418-018-1251-5) contains supplementary material, which is available to authorized users.

Metabolomic Signatures in Pediatric Crohn’s Disease Patients with Mild or Quiescent Disease Treated with Partial Enteral Nutrition: A Feasibility Study

“… 69 β-Carboline alkaloids may occur in many plant-derived foods, thermally processed protein-rich foods, and beverages, 70 and were demonstrated to exhibit anti-inflammatory activity via potent inhibition of nitric oxide (NO), TNFα, and interleukin-6 (IL6). 71 , 72 …”

“…69 β-Carboline alkaloids may occur in many plant-derived foods, thermally processed protein-rich foods, and beverages, 70 and were demonstrated to exhibit anti-inflammatory activity via potent inhibition of nitric oxide (NO), TNFα, and interleukin-6 (IL6). 71,72 1,3-DCP, an unannotated compound (C8H8F3N3O4S2), and AFMK were the three main compounds showing high correlations with the WBC count. The first two compounds were positively correlated with WBCs, while AFMK was inversely correlated with WBCs.…”

Recent Advances in the Synthesis of β-Carboline Alkaloids

“…First, the coupling of 177b with various amino acid esters was performed, then a formyl moiety was formed via acidic treatment of the acetal, followed by the same three steps described previously to form the other four metatacarbolines (32)(33)(34)(35). The first total synthesis of 6-hydroxymetatacarboline D (36) has been developed in 12 steps by Meng et al via CuBr2-catalyzed mild oxidation method by the dehydrogenation of the DHβC's C-ring (Scheme 17) [129]. The synthesis starts from 5-hydroxytryptophan (179), which was converted into Boc-and benzyl-protected compound 182 by applying protecting group chemistry.…”

“…Noctiluca milaris [10] Strychnos johnsonii [11] Lycoris longituba [12] Selaginella delicatula [13] Trichosanthes kirilowii Maxim [14] Rauwolfia caffra [15] Didemnum sp [16] MAO Cnemidocarpa stolonifera [20] apoptosis in PC3 human prostate cancer cell line [20] 8: Eudistoma olivaceum [21] 9: Eudistoma olivaceum [22] 10: Lissoclinum fragile [23] 11: Eudistoma olivaceum [24] 12: analogues of natural products 13: soybean [28] Flindersia laevicarpa [29] 14: analogues of natural products 15: Flindersia Caevicarpa [29] 16: Picrasma quassioides [30] 13: anti-neuroin-flammatory activities [28] 14: n.a. 15: vasorelaxant effect [31] binding affinity to imidazoline I2B receptors [32] 16: cytotoxic activity [33] AMP phosphodiesterase inhibitor [34] anti-inflammatory agent [35,36] trigonostemine [37] 17, 18, 19: Trigonostemone filipes [38] 20: Malassezia furfur [39] Paracoccus marine bacteria [40] Dichotomomyces cejpii [41] 21: Hyrtio erectus [42] Alocasia macrorrhiza [43] 17, 18, 19: cytotoxic activity [44] 20: antiproliferative activity [45] anticancer activity [46,47] 21: antiproliferative activity [48,49] antimalarial activity [46] antiphospholipase A2 [50] and antioxidant activity …”

Inducible nitric oxide synthase inhibitors: A comprehensive update

“…Further investigations on these hits for their inhibitory effect on PGE 2 production and on expression of iNOS and COX‐2 proteins revealed that β‐carboline‐type alkaloids weakly inhibit iNOS expression and are inactive against COX‐2. In a sharp contrast, cathinone‐type alkaloids ( 87 and 88 ) inhibited both the production of NO and release of PGE 2 with good potency . Evaluation of some alkaloids, phenolic compounds, and fatty acid methyl esters, isolated from fruiting bodies of mushroom Calvatia nipponica (Agaricaceae), for NO inhibitory activity in LPS‐induced RAW‐264.7 macrophages has led to identification of fatty acid methyl ester 89 as a NO inhibitor (IC 50 27 µM) …”