Bioprospection of anti‐inflammatory phytochemicals suggests rutaecarpine and quinine as promising 15‐lipoxygenase inhibitors

Abstract

15-Lipoxygenase (15-LOX) belongs to the family of nonheme iron containing enzymes that catalyzes the peroxidation of polyunsaturated fatty acids (PUFAs) to generate eicosanoids that play an important role in signaling pathways. The role of 15-LOX has been demonstrated in atherosclerosis as well as other inflammatory diseases. In the present study, drug-like compounds were first screened from a set of anti-inflammatory phytochemicals based on Lipinski's rule of five (ROF) and in silico toxicity filters. Two lead compounds-quinine (QUIN) and rutaecarpine (RUT) were shortlisted by analyzing molecular interactions and binding energies of the filtered compounds with the target using molecular docking. Molecular dynamics simulation studies indicate stable trajectories of apo_15-LOX and docked complexes (15-LOX_QUIN and 15-LOX_RUT). In vitro 15-LOX inhibition studies shows that both QUIN and RUT have lower inhibitory concentration (IC 50 ) value than the control (quercetin). Both QUIN and RUT exhibit moderate antioxidant activities. The cell viability study of these compounds suggests no significant toxicity in HEK-293 cell lines. Further, QUIN and RUT both did not show any inhibition against selected Gram-positive and Gram-negative bacterial species. Thus, based on our present findings, rutaecarpine and quinine may be suggested as promising 15-LOX inhibitor for the prevention of the atherosclerosis development. K E Y W O R D S 15-lipoxygenase, anti-inflammatory phytochemicals, atherosclerosis, quinine, rutaecarpine

Synthesis, Antitumor Activity, Oil-Water Partition Coefficient, and Theoretical Calculation of 2 New Rutaecarpine Derivatives With Methoxy Groups

“…Generally, evodiamine is prepared via condensation of 3,4-dihydro-b-carboline and Nmethylisatoic anhydride. Because evodiamine and rutaecarpine have similar structures, we developed a 2-component protocol for a rapid preparation of the 2 methoxy-substituted rutaecarpine (RUT) derivatives using 7-methoxy-1H-benzo[d] [1,3]oxazine-2,4-dione and 3,4-dihydro-b-carboline or 6-methoxy-4,9-dihydro-3H-pyrido [ 3,4-b]indole according to the synthetic method of evodiamine, 20 which could avoid tedious purification procedure. The synthetic process is elucidated in Scheme1.…”

“…The 7-methoxy-1H-benzo[d] [1,3]oxazine-2,4-dione (compound 1) was prepared through the cyclization reaction of 2-amino-4-methoxy benzoic acid with triphosgene in dry tetrahydrofuran. The 3, 4-dihydro-b-carboline (compound 2a) or 6-methoxy-4, 9-dihydro-3H-pyrido [3, 4-b]indole (compound 2b) were synthesized according to the method described in Nie et al and Garner and Corminboeuf, 4,20 which were then condensed with 7-methoxy-1H-benzo[d] [1,3]oxazine-2,4-dione (compound 1) in dichloromethane (CH 2 Cl 2 ) at 45 °C to produce the desired hybrids of 2-methoxyl rutaecarpine (compounds 3a) and 2,10-dimethoxy rutaecarpine (compounds 3b). The obtained compounds were characterized through 1 H and 13 C NMR spectroscopic determination to confirm their structures.…”

“…The synthetic route of the target compounds is depicted in Scheme 1. [1,3]oxazine-2,4-dione (compound 1) was prepared through the cyclization reaction of 2-amino-4-methoxy Figure 2. Optimized geometric structure (A for RUT, B for 3a, and C for 3b) and electrostatic potential map of compounds (D for RUT, E for 3a, and F for 3b) (red color for strong repulsion and blue color for strong attraction).…”

“…The compounds, 3,4-dihydro-β-carboline (2a) and 6-methoxy-4, 9-dihydro-3H-pyrido [3, 4-b]indole (2b), were prepared by refluxing tryptamine or methoxy-tryptamine with ethyl formate and then adding phosphorus oxychloride. 4 A solution of 7-methoxy-1H-benzo[d] [1,3]oxazine-2,4-dione1 (1.0 g, 5 mmol) and 3,4-dihydro-β-carboline 2a (0.65 g, 5 mmol) in CH 2 Cl 2 (150 mL) was stirred at 45 °C for 16 hours and then cooled to room temperature. The solvent was concentrated under vacuum, and the crude product was purified by column chromatography (hexane/ethylacetate [EtOAc] = 5:1) to give 1.3 g of compound 3a as a white solid.…”

“…Rutaecarpine (RUT) is a quinazolinocarboline alkaloid, isolated from the fruit of Evodia rutaecarpa (Chinese name: Wu-Chu-Yu). 1 This phytochemical has been widely investigated for its promising biological activities, including antiangiogenesis, 2 anti-inflammatory, 3 antiproliferative, 4 antihyperlipidemic, hypoglycemic, 5 and hepatoprotective 6 activities. Among them, the antiproliferative activity of the multitargeting molecule RUT has been reported rarely, 7,8 because of its poor activity and water solubilities.…”