1-Methyl-2-nonylquinolin-4(1H)-one

An abnormally high serum phosphate level induces calcific aortic stenosis (CAS), which is characterized by ectopic valve calcification and stenosis of the orifice area. Inhibition of ectopic calcification is a critical function of any internal medical therapy for CAS disease. The aim of the present study was to investigate the inhibitory effects of several derivatives of evocarpine, methanolic extracts from the fruits of Evodia rutaecarpa Bentham (Japanese name: Go-Shu-Yu) on the high phosphate-induced calcification of human aortic valve interstitial cells (HAVICs) obtained from patients with CAS. High phosphate (3.2 mM) concentrations significantly increased the calcification of HAVICs after 7 days of culture. This calcification was completely inhibited in the presence of sodium phosphonoformate (PFA), a selective inhibitor of the type III sodium-dependent phosphate cotransporter (PiT-1). PiT-1 contributes to phosphate uptake, resulting in calcification. 1-Methyl-2-undecyl-4(1H)-quinolone (MUQ; 30-300 nM), but not evocarpine or its derivatives dihydroevocarpine and 1-methyl-2-nonyl-4(1H)-quinolone, inhibited the high phosphate-induced HAVICs calcification in a concentration-dependent manner.

1-Methyl-2-undecyl-4(1H)-quinolone (1) was previously isolated as a selective MAO-B inhibitor from the Evodiae Fructus. Further bioassay-guided purification led to the identification of five known quinolone alkaloids, 1-methyl-2-nonyl-4(1H)-quinolone (2), 1-methyl-2-[(Z)-6-undecenyl]-4(1H)-quinolone (3), evocarpine (4), 1-methyl-2-[(6Z,9Z)-6,9-pentadecadienyl]-4(1H)-quinolone (5), and dihydroevocarpine (6). All the isolates showed more potent inhibitory effects against MAO-B compared to MAO-A. The most MAO-B selective compound 5 among the isolates inhibited MAO-B in a competitive manner, according to kinetic analyses by Lineweaver-Burk reciprocal plots.