Synthesis of new anticancer and anti-inflammatory isoxazolines and aziridines from the natural (-)-deltoin.

Abstract

This work describes the synthesis, the bioactivity and the structure-activity relationship of new derivatives from a natural coumarin. (-)-Deltoin 1 and the corresponding isoxazolines and aziridines were characterized by spectroscopic means. The cytotoxic (HTC-116, IGROV-1 and OVCAR-3 cancer cell lines) and 5-lipoxygenase activity of (-)-deltoin 1 and its structural analogues have been evaluated. The phytochemical investigation of the ethyl acetate extract of the flowers of Ferula lutea (Poir.) Maire has led to the isolation of (-)-deltoin 1. A series of new isoxazoline 2a,a'-2f,f' and aziridine 3a,a'-3e,e' derivatives have been prepared by 1,3-dipolar cycloaddition. It has been found that the derivatives 2a (IC50 = 3.3 ± 0.1 μm), 3a,a' (IC50 = 5.9 ± 0.1 μm), 3b,b' (IC50 = 6.1 ± 0.7 μm) and 3c,c' (IC50 = 7.3 ± 0.9 μm) bearing a phenyl isoxazoline, a phenylaziridine, a 4-methlphenylaziridine and a 4-methoxyphenylaziridine, respectively, are more cytotoxic than (-)-deltoin 1 (IC50 = 14.3 ± 0.2 μm). The diastereoisomers in mixture (2f,f') with a 6-chloropyridin-2-yl system have shown the best anti-5-lipoxygenase activity (% inhibition = 53.1 ± 4.8% at 200 μm). Some analogues have been found more bioactive than deltoin 1. Their activity has been related to the nature of the added heterocycles. It would be interesting to evaluate their in-vivo activity.