Novel phthalide derivatives from the rhizomes of Ligusticum chuanxiong and their inhibitory effect against lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells

Five new phthalide derivatives, chuanxiongnolides L1-L5 (1-5), together with three known phthalide dimers (6-8), were isolated from the rhizomes of Ligusticum chuanxiong Hort.. Compound 1 represents a novel type of phthalide derivative, biogenetically derived from coniferyl alcohol and ligustilide. Compound 2 is the first example of an E-ring expanded phthalide dimer with a 5/6/6/6/6 fused-ring system, which is different from the 5/6/6/6/5 fused-ring system in normal phthalide dimers. Their structures were established using spectroscopic data, and the absolute configurations were determined by a circular dichroism (CD) exciton chirality method. To confirm the absolute configuration of compound 1, electronic circular dichroism (ECD) calculations were also conducted. Compounds 1, 2, 6, and 7 exhibited inhibitory effects against lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells with half maximal inhibitory concentration (IC50) values ranging from 3.0 to 12.6 mu M. Furthermore, plausible biosynthetic routes for 1 and 2 were also proposed.