Neuroprotective coumarins from the root of Angelica gigas: structure-activity relationships.

An n-butanol-soluble fraction of the root of Angelica gigas Nakai (Umbelliferae) exhibited significant protection against glutamate-induced toxicity in primary cultured rat cortical cells. Using neuroprotective activity-guided fractionation, nine coumarins; marmesinin (1), nodakenin (2), columbianetin-O-beta-D-glucopyranoside (3), (S)-peucedanol-7-O-beta-D-glucopyranoside (4), (S)-peucedanol-3'-O-beta-D-glucopyranoside (5), skimmin (6), apiosylskimmin (7), isoapiosylskimmin (8) and magnolioside (9), were isolated from the n-butanol fraction. Of these nine coumarins, three dihydrofuranocoumarins; 1, 2 and 3, exhibited significant neuroprotective activities against glutamate-induced toxicity, exhibiting cell viabilities of about 50% at concentrations ranging from 0.1 to 10 microM. To explore the structure-activity relationships of coumarins, sixteen previously isolated compounds; 10-25, were simultaneously evaluated in the same system. Our results revealed that cyclization of the isoprenyl group, such as dihydropyran or dihydrofuran, or the furan ring at the C-6 position of coumarin, as well as lipophilicity played an important role in the neuroprotective activity of coumarins.