Arch Pharm Res Vol 27, No 7, 738-741, 2004 ~arma~l i~eseard3 ...... -h~tl~ ~/~pr-p-sk ~o~./< r Inhibitory Lignans against NFAT Transcription Factor from Acanthopanax koreanum Xing Fu Cai, Im Seon Lee, Nguyen Tien Dat, Guanghai Shen, Jong Seong Kang, Dong Hyun Kim1, and Young Ho Kim College of Pharmacy, Chungnam National University, Daejon 305-764, Korea and 1College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea (Received February 13, 2004) Three lignans isolated from the roots of A. koreanum (Araliaceae), namely eleutheroside E (1), tortoside A (2), and hemiariensin (4), were evaluated for their ability to inhibit NFAT transcrip- tion factor. Of these compounds, compound 4, possessing a diarylbutane skeleton, exhibited potent inhibitory activity against NFAT transcription factor (ICs0:36.3 • 2.5 pM). However, the activities of 1 (ICso: > 500 ~M) and 2 (ICso: 136.1 _+ 9.4 IIM), which possess bisaryldioxabicy- clooctane skeletons, were lower. As the lignan derivatives of the same skeletons, hinokinin (5) and (-)-yatein (6) with diarylbutane skeletons and (+)-syringaresinol (3) with a bisaryldioxabicy- clooctane skeleton were also studied for their inhibitory effects on NFAT transcription factor. Key words: Acanthopanax koreanum, Araliaceae, Lignan, NFAT transcription factor, Inhibi- tory effect INTRODUCTION NFAT, nuclear factor of activated T-cells, is a cytoplasmic protein and is activated by the stimulation of cell surface receptors coupled to Ca 2§ mobilization. NFAT protein is dephosphorylated by the Ca2+-activated phosphatase, calcineurin, and then migrates to the nucleus to induce transcription of genes required for T-cell activation, one of which is IL-2 (Winter etal., 1993; Abbas etal., 1997). The activation of NFAT normally plays a significant role in the induction of immune response. However, excessive acti- vation provokes immunopathological reactions including autoimmunity, transplant rejection, and inflammation (Abbas et al., 1997). Thus, the modulation of NFAT transcription factor (NFAT TM) should be useful in the treatment of inflammations and immune diseases. Until now, only a few inhibitors of natural product origin have been reported to have inhibitory activity against NFATTF. Recently, lignans isolated from Schisandra chinensis (Lee et aL, 2003), and phthalides and an acetylenic component isolated from Cnidium officinale (Lee et aL, 2002), were Correspondenceto: Young Ho Kim, College of Pharmacy, Chung- nam National University, Daejeon, 305-764, Korea Tel: 82-42-821-5933, Fax: 82-42-823-6566 E-mail: yhk@cnu.ac.kr reported to regulate NFATTF. In an ongoing screening study of NFAT TM regulators from medicinal plants, three lignans isolated from the roots of Acanthopanax koreanum (Araliaceae), which are used for the treatment of rheumatism in traditional Oriental medicine (Bensky et al., 1986), and three lignan derivatives with the same skeleton were investigated in terms of their abilities to inhibit NFATTF. MATERIALS AND METHODS General Melting points were measured using a Yanaco micro melting point, optical rotation with a Jasco DIP-370 automatic polarimeter, UV spectra with a Beckman Du- 650 UV-VIS recording spectrophotometer, and FT-IR spectra with a Jasco Report-100 infrared spectrometer. Preparative HPLC was carried out using a Waters HPLC system (600 pump, 600 controller, and a 996 photodiode array detector). NMR spectra were measured using a Bruker DRX 300 spectrometer (1H, 300 MHz; 13C, 75 MHz), and FAB-MS using a JEOL JMS-HX/HX110A tandem mass spectrometer. Column chromatography was performed using silica-gel (Kieselgel 60, 70-230 mesh and 230-400 mesh, Merck), and thin layer chromatography (TLC) on pre-coated Silica-gel 60 F2s4(0.25 mm, Merck) and RP-18 738