Journal of Natural Products Vol. 56, No. l0,pp. 1805-1810, October 1993
1805
KINASE INHIBITORS FROM POLYGONUM CUSPZDATUM GAMINI S.J A Y A T I L AHIRANTHI KE, JAYASURIYA, ELJNGSEOKLEE,NUPHAVAN M. KOONCHANOK, ROBERT L. GEAHLEN,CURTISL. ASHENDEL, JERRY L. MCLAUGHLIN,and CHINGJERCUG* Depamnent of M e d i c i d Chemistry and P b a ~ o ~Schwl y , ofPbarnracy and Phanaca[ Sciences, Punhe Uniwsity, Wcrt Lufiyette,lndbna 47907
Aasmcr.-Bioassaydirected fractionation of a medicinal plant, Polygonum nrrpidtwn (Polygonaceae), has led to the discovery of a hydroxystilbene, resveratrol [11,as an inhibitor of aprotein-tyrosine kinase(p56~pareiallypurifiedfrombovine thymus. Both transandcis isomers of resveratrol possess comparableprotein-tyrosine kinase inhibitory activity. Cornpatison of the ICsovalues of resveratrol for protein-tyrosine k i inhibitory ~ activity with those of piceid (resveratrol-O’-~-glucoside) I21 and res~eratrol-0~ -p-glucoside 131 shows the requirement of free hydroxyl groups on both phenyl rings for the protein-tyrosine kinase inhibition. Protein kinase C inhibitory analysis suggests the requirements oftwo free hydroxyl groups on one phenyl ring only.
Numerous cytotoxic compounds have been isolated from natural sources using a cytotoxicity-based screening system. Most of these compounds lack selectivity in attacking tumor cells and display minimal therapeutic indices. It is, therefore, essential to envisagemore specific screening approachesfor discovering new anticancer drugs with greater selectivity. One of the biochemical mechanism-based screening systems used by our natural product anticancer drug discovery group for selecting active plants and for directing the fractionation and purification of active constituents is based on the inhibition ofprotein-tyrosine kinase (PTK) activity. PTKs are a large group of enzymes that catalyze the transfer of the y-phosphate of ATP to the hydroxyl group of tyrosine on many key proteins which can then induce the cascade of altered cell parameters characteristic of transformed cells (1-5). Our previous studies of the dried roots of a Chinese medicinal plant, Polygonum cuspidaturn Sieb. and Zucc. (Polygonaceae), led to the isolation of a new class of PTK inhibitor, derived from the basic skeleton of anthraquinone (6). We now report the isolation of a second class of PTK inhibitors, namely stilbenes, from this medicinal plant.
RESULTS AND DISCUSSION As part of an ongoing study to discover and evaluate kinase inhibitors from plants, we observed that the MeOH fraction ofP. cuspidaturn roots exhibited inhibitory activity (IC5,,
