ANTITUMOR AGENTS .154. CYTOTOXIC AND ANTIMITOTIC FLAVONOLS FROM POLANISIA-DODECANDRA

Three flavonols, 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone [1],5,4 '-dihydroxy-3,6,7,8,3'-pentamethoxyflavone [2], and quercetin beta-D-g lucopyranosyl-7-0-alpha-L-rhamnopyranoside [3], were isolated from Pol anisia dodecandra. Compound 1 showed remarkable cytotoxicity in vitro against panels of central nervous system cancer (SF-268, SF-539, SNB-7 5, U-251), non-small cell lung cancer (HOP-62, NCI-H266, NCI-H460, NCI -H522), small cell lung cancer (DMS-114), ovarian cancer (OVCAR-3, SK- OV-3), colon cancer (HCT-116), renal cancer (UO-31), a melanoma cell l ine (SK-MEL-5), and two leukemia cell lines (HL-60 [TB], SR), with GI( 50) values in the low micromolar to nanomolar concentration. range. Th is substance also inhibited tubulin polymerization (IC50=0.83 +/- 0.2 mu M) and the binding of radiolabeled colchicine to tubulin with 59% i nhibition when present in equimolar concentrations with colchicine. Co mpound 2 also showed cytoxicity against medulloblastoma (TE-671) tumor cells with an ED(50) value of 0.98 mu g/ml. Compound 1 appears to be the first example of a flavonol to exhibit potent inhibition of tubuli n polymerization and, therefore, warrants further investigation as an antimitotic agent.