Antitumor agents, 162. Cell-based assays for identifying novel DNA topoisomerase inhibitors: studies on the constituents of Fatsia japonica.
Two pleiotropic multi-drug resistant (PDR) KB cell lines were hypersusceptible to a cytotoxic extract from Fatsia japonica. Fractionation of an active extract using a cell-based assay for DNA topoisomerase inhibitors led to the isolation of three known triterpene glycosides, FJ-1-3 [1-3]. The structures of 1-3 were identified as 3-O-alpha-L-arabinopyranosyl-oleanolic acid [1], 3-O-alpha-L-arabinopyranosyl-hederagenin [2], and 3-O-[beta-D-glucopyranosyl(1-->4)-alpha-L-arabinopyranosyl]-hed eragenin [3], respectively. However, these isolates were not DNA topoisomerase II inhibitors in vitro and nor were they active when re-tested for differential cytotoxicity. Compounds 1-3 appear to function by interfering selectively with cellular drug accumulation. Other fractions probably contained compounds active against DNA topoisomerase I; however, the enriched preparations were not cytotoxic. The present findings indicate a simple modification to improve the cell-based bioassay procedure employed to guide fractionation.
Kitanaka
S
S
Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill 27599, USA.
Yasuda
I
I
Kashiwada
Y
Y
Hu
C Q
CQ
D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification* / Q000494:pharmacology / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D006868:Hydrolysis; D007624:KB Cells; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity; D018515:Plant Leaves / Q000737:chemistry; D012503:Saponins / Q000302:isolation & purification* / Q000494:pharmacology / Q000633:toxicity; D059005:Topoisomerase II Inhibitors
C098366:3-O-(glucopyranosyl-1-4-arabinopyranosyl)hederagenin; D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D012503:Saponins; D059005:Topoisomerase II Inhibitors; C036411:cauloside A; C098365:3-O-alpha-L-arabinopyranosyl-oleanolic acid; D009828:Oleanolic Acid