title: Structure activity relationships of antiproliferative rocaglamide derivatives from Aglaia species (Meliaceae).
abstract: Eleven rocaglamide derivatives (cyclopentatetrahydrobenzofurans) and one structurally related aglain congener all isolated from different Aglaia species (Meliaceae) were tested for growth inhibiting properties using the human cancer cell lines MONO-MAC-6 and MEL-JUSO. Proliferation of both cell lines was efficiently inhibited in a dose and compound dependent manner. Applying MTT-Assay, the IC50 of the most active compound didesmethyl-rocaglamide (1) was observed at 0.002 and 0.006 micrograms/ml (0.004 and 0.013 microM) depending on the cell line investigated. Bulky aminoacyl substituents at C-2, acetylation of the OH substituent at C-1 or insertion of a OH or OMe substituent at C-3 of the rocaglamide skeleton all diminished the activity of the compounds investigated. The aglain derivative 12 was inactive up to a concentration of 3 micrograms/ml (4.6 microM). This loss of activity is assumed to be mainly due to the presence of a pyran ring in the aglains vs. a furan ring as found in rocaglamide derivatives. Rocaglamide derivatives may act primarily by inhibition of cell proliferation as evidenced by the absence of a significant cytotoxic effect in long-term cultures of MONO-MAC-6 cells treated with high doses of didesmethylrocaglamide. Our data suggest that rocaglamide derivatives could exert a potential role in the treatment of malignant diseases and are worth to be investigated in further studies of experimental medicine and pharmacology.
authors.affiliation: Department of Pharmaceutical Biology, University of Würzburg, Germany.
authors.forename: F I
authors.initials: FI
authors.lastname: Bohnenstengel
authors.forename: K G
authors.initials: KG
authors.lastname: Steube
authors.forename: C
authors.initials: C
authors.lastname: Meyer
authors.forename: B W
authors.initials: BW
authors.lastname: Nugroho
authors.forename: P D
authors.initials: PD
authors.lastname: Hung
authors.forename: L C
authors.initials: LC
authors.lastname: Kiet
authors.forename: P
authors.initials: P
authors.lastname: Proksch
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D001572:Benzofurans / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007948:Leukemia, Monocytic, Acute; D008545:Melanoma; D015394:Molecular Structure; D018547:Plant Stems; D013329:Structure-Activity Relationship; D014197:Trees; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001572:Benzofurans; C107772:rocaglamide