Novel anti-cancer and pesticidal components from Goniothalamus giganteus (Annonaceae)
Abstract
This project involved the bioactivity-directed isolation and characterization of a number of cytotoxic and potentially pesticidal agents from the bark of Goniothalamus giganteus Hook. f. & Thomas (Annonaceae). Ethanol extraction, partition, and repeated chromatographic separations, with brine shrimp toxicity (BST) directing the fractionation, resulted in the isolation of seventeen compounds: xylomaticin (1), (2,4-cis and trans)-xylomaticinones (2), longicoricin; (3), (2,4-cis and trans)-isoannonacins (4), goniotetracin (5), longifolicin (6), (2,4-cis and trans)-gonioninones (7), 4-deoxyannomontacin (8), (2,4-cis and trans)-annomontacinones (9), (2,4-cis and trans)-gigantetrocinones (10), goniotrionin (11), longimicin C (12), (2,4-cis and trans)-gigantecinones (13), 4-deoxygigantecin (14), pyranicin (15), pyragoniocin (16), and goniotriocin (17). All are Annonaceous acetogenins, a rapidly growing class of new bioactive compounds which have excellent potential as antitumor and pesticidal agents. Ten of these compounds (2, 5, 7-9, 11, 13, 15-17) are new to the literature, six of these (1, 3-6,10) are reported for the first time from this species, and three (15-17) represent two new classes of acetogenins: the mono-tetrahydropyrans (15, 16) and the hydroxylated nonadjacent tetrahydrofurans (17). All of the isolated compounds showed significant bioactivity. The acetogenins are very active in the BST, in the yellow fever mosquito larvae assay, where they are comparable or more potent than rotenone, and in showing significant and selective toxicities against our seven-day MTT human solid tumor cytotoxicity tests; these results were usually comparable or more potent than those of the positive control compound, Adriamycin. Six compounds, representing the mono-tetrahydrofuran (THF) (gigantetrocin A, annomontacin), adjacent bis-THF (asimicin, parviflorin), and non-adjacent bis-THF (sylvaticin, bullatalicin) classes of Annonaceous acetogenins, were compared to technical grades of synthetic amidinohydrazone (hydramethylnon), carbamate (propoxur, bendiocarb), organophosphate (chlorpyrifos), and pyrethroid (cypermethrin) insecticides to determine their dietary toxicities to insecticide-resistant and insecticide-susceptible strains of the German cockroach, Blattella germanica (L.). The adjacent bis-THF acetogenins showed the highest potency among all the compounds tested. The acetogenins caused high percentage of mortality and delays in development of the 5$\rm\sp{th}$ instars of both strains. Low resistant ratios (RR$\sb{50})$ were obtained for the natural acetogenins and ranged from 0.9-3.9 while the range was 1.0-8.0 for the synthetic compounds.
Degree
Ph.D.
Advisors
McLaughlin, Purdue University.
Subject Area
Pharmacology|Oncology
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