Cell-cycle specific cytotoxicity mediated by rearranged ent-kaurene diterpenoids isolated from Parinari curatellifolia
| Autor: | Norman R. Farnsworth, Heebyung Chai, Lisa A. Shamon, Jeffrey M. Besterman, T E Chagwedera, A. Douglas Kinghorn, Geoffrey A. Cordell, John M. Pezzuto, k-Soo Lee |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
G2 Phase
Magnetic Resonance Spectroscopy Guanosine Toxicology Cell Line chemistry.chemical_compound Biosynthesis Parinari curatellifolia Neoplasms Cytotoxic T cell Humans Cysteine Cytotoxicity Mercaptoethanol biology Molecular Structure Spectrum Analysis Cell Cycle General Medicine Cell cycle Plants biology.organism_classification Flow Cytometry chemistry Biochemistry Cell culture Africa Medicine Traditional Diterpenes DNA Cell Division |
| Zdroj: | Chemico-biological interactions. 99(1-3) |
| ISSN: | 0009-2797 |
| Popis: | Two structurally novel cytotoxic ent-kaurene diterpenoids, 13-methoxy-15-oxozoapatlin and 13-hydroxy-15-oxozoapatlin, were isolated from the root bark of Parinari curatellifolia, together with the known compound, 15-oxozoapatlin, on the basis of bioactivity-guided chromatographic fractionation and found to demonstrate broad-spectrum cytotoxic activity against a panel of cultured human cancer cell lines. The structures of these compounds were determined by analysis of their spectroscopic data. The presence of an alpha, beta-unsaturated carbonyl group in 13-methoxy-15-oxozoapatlin suggested that the cytotoxic potential of this compound could be mediated through reaction with cellular nucleophiles by means of a Michael-type addition. The compound 13-methoxy-15-oxozoapatlin reacted with the nucleophiles L-cysteine and beta-mercaptoethanol. The adduct with beta-mercaptoethanol was isolated, structurally characterized and found to be approximately 5-fold less cytotoxic than 13-methoxy-15-oxozoapatlin itself. The compound 13-methoxy-15-oxozoapatlin did not interact with DNA nor guanosine, and it was not mutagenic for Salmonella typhimurium strain TM677. The effects of 13-methoxy-15-oxozoapatlin on the growth of human cancer cells were analyzed utilizing cultured ZR-75-1 breast cancer cells. Biosynthesis of DNA, RNA and protein was reduced in treated cells, and accumulation at the G2/M phase of the cell cycle was observed. The compound 13-methoxy-15-oxozoapatlin did not mediate antimitotic activity with dibutyryl cAMP-treated cultured astrocytoma cells, suggesting that the cell cycle effect is G2 specific. No antitumor activity was observed when athymic mice carrying KB cells were treated with 13-methoxy-15-oxozoapatlin. These data indicate that the cytotoxic activity of 13-methoxy-15-oxozoapatlin is mediated in part by covalent reaction with a cellular component (such as sulfhydryl-containing protein) by means of a Michael-type addition, and this results in the blockage of cell-cycle progression. |
| Databáze: | OpenAIRE |
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