Cell-cycle specific cytotoxicity mediated by rearranged ent-kaurene diterpenoids isolated from Parinari curatellifolia.

Abstract

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.

• Authors: I S Lee, L A Shamon, H B Chai, T E Chagwedera, J M Besterman, N R Farnsworth, G A Cordell, J M Pezzuto, A D Kinghorn
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 99 Issue 1-3 Pg. 193-204 (Jan 05 1996) ISSN: 0009-2797 [Print] Ireland
• PMID: 8620568 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 13-hydroxy-15-oxozoapatlin
• 13-methoxy-15-oxozoapatlin
• Diterpenes
• Mercaptoethanol
• Cysteine

Topics

• Africa
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Cell Line
• Cysteine (metabolism)
• Diterpenes (isolation & purification, pharmacology, toxicity)
• Flow Cytometry
• G2 Phase (drug effects)
• Humans
• Magnetic Resonance Spectroscopy
• Medicine, Traditional
• Mercaptoethanol (metabolism)
• Molecular Structure
• Neoplasms (metabolism)
• Plants (chemistry)
• Spectrum Analysis