Qiuwen Mi

Potential Anticancer Activity of Naturally Occurring and Semisynthetic Derivatives of Aculeatins A and B from Amomum aculeatum

Activity-guided fractionation of hexanes- and CHCl 3-soluble extracts of Amomum aculeatum leaves, collected in Indonesia, led to the isolation of three new dioxadispiroketal-type ( 3- 5) and two new oxaspiroketal-type ( 6 and 7) derivatives. Nine semisynthetic derivatives ( 1a- 1h and 2a) of the parent compounds, aculeatins A ( 1) and B ( 2), were prepared. All isolates and semisynthetic compounds were tested against a small panel of human cell lines. Of these, aculeatin A ( 1; ED 50 0.2-1.0 microM) was found to be among the most cytotoxic of the compounds tested and was further evaluated in an in vivo hollow fiber assay; it was found to be active against MCF-7 (human breast cancer) cells implanted intraperitoneally at doses of 6.25, 12.5, 25, and 50 mg/kg. However, when 1 was tested using P388 lymphocytic leukemia and human A2780 ovarian carcinoma in vivo models, it was deemed to be inactive at the doses used.

Pervilleines B and C, new tropane alkaloid aromatic esters that reverse the multidrug-resistance in the hollow fiber assay

P-Glycoprotein (Pgp)-mediated drug efflux can yield a multidrug-resistance phenotype that is associated with poor response to cancer chemotherapy. Pervilleines B and C (PB and PC), two new tropane alkaloid aromatic esters obtained from a chloroform extract of the roots of Erythroxylum pervillei as the result of bioactivity-guided fractionation, were found to restore the vinblastine (VLB) sensitivity of cultured multidrug-resistant KB-V1 cells, with 50% inhibitory concentration values of 0.17 microM in each case. To explore the potential relevance of this response, KB-V1 cells were placed in hollow fibers and implanted into NCr nu/nu mice. Cell growth was not significantly inhibited when VLB or PB or PC were administered as single agents, but when used in combination with vinblastine inhibition of up to 77.7% was observed. Equimolar doses of verapamil were less effective. These data suggest that PB and PC are effective inhibitors of Pgp and should be further evaluated for clinical utility.

Antitumour activity of 3-chlorodeoxylapachol, a naphthoquinone from Avicennia germinans collected from an experimental plot in southern Florida

As part of an ongoing collaborative effort to discover new anticancer agents from plants, an extract obtained from the leaves and twigs of Avicennia germinans, collected in a coastal area of southern Florida, was identified as possessing cytotoxic activity in a panel of human cancer cell lines. Fractionation of the petroleum ether partition, using cytotoxicity to guide the fractionation, led to the isolation of 3‐chlorodeoxylapachol. The antitumour potential of 3‐chlorodeoxylapachol was demonstrated with the in‐vivo hollow fibre assay, a model of antitumour activity using human cancer cell‐filled fibres implanted into mice. The possibility that this compound is an artefact of the isolation procedure was ruled out by liquid chromatography—mass spectrometry analysis of extracts prepared without the use of chlorinated solvent. In conclusion, 3‐chlordeoxylapachol, a secondary metabolite obtained from the chloroform‐soluble extract of a mangrove tree, was cytotoxic in a panel of human cancer cells, and active against KB human cancer cells in the murine hollow fibre antitumour model, with selectivity in KB cells for the intravenous site at lower doses, indicating possible metabolic activation.