Ad Kinghorn

Novel Strategies for the Discovery of Plant-Derived Anticancer Agents.

Work has continued on the investigation of plants, collected mainly from tropical rainforests, as potential sources of new cancer chemotherapeutic agents. About 400 primary samples are obtained each year, with the chloroform-soluble extract of each being screened against a battery of in vitro assays housed at the three consortial sites in our current National Cooperative Drug Discovery Group (NCDDG) research project. An HPLC-MS dereplication procedure designed to screen out “nuisance” compounds has been refined. Several hundred secondary metabolites that are active in one or more of the primary assays utilized have been obtained in the project to date, and are representative of wide chemical diversity. Some of these are also active in various in vivo assays, inclusive of the hollow fiber assay, which was installed recently as part of our collaborative research effort. A number of bioactive compounds of interest to the project are described.

Cytotoxic Constituents of Muntingia calabura Leaves and Stems Collected in Thailand

AbstractFrom samples of Muntingia calabura leaves and stems of Thai origin were obtained the cytotoxic flavonoids chrysin, 2′, 4′-dihydroxychalcone, and galangin 3, 7-dimethyl ether. These compounds were active against one or more of a panel of human and murine cell lines. Also isolated were the inactive compounds, 5, 7-dihydroxy-8-methoxyflavonol, tiliroside and buddlenoid A.

Cytotoxic clerodane diterpenes from Polyalthia barnesii.

Three cytotoxic clerodane diterpenes were purified from an ethyl acetate-soluble extract of the stem bark of Polyalthia barnesii, namely, 16 alpha-hydroxycleroda-3,13(14)Z-dien-15,16-olide, a known compound, and two novel compounds, 3 beta, 16 alpha-dihydroxycleroda-4(18),13(14)Z-dien-15,16-olide and 4 beta, 16 alpha-dihydroxyclerod-13(14)Z-en-15,16-olide. These compounds were found to exhibit broad cytotoxicity against a panel of human cancer cell lines.

Two diarylheptanoids and a lignan fromCasuarina junghuhniana

Abstract A new diarylheptanoid, casuarinondiol, and two known compounds, alnusdiol (a further diarylheptanoid) and (±)-lyoniresinol 2α-O-rhamnoside (a lignan), have been isolated from the roots ofCasuarina junghuhniana and characterized spectroscopically. These are the first representatives of these compound classes to have been obtained from a plant in the Casuarinaceae.

Triterpenes from the combined leaf and stem of Lithospermum caroliniense

An investigation of the combined leaf and stem of Lithospermum caroliniense afforded two new pentacyclic triterpenoids based on the olean-12-ene and taraxast-12-ene skeletal types. The structures of these compounds were elucidated on the basis of spectral analysis as 1 alpha,3 beta,23-trihydroxyolean-12-ene-28-oic acid and 3 alpha,19 beta,21 alpha,23-tetrahydroxytaraxast-12-ene-28-oic acid.

Design, synthesis, and biological evaluation of analogues of the phyllanthusmin class of arylnaphthalene lignan natural products

Recently a series of arylnaphthalene lignans was isolated from Phyllanthus poilanei by the Kinghorn lab. These compounds bear a strong structural resemblance to etoposide, a semi-synthetic DNA topoisomerase II (topo II) poison, and the natural product podophyllotoxin. Although the newly isolated compounds do not appear to act on topo II, they have demonstrated potent in vitro antiproliferative activity against HT-29 human colon cancer cells. Moreover, one of these compounds, phyllanthusmin D, also showed promising activity in a hollow fiber assay using HT-29 cells in mice. In an effort to understand the basic structure-activity requirements of this class of natural product and to remedy the limited aqueous solubility of these molecules, a series of structural analogues were synthesized and tested for biological activity. These studies have focused primarily on the role of the saccharide moiety in the activity of this class, although variation of the aryl substituents has also been examined.

Potential cancer chemopreventive activity of some goji berry pyrrole alkaloids isolated from a mislabeled commercial sample

Goji berry [fruit of Lycium barbarum L. (Solanaceae)] has a long history of usage in Asian countries as a culinary ingredient, traditional medicine and functional food. Goji has more recently become increasingly popular in Europe and North America as a “super fruit” and botanical dietary supplement. One commercial dietary supplement that was screened in an ongoing search for natural inhibitors of carcinogenesis showed hydroxyl radical-scavenging (HRS) and quinone reductase-inducing (QRI) activities. This sample was shown by chemotaxonomy and microscopy to be mislabeled, and was identified as Goji. Isolation directed by the above bioassays yielded a new pyrrole alkaloid (1) along with seven known compounds (2 – 8). Compound 1 demonstrated HRS activity with an ED50 value of 16.7 µM, and compound 2 was active in both HRS (ED50 11.9 µM) and QRI [CD (concentration required to double quinone reductase activity) 2.4 µM)] assays. Further investigation confirmed the presence of compounds 1 – 2 and 4 – 8 in a Goji extract that was previously shown to prevent N-nitrosomethylbenzylamine-induced esophageal cancer in rats. Taken together with the dietary source of these molecules having a long history of human consumption, the results of the study indicated that this class of compounds, especially compound 2, could be potential in vivo cancer chemopreventive agents.