Examples of Anticancer and Chemopreventive Agents Derived from Natural sources and Their Mechanisms of Action


Mechanism of Action

Vinblastine, Taxanes Bryostatin

Calicheamicin, Bleomycin


Ecteinascidin-743, PBDs

Mitomycin C








Sulforaphane, flavones etc.

Spindle Inhibitors

Protein Kinase C

DNA Cleavage

DNA Intercalation

DNA Alkylation

DNA Cross-linking

Topo I Inhibition

Topo II Inhibition

CDK Inhibition

Vascular Targeting

Photodynamic Therapy (PDT)


Interleukins, Asparaginase Chemopreventive

It follows that there should be a greater chance of obtaining hits in high-throughput assays if natural product extracts are screened rather than libraries of synthetic compounds. However, with the upsurge of interest in parallel and combinatorial libraries in the 1990s, the desirability of using extracts of plant, bacterial, and fungal materials waned due to issues relating to their availability and stability, and especially the fact that they are usually complex mixtures. When a hit was obtained, it was necessary to separate the active agent from the complex mixture, identify its structure (including stereochemistry), and then either synthesize it or otherwise extract larger amounts from the original material, which may not have been available in useful amounts. Another perceived problem was that false-positives and false-negatives could be obtained in a screen due to the presence of other agonists or antagonists in the complex mixture.

However, technological developments have solved some of these problems and have now made the screening of natural product extracts more attractive. For example, a number of companies now supply natural product extracts in a multiwell plate format and guarantee the availability of more raw material in bulk should a hit be obtained from the screen. More importantly, bioassay-guided fractionation technology has revolutionized the separation and identification of hits in natural product extracts. The instrumentation involves an automated HPLC system directly coupled to a bioassay. An extract that shows activity in an initial screen is separated into fractions (usually broad ones at first) by the HPLC system (normally semipreparative or preparative), and a sample of each fraction is sent automatically to the bioassay. Active fractions are then sent back to the HPLC column and refractionated (into narrower fractions), each one again being sent to the bioassay. This process may be repeated for a number of cycles (usually fully automatically) until the narrowest fraction that contains the biological activity is obtained. At this stage, the purity may be sufficient to identify an active compound by techniques such as NMR or MS. If not, then only limited further purification should be required to achieve structural identification.

It is also worth noting a resurgence of interest in ethnopharmacology (or eth-nopharmacy), the study of plant materials or other natural products that have been used by a local community as a traditional cure for a particular disease. The assumption is that these materials may contain an active constituent that can be identified, purified, and obtained in large amounts (by extraction or synthesis) for further studies. One recent example of this approach is the identification of a novel agent potentially useful for the treatment of leukemia and nonmelanoma skin cancers. Researchers at the University of Birmingham (U.K.) and Peplin Ltd. (Brisbane, Australia) discovered a new agent (known as PEP005 or 3-Angelate) in the sap of a weed (petty spurge, milk weed, Euphorbia peplus) traditionally used for treating corns and warts, on the basis that constituents apparently able to control cell growth and cause cell death may also have useful antitumor activity. The isolated agent has been shown to be 100-fold more cytotoxic toward certain tumor cells in vitro than healthy cells and is believed to work by activating protein kinase C which triggers apoptosis.

Given these developments, it is possible that more novel anticancer agent leads will be derived from natural product sources in the future.

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