The importance of natural products to drug discovery, in particular, to anticancer drug discovery, has historically been very large. Natural products have provided some of the most significant cancer chemotherapeutics, largely because they provide drugs that are inaccessible by other routes. Compounds such as paclitaxel (Taxol) would never be prepared by standard  medicinal chemistry approaches to drug discovery. Isolation of bioactive natural products offers a unique and effective route to the discovery of new anticancer agents. The process is not easy, however, and successful discovery of a new drug substance requires an excellent collection of natural extracts, a selective and predictive bioassay, and skilled isolations chemists.st country as an economic incentive to maintain their tropical forests. The new bioactive compounds below have all been isolated from plants collected in this program, and two of them are being investigated further as potential anticancer agents. We are partnered with Eisai Research Institute (ERI) in this work, and any compounds with significant anticancer activity will be offered to ERI for development.

We are involved in a search for novel anti-cancer agents from Nature in a major collaborative project with investigators from the University of Virginia, the University of Pittsburgh, and Galileo Pharmaceuticals. Plant and marine extracts are fractionated using a variety of selective mechanism-based bioassays, and structure elucidation is carried out primarily by spectroscopic methods. We also synthesize promising lead compounds to explore their structure-activity relationships and to obtain adequate material for biological testing. Compounds isolated range from simple quinones to alkaloids, diterpenoids, and other complex natural products.

One of our key tools for this work is a set of new selective biooassays. An increasingly advanced understanding of cancer as a disease of the cell points to highly sophisticated interventions that will inhibit proliferation or induce death in a cancerous cell. For instance, it is now known that a particular type of cell death  known as programmed cell death or apoptosis can be triggered by blocking the activity of the cellular enzyme Chk1. Apoptosis is a particularly desirable type of cell death because it uses a built-in signaling pathway resident in every cell. It causes no inflammation that can result in damage of surrounding tissue. Apoptosis is the mechanism a tadpole uses to absorb its tail as it becomes an adult frog. Apoptosis successfully used against a tumor would result in the shrinkage and dissipation of the tumor without harm to tissues in which the tumor resides. We are seeking to reverse the tables by triggering apoptosis in cancer cells by interrupting the cancer cell s Chk1 signaling pathway, or by inhibiting other important cell cycle enzymes such as Akt and Ckh2. We will use the cornucopia of compounds found in Nature as a source of inhibitors, for the reasons outlined above.

Some representative structures of compounds with potential anticancer activity isolated in our group over the last few years are shown below: