New Synthetic Methodology (figure 1)

Efficiently increasing molecular complexity is a major goal of modern synthetic organic chemistry. As molecular architects, we are now working on multicomponent, sequential reactions in one flask to bring together three or four simple building units in a rational and controlled fashion to form much more complex (i.e. valuable) products. We are also developing practical ways to use sigmatropic rearrangements for short and stereocontrolled syntheses of vitamin D side chain units.

New Vitamin D Analogs (figure 2) (figure 3)

Not only is vitamin D important for maintaining the good health (i.e. strength) of our bones, but it is important also in regulating the growth of cells in many parts of our bodies. Inhibiting uncontrolled growth of human cells is a major goal in cancer chemotherapy. However, vitamin D cannot be used for such chemotherapy because it is too broadly active. Therefore, we (and others) are developing new analogs that are selectively antiproliferative but not calcemic. In collaboration with the toxicology department in the Hopkins School of Hygiene and public Health, each of our new analogs is evaluated in vitro for antiproliferative potency and in vivo for non-calcemic activity; we have successfully completed a six month rodent study using some of these non-calcemic synthetic analogs for prevention of skin tumorigenesis. Several of our new, patented synthetic analogs have a sufficiently high therapeutic index (i.e. high potency, low toxicity) that an international pharmaceutical company is now throughly evaluating these rationally designed analogs as potential new drug candidates.

New Antimalarial Peroxide Drugs (figure 4),(figure 5)

Because 300-500 million people worldwide currently have malaria and because malaria parasites have developed resistance to many quinoline-based standard antimalarial drugs (i.e. chloroquine) an international search for new non-alkaloidal antimalarial compounds is in progress. Based on Chinese folk medicine, a new peroxide drug has been isolated from the Artemisia annua plant; although this substance (called artemisinin) is currently used in tropical areas of the world to effectively cure malaria patients, it is not yet approved for use in the U.S. We are applying our understanding of the chemical mechanism of action of this family of peroxides to design rationally and to synthesize efficiently various analogs. In collaboration with the pharmacology department at the Hopkins School of Medicine, each of our new peroxide analogs is tested in vitro for antimalarial potency; the best analogs are then sent out for in vivo testing. Several of our new peroxides are orally active in vivo and are safer than the currently used antimalarial drugs. We are planning further animal tests in preparation for filing an investigational new drug (IND) application with the U.S. FDA and in preparation for performing human clinical trails in the Hopkins School of Medicine. Recently, we discovered that some dimeric peroxides are not only highly antimalarial but also highy antiproliferative; we are actively designing, preparing, and testing such types of dimers for chemotherapy of both malaria and cancer.