The research interests of the group are multi-faceted. One major effort is in the area of development of new agents to treat a variety of cancers, particularly ovarian and cervical cancers. trans-Retinoic acid (t-RA,1) is known to be a very important in the normal growth and differentiation of human cells. However, it is quite toxic and therefore has limited clinical use. Our focus has been to synthesize structures which are similar to 1 in terms of biological activity but which are much less toxic.

Heteroarotinoids are defined as retinoid systems which possess at least one heteroatom in the partially saturated ring and at least one aromatic ring. Heteroarotinoids 2-4 are examples which have been prepared and which exhibit strong inhibition of cell growth in a variety of cancer cell lines, and yet they are less toxic then 1. One example of 4 was selected by the National Institutes of Health (NIH) for preclinical screening (now in progress) for the potential use in treating ovarian and cervical cancer. Collaborative efforts are with biochemists and molecular biologists who determine the inhibitory prowess, the receptor specificity, and the transactivation characteristics of the agents. The ability of the heteroarotinoid to interact with specific receptors is very critical since such complexes formed by this interaction can initiate transcription by selected genes. Thus, the generation of specific proteins from this complexation process has potential ramifications in terms of regeneration of target organs. The broad training received by individuals working in this field has allowed them access to positions in more then the chemical sciences.

The second effort is in the development of novel antiarrhythmic agents to treat pain and cardiovascular disorders which arise when humans experience heart attacks or other malfunctions of the heart. Life-threatening arrhythmias often occur during a major heart attack and cause the heart to beat in an abnormal manner which can lead to heart failure.

It has been discovered that agents derived from the family of 3,7-diheterabicyclo [3.3.1]-nonanes (DHBCNs-5) possess analgesic and useful antiarrhythmic properties. Depending upon the nature of the substituents, it is possible to introduce more then one type of antiarrhythmic activity into one structure. For example, being able to regulate carefully the potassium and sodium channels in a specific manner greatly influences heart action. Moreover, a single agent which also possesses ability to extend the action potential duration of an individual beat of the heart can also be beneficial. Consequently, we are creating single agents with multi-class activity. Although the chair-chair conformer in 5a has greater antiarrhythmic action in animal models, the boat-chair form in 5b is also a useful agent in some examples. We are currently focusing on agents related to 6. The research involves determining the nature of the major conformer in solution via NMR analysis and the energetics for the interconversion between both conformers. A joint project with scientists in Kazakhstan resulted in the Kazakhstan team winning the State Prize of Kazakhstan for the research (2003).

Recent Publications - Anticancer Agents

Recent Publications - Analgesic/Antiarrhythmic Agents