) This renewal application describes plans for the continuation of a research program involving synthesis, computer modeling, spectroscopic, mechanistic/mode of action, biological, and medicinal studies focused on compounds of demonstrated or potential importance in cancer research and chemotherapy. It is the objective of this program to develop fundamentally new methods and strategies for the synthesis of such compounds, to elucidate the structural basis for their mode of action, and to test and exploit these new findings in the rational design of new cancer chemotherapeutic agents or compounds of interest in cancer research Five comprehensive projects are proposed for investigation during the continuation period. A major continuation study on the cancer chemotherapeutic agent taxol is directed at the synthesis and evaluation of novel taxol conjugates, a lead representative of which is 10,000 times more water soluble than taxol, exhibits greater cytotoxicity, and enters cells through a facilitated active transport process. A second major project is directed at the continuation of our studies on bryostatin (an emerging therapeutic agent now in clinical trials) with the goal of advancing new analogues of bryostatin that exhibit significantly more potent growth inhibitory activity against various human cancer cell lines than bryostatin itself and identifying even more effective clinical candidates as well as the basis for the activity of bryostatin. A third major project is focused on elucidation of the structural and functional role of RACKS (receptors for activated C kinases), a newly discovered class of proteins of fundamental importance in cellular signal transduction and new targets for the design of novel cancer chemotherapeutic agents. A fourth project, prompted by the percentage of kinases encoded in the human genome and the role of kinases as targets for the treatment of cancer and other diseases, is directed at the development of new kinase inhibitors based on a novel metal catalyzed cycloaddition sequence. A fifth project is centered on investigating the structural basis for the activity of apoptolidin, a recently identified agent that exhibits the remarkable ability to selectively induce apoptosis in transformed cell lines. Overall, this research program is expected to be of significant value in chemistry, biology, and medicine.
Showing the most recent 10 out of 90 publications
