The long term goals of this program include the laboratory synthesis of complex natural products possessing desirable biological activity as well as the development of new synthetic methodology that will simplify this task. In addition, we will attempt to identify, and to synthesize and test, structurally simplified analogues of these naturally occurring lead compounds which can be accessed in a more practical manner than the natural compounds themselves. Our synthetic efforts will place an emphasis on tactics which allow for as brief and high yielding a synthesis as possible. We expect to complete a total synthesis of the highly promising anti-cancer and anti-Alzheimer's agent bryostatin 1 and to optimize this route as much as possible to allow for the laboratory synthesis of this exceedingly scarce substance. We will determine, through synthesis, those structural features responsible for the biological functions of this agent, and use this information in the preparation of simplified analogues. We will expand and continue our efforts in the bryostatin analogue area as we expect that we can prepare agents that function even better than brio 1 itself or our present analogues. We also plan to initiate studies to better define the cellular targets of bryostatin and to examine selectivity profiles for the analogues we prepare. Full biological characterizations of these analogues will be obtained. In addition, we plan to initiate work on two new structures which we expect can be prepared using the tactics developed in the course of our bryostatin and epothilone work, namely acutiphycin and peloruside. We will also examine a short approach to the anti cancer agent haterumalide, as an initial entry into tetrahydrofuran containing materials. Throughout all of this work, we hope to implement new organic reactions and strategies which will both facilitate the construction of the targeted compounds, as well as prove useful in a broader context. Many organic compounds with promising anti-cancer activity have been isolated from marine sources such as sponges;the remarkable agent bryostatin 1 is an example. In over 80 clinical trials, bryostatin 1 has shown very promising activity, especially when used in combination with other agents such as taxol. If the potential of this agent is to be realized, it is imperative that we find ways to make either bryostatin or similar compounds in the laboratory, as we will never be able to obtain an adequate supply otherwise. This work will be directed towards these tasks.
Showing the most recent 10 out of 32 publications
