The overall objective of this research program is the development of efficient synthetic procedures for construction of the latrunculins (A and B), two architecturally novel marine toxins, isolated from Latruncula magnifica (Keller) a sponge endemic to the Red Sea. The Latrunculins represent a new class of highly potent compounds that specifically bind to cytoskeletal proteins and thereby disrupt microfilament organization in cultured cells without effecting the microtubular system. The mode of action while still unknown, most closely resembles the activity displayed by the cytochalasins, the only other class of drugs known to bind to actin filaments and to specifically disrupt the microfilamentous structures. The latrunculins, however, exert their effects at concentrations 1/10 to 1/100 that of the cytochalasins. Concommitant with the development of our approach to these targets, we will: (A) Develop the chemistry of mixed acetals vis-a-vis control of acyclic stereochemistry; and (B) Explore the use of chiral ketone enolates derived from amino acids as a means of acyclic steroechemical control in the aldol and closely related reactions. In addition to the above quite specific synthetic goals, a more general underlying and long range aim of this research program is the development of a better understanding of the molecular architecture responsible for both the actin binding properties and disruption of the microfilamentous structures caused by these and related systems. Thus, as we develop our method of procedure for the latrunculins, we will also introduce various model systems which will be amenable to construction and subsequent testing, such that in the end we will be able to dissect out the critical architectural feature or features responsible for the observed regulatory effects. Once such features are identified, the design of new and more effective drugs to regulate the actin-microfilament system should be feasible. The latter would, of course, have direct application to the control and treatment of heart and other cardiovascular disease.
