The overall objective of this research program is the development of efficient synthetic procedures for construction of structurally complex macrolide natural products. The specific targets include latrunculin A, acutiphycin, 20,21-didehydroacutiphycin, aplysiatoxin, debromoaplysiatoxin and oscillatoxin A. The latrunculins (A and B) represent a new class of highly potent macrolides 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 mocrofilamentous structures. The latrunculins, however are 10 to 100 times more active than the cytochalasins. Acutiphycin and 20,21-didehydroacutiphycin are macrolides, isolated from the lipophilic extract of the freshwater algae, Oscillatoria acutissima.3 They display cytotoxicity against KB and NIH/3T3 cells as well as significant antineoplastic activity in vivo against murine Lewis lung carcinoma.3 Aplysiatoxin, debromoaplysiatoxin, and oscillatoxin A, also isolated from algae, are potent tumor promoters possessing complex macrolide structures. Each of the above macrolides represents an extremely important target from the point of view of synthetic chemistry and biological potency (i.e., antitumor or tumor promoter activity). In addition to the above quite specific synthetic targets, 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 the biological properties of these and related macrolides. Thus, as we develop our method of procedure for each of the above targets, we will also introduce various model systems which will be amenable to construction and subsequent screening, such that in the end we will be able to dissect out the critical structural feature of features responsible for the observed biological activities. Once such features are identified, the design of new and possible more effective agents should be feasible.
