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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033833-04
Application #
3283921
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1985-09-01
Project End
1991-08-31
Budget Start
1988-09-01
Budget End
1989-08-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104