STRUCTURAL/SYNTHETIC STUDIES OF BIOACTIVE MARINE AGENTS

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DESCRIPTION: The objectives of this proposal include the structure determination and total synthesis of novel marine natural products displaying potent biological activity. Targets are said to include bistramide A, a tunicate isolate inducing cellular differentiation, pateamine A, a marine sponge isolate exhibiting immunomodulating properties, and curacin A, a marine bacterial antimitotic agent which inhibits tubulin polymerization. It is reported that bistramide A promises to be a useful new tool for the study of mechanisms involved in cellular differentiation, a capacity lost by some cancerous cells and that methods for the preparation of crystalline derivatives of bistramide A suitable for x-ray analysis are proposed as a means to determine its relative and absolute stereochemistry. The principal investigator notes that a convergent, stereoflexible route is proposed for the enantioselective, total synthesis of bistramide A and that key features of the synthesis include an Ireland-Claisen rearrangement and a samarium diiodide mediated, sequential acyl substitution/redox process. It is indicated that the synthesis of structural derivatives and a bistramide A affinity matrix will allow preliminary investigations into the mode of action of these agents. The principal investigator states that as a first step towards understanding how pateamine A exerts its immunomodulating effects, an initial objective in collaboration with Professor M. Munro (University of Canterbury. New Zealand) is determination of its relative and absolute stereochemistry by using a combination of semi-synthesis, natural product degradation, molecular modeling, and NMR spectroscopy and that structural verification is to be accomplished by executing a convergent, enantioselective synthesis of pateamine. It is indicated that the convergent nature of the synthesis will allow access to significant quantities of pateamine A and structural derivatives for further evaluation as potential immunosuppressive agents by Dr. G. Faircloth (PharmaMar, USA) and for investigations into their mechanism of action. It is noted that a convergent, enantioselective synthesis of four diastereomers of curacin A will enable spectroscopic comparison to an authentic sample for stereochemical determination of this antimitotic agent. The principal investigator states that a key step in the synthetic approach includes a novel Stille-type coupling of a cyclopropyl stannane to a cysteine derived- thiazoline triflate to prepare the structurally unique cyclopropyl-thiazoline portion of curacin A and structural variants in this region of the molecule. These derivatives are to be evaluated for their ability to inhibit tubulin polymerization by Dr. E. Hamel (National Cancer Institute-NIH). It is suggested that these investigations may lead to a novel class of antineoplastic agents that exert their effects via the colchicine binding site of tubulin in contrast to other known inhibitors of tubulin polymerization which exert their effects at the vinblastine binding site.