The plan of this revised application is to develop new synthetic methodologies and strategies for the construction of 2- aminoimidazole- and guanidine-based marine natural products possessing important biological activities. It is indicated that notable representatives include the tricyclic marine pigments zoanthoxanthins (1) and (2), the C11N5 family of oroidin alkaloids (3-7), dimeric oroidin alkaloids (8-10) and the red-tide toxins, saxitoxin (11) and gonyautoxins (12). It is reported that collectively, these and other structurally related compounds possess potent pharmacological properties that include antiviral, antileukemic, antineoplastic, antiserotonergic as well as alpha-adrenoceptor and ion-channel blocking activities and that in addition, a rare example of ATPase stimulating activities of myosin and actomyosin has recently been observed. The principal investigator notes that although each class of metabolites is structurally unique, they represent, however, a collection of structures whose diversity is related by the rich chemistry that they share in common. The proposed research is to focus on developing methodologies and strategies that involve oxidative and non-oxidative transformations of 2-aminoimidazoles that will have general applicability to synthesis of the above heterocycles. It is noted that in particular, the utility of these methods is delineated in the proposed synthesis of the bicyclic oroidin alkaloid hymenialdisines (6), the dimeric oroidin alkaloids, ageliferin (8) (R=H) and sceptrin (9), and the potent neurotoxins saxitoxin (11) and gonyautoxin (12). The principal investigator indicates that the proposed methods and routes are essentially devoid of protecting groups and are based on biogenetic considerations. He suggests that an integral feature of the research plan is a criterion for substantiating possible biosynthetic pathways. It is indicated that the synthetic plan calls for the development of methods for transforming 2- aminoimidazole into key intermediates for the synthesis of the naturally occurring compounds and that the preparation of these intermediates and the facility of the ensuing molecular rearrangements would tend to support or disclaim the biogenetic hypothesis. It is suggested that versatile and efficient syntheses of these metabolites would provide access to structurally modified or specifically labeled substrates for biomedical research.
| Barrios Sosa, A C; Yakushijin, K; Horne, D A (2000) A practical synthesis of (Z)-debromohymenialdisine. J Org Chem 65:610-1 |
| Miyake, F Y; Yakushijin, K; Horne, D A (2000) A facile synthesis of dragmacidin B and 2,5-bis(6'-bromo-3'-indolyl)piperazine. Org Lett 2:3185-7 |
| Miyake, F Y; Yakushijin, K; Horne, D A (2000) A concise synthesis of topsentin A and nortopsentins B and D. Org Lett 2:2121-3 |
