Abstract:
Natural products, especially of marine origin, have inspired the development of novel therapeutic agents. The vast and various marine habitats are home for organisms generating structurally diverse and unique natural products as potential drug leads. New Zealand waters along the long coastline have proven to be excellent sources of bioactive secondary metabolites. Six species of New Zealand ascidians were isolated in search for novel metabolites. Fractionation of the crude extracts using reserve-phase column chromatography led to the isolation of three metabolites: two aliphatic sulfates, 2,6-dimethylheptyl sulfate and decadienyl sulfate from Styela sp. and (+)-enantiomer of 1,2,3-trithiane from Hypsistozoa fasmeriana. Storniamide A is a polyaromatic pyrrole alkaloid isolated from a Patagonian sponge Cliona sp. Permethyl storniamide A is a structural analogue of storniamide A with methylation of the hydroxyl groups on all the aromatic rings and is known for the capability of reversing multidrug resistance of cancer caused by P-glycoprotein at noncytotoxic concentration. However, no report so far has discussed the relationship between the structure and the MDR reversing activity. Herein a nine-step reaction route has been developed to synthesize storniamide A permethylether involving two key steps: a one-pot reaction using phenethylamine and phenylpyruvic acid to assemble the pyrrole core; and a coppercatalysed Buchwald coupling of vinyliodide to the diamide pyrrole precursor forming the enamide moiety. Characterization of the product confirmed the final product, with ease of purification and a higher yield compared to previous reported synthesis method. A total number of 8 novel diamide pyrrole precursors varying on the methoxy groups on aromatic rings were also prepared for further studies of relationship between structure and MDR reversing activity.