Argyrins are natural peptide products produced by myxobacteria and actinomycetes that have exhibited an antibacterial spectrum of activity by inhibiting bacterial protein synthesis.1 Argyrin B binds a novel allosteric pocket in elongation factor G (EF-G), distinct from the known EF-G inhibitor antibiotic fusidic acid, revealing a new mode of protein synthesis inhibition, which represents an interesting advance in the development of new antibiotics with alternative modes of action. Despite the considerable potential of the argyrins as drug candidates, detailed structure-activity relationship (SAR) studies and a molecular understanding of their precise mode of action are necessary in order to fully realize its medicinal potential. To this end, an elegant solution-based synthesis of argyrin B analogues was performed. The derivatives produced would then undergo further SAR studies as proteasome inhibitors to complement those already performed, as well as those at EF-G. These studies would allow us to differentiate the original argyrin core structures into proteasome and EF-G specific inhibitors as well as elucidating which structural motifs are essential for each target. Dean, C.R., Nyfeler, B., Hoepfner, D., Palestrant, D., et al. PLoS ONE. 2012, 7, e42657; 2 Sasse, F., Steinmetz, H., Schupp, T., et al. J. Antibiot. 2002, 55, 543-551; 3 Malek, N.P., Nickeleit, I., Zender, S., Sasse F., et al. Cancer Cell. 2008, 14, 23-35; 4 Ley, S.V., Priour, A,. et al. Eur. J. Org. Chem. 2002, 3995-4004 ; 5 Kalesse, M., Bülow, L., Nickeleit,I., et al. ChemMedChem. 2010, 5, 832-836;

Synthesis of argyrin B analogue for SAR studies

251st National Meeting (2016)

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