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Simultaneous determination of the conformation and relative configuration of archazolide a by using nuclear overhauser effects, J couplings, and residual dipolar couplings.

Natural products with promising drug activity must undergo a long configuration and conformation characterization before their target-binding mode can be investigated and exploited. One prime candidate, the polyketide archazolide A (ArcA, Figure 1), is a unique 24-membered-macrolide molecule isolated from the myxobacterium Archangium gephyra. This compound and its derivatives are of interest because they exhibit very potent cytotoxic activity by inhibiting the growth of numerous cell lines at concentrations down to the subnanomolar range. Their activity is known to involve a selective interaction with the membrane-bound portion of the vacuolar-type adenosine triphosphatase (V-ATPase), a proton-translocating enzyme that has been linked to various diseases such as osteoporosis, renal acidosis, and various cancers. This strong interaction has stimulated the investigation of the binding mechanism of ArcA at a molecular level. For the determination of the receptor-bound structure of ligands, it is essential to elucidate the configuration at all stereogenic centers. For ArcA, this has been achieved by a demanding procedure based on combined chemical derivatization and NMR spectroscopy methods. The success of this analysis on ArcA has led to the design of a synthetic route, which has allowed the confirmation of the configuration, given access to more advantageous yields, and enabled strategic derivatization to modulate the drug activity.