Simultaneous structure–activity studies and arming of natural products by C–H amination reveal cellu

Abstract

Natural products have a venerable history of, and enduring potential for the discovery of useful biological activity. To fully exploit this, the development of chemical methodology that can functionalize unique sites within these complex structures is highly desirable. Here, we describe the use of rhodium(II)-catalysed C–H amination reactions developed by Du Bois to carry out simultaneous structure–activity relationship studies and arming (alkynylation) of natural products at ‘unfunctionalized’ positions. Allylic and benzylic C–H bonds in the natural products undergo amination while olefins undergo aziridination, and tertiary amine-containing natural products are converted to amidines by a C–H amination–oxidation sequence or to hydrazine sulfamate zwitterions by an unusual N-amination. The alkynylated derivatives are ready for conversion into cellular probes that can be used for mechanism-of-action studies. Chemo- and site-selectivity was studied with a diverse library of natural products. For one of these—the marine-derived anticancer diterpene, eupalmerin acetate—quantitative proteome profiling led to the identification of several protein targets in HL-60 cells, suggesting a polypharmacological mode of action. Natural products are enduring leads for exploring cell biology, yet structure–activity relationship studies and 'arming' of these small molecules for subsequent cellular probe synthesis remains a challenge. Here, a strategy for derivatization of natural products by C–H amination, aziridination and unusual N-aminations is described. Selective derivatization of eupalmarin acetate led to identification of this natural product's target.

Cite this article

Li, J., Cisar, J., Zhou, CY. et al. Simultaneous structure–activity studies and arming of natural products by C–H amination reveal cellular targets of eupalmerin acetate. Nature Chem 5, 510–517 (2013). https://doi.org/10.1038/nchem.1653

View full text

>> Full Text:   Simultaneous structure–activity studies and arming of natural products by C–H amination reveal cellu