Synthesis and conformational dynamics of the reported structure of xylopyridine A.

Natural products have served as a rich source for the discovery of new nucleic acid targeting molecules for more than half a century. However, our ability to design molecules that bind nucleic acid motifs in a sequence- and/or structure-selective manner is still in its infancy. Xylopyridine A, a naturally occurring molecule of unprecedented architecture, has been found to bind DNA by a unique mode of intercalation. Here we show that the structure proposed for xylopyridine A is not consistent with the characterization in the original isolation report and does not bind B-form DNA. Instead, we report that the originally proposed structure for xylopyridine A represents a new class of conformationally dynamic structure-selective quadruplex nucleic acid binder. The unique molecular conformation locks out nonspecific intercalative binding modes and provides a starting point for the design of a new class of structure-specific nucleic acid binder.