Synthesis and Conformational Dynamics of the Reported Structure of Xylopyridine A

• Published in: Journal of the American Chemical Society 2013-06, Vol.135 (24), p.9213-9219
• Main Authors: Rarig, Robert-André F, Tran, Mai N, Chenoweth, David M
• Format: Article
• Language: English
• Subjects: DNA - metabolism; Intercalating Agents - chemical synthesis; Intercalating Agents - chemistry; Intercalating Agents - pharmacology; Models, Molecular; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Xanthones - chemical synthesis; Xanthones - chemistry; Xanthones - pharmacology; Xylariales - chemistry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja404737q

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.