3 years ago

Synthesis of Naphthyridine Dimers with Conformational Restriction and Binding to DNA and RNA

Synthesis of Naphthyridine Dimers with Conformational Restriction and Binding to DNA and RNA
Yuki Mori, Kazuhiko Nakatani, Nozomi Natsuhara, Sanjukta Mukherjee, Asako Murata, Bimolendu Das
One of the important determinants in the efficiency of a molecular interaction is the necessity for conformational changes in host and/or guest molecules upon binding. In small-molecule interactions with nucleic acids, conformational changes on both molecules are often involved, especially in intercalating binding. Mismatch binding ligands (MBLs) we described here consist of two heterocycles that predominantly exist in one conformation, so it is of interest to determine if such molecules can bind to any DNA and RNA structures. One molecule, 1-NHR, which predominantly exists as the unstacked conformation in aqueous solvent, has been successfully synthesized and characterized. Compound 1-NHR did not efficiently bind to GX/Y DNA and RNA sequences, but the binding pattern is different from that of authentic MBL naphthyridine carbamate dimer. In vitro selection of RNA that specifically binds to 1-NHR was performed from pre-miR-29a loop library RNA, and one RNA, to which 1-NHR bound with high affinity, has been successfully identified. Although it was anticipated that 1-NHR, with a predominantly unstacked conformation, would show entropy-driven binding, isothermal titration calorimetry analysis suggested that the binding of 1-NHR to RNA was enthalpy driven with an apparent Kd of about 100 nm. Get in there! Mismatch binding ligands (MBLs) composed of two heterocycles joined by short linkers to restrict conformational changes are investigated for their ability to bind to DNA and RNA, as revealed by conformation analysis and experimental results (see figure). The effects of solvent on stacked or unstacked conformations of MBLs are also revealed.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/asia.201701293

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