Various chemical mutagens and DNA replication errors induce various DNA lesions associated with local structural changes like apurinic/apyrimidinic sites. Such changes trigger biological and biomedical phenomena such as the onset and progress of cancer and cellular senescence. Sensitive molecular probes for investigating local structures and sequences of nucleic acids are thus required as research tools in the field of chemical biology and medical chemistry. Therefore, numerous reports discuss various molecular probes, including fluorescent dye molecules that can detect microstructural changes of nucleic acids. Recently, various base-modified fluorescent nucleosides that describe environmental changes like viscosity and polarity have been developed as probes and have been applied for detecting the local structure of DNA and RNA. However, few classes of base-modified nucleosides are capable of discriminating between different local structures of nucleic acids by large changes in fluorescence wavelength and intensity. In our continuous efforts to develop environmentally sensitive fluorescent (ESF) nucleosides that signal local environmental changes by changes in fluorescence wavelength and intensity, we recently reported highly solvatochromic 2-naphthylethynylated 2'-deoxyadenosines. Using ODN probes containing these nucleosides, we clearly detected the DNA duplex formation by the fluorescence changes. However, a strong demand still exists for further development of ESF nucleosides with high sensitivity and that are widely applicable to various local structures of DNA and RNA. To address this need, we focused on 8-aza-7-deazaadenines. The electron-donating/accepting ability of 8-aza-7-deazaadenine is different from that of natural adenine because the redox potentials of both nucleosides are different; thus, we expected the improvement of solvatochromic properties and quantum yield. We report herein the synthesis and photophysical properties of 2-naphthylethynylated 8-aza-7-deaza-2'-deoxyadenosines 1a-c. To the best of our knowledge, this is the first example of ESF nucleosides possessing a C2-substituted 8-aza-7-deazaadenine skeleton. Highly solvatochromic 1c introduced into ODN probes and evaluated their capacity to discriminate apurinic/apyrimidinic sites in DNA duplexes.

Design and synthesis of C2-substituted 8-aza-7-deaza-2'-deoxyadenosines as environmentally sensitive fluorescent nucleosides

254th National Meeting (2017)

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