Fluorescent charge-neutral analogue of xanthosine: synthesis of a 2'-deoxyribonucleoside bearing a 5-aza-7-deazaxanthine base.
A concise route is described to prepare the 5-aza-7-deazapurine 2'-deoxyriboside (4), which presents the puADA hydrogen-bonding pattern, analogous to the hydrogen-bonding pattern presented by 2'-deoxyxanthosine (2). The route begins with the commercially available 1-alpha-chloro-2-deoxy-3-5-bistoluoyloxyribofuranose (10), which proves to be a versatile point of entry to beta-2'-deoxyribofuranosides. In the first step, 2-nitroimidazole (8) is coupled with 10 to yield intermediate 11. Reduction of the nitro group to an amino group yields 12, which is treated with phenyl isocyanatoformate to complete the nucleobase to yield 13. Removal of the toluoyloxy protecting groups of 13 yields the target nucleoside 4 in 40% overall yield in four steps. In an alternative strategy, convergent coupling of 14 with 10 under basic conditions was attempted but found to yield the heterocycle glycosylated at the undesired position. Compound 13 displays potentially useful fluorescence properties. After excitation at 250 nm, a solution of 13 in MeCN shows a fluorescence emission with a maximum at 410 nm. Furthermore, 13 is neutral at physiological pH, a property that it shares with natural nucleobases but not xanthosine itself, which is an acid with a pK(a) of ca. 5.6. Furthermore, as part of the design, 4 is made capable of presenting an unshared pair of electrons to the DNA minor groove.
Rao
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Department of Chemistry and Department of Anatomy and Molecular Biology, University of Florida, Gainesville, Florida 32611, USA.
Benner
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SA
D001372:Aza Compounds / Q000138:chemical synthesis*; D003853:Deoxyribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D012263:Ribonucleosides / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D019820:Xanthine / Q000138:chemical synthesis*; D014970:Xanthines
C433383:5-aza-7-deazaxanthine; D001372:Aza Compounds; D003853:Deoxyribonucleosides; D007202:Indicators and Reagents; D012263:Ribonucleosides; D014970:Xanthines; D019820:Xanthine; C005893:xanthosine