Synthesis of 4-Aminophthalimide and 2,4-Diaminopyrimidine C-Nucleosides as Isosteric Fluorescent DNA Base Substitutes

Abstract

The 4-aminophthalimide C-nucleoside 1 was designed as an isosteric DNA base surrogate, and a synthetic route to nucleoside 1 together with the 2,4-diaminopyrimidine-C-nucleoside 2 as a potential counterbase was worked out. The key steps in both synthetic routes represent a stereoselective Heck-type palladium-catalyzed cross-coupling with 2'-deoxyribofuranoside glycal followed by stereoselective reduction with NaBH(OAc)3. The nucleoside 1 shows a solvatofluorochromic behavior and significantly red-shifted fluorescence in solvents of high polarity and with hydrogen bonding capabilities. Both nucleosides 1 and 2 can be further processed to the corresponding phosphoramidite as DNA building blocks that allow incorporation of these chromophores as artificial DNA bases by automated DNA synthesis. The combination of the poor stacking properties of 1 and the hydrogen bonding interface at the phthalimide functionality that does not fit to any of natural DNA bases in the counterstrand yields destabilization of the duplex by 4-11 °C. The fluorescence of 1 in a representative double stranded DNA is characterized by a large Stokes' shift and a quantum yield of approximately 12%. These are remarkable optical properties considering the very small size of the chromophore and indicate a high potential of these nucleoside analogues for fluorescent DNA analytics and imaging.

Conformational control of benzophenone-sensitized charge transfer in dinucleotides

“…The second advantage is that two different solvents can be chosen since the dinucleotides are soluble in H 2 O and MeOH. H 2 O represents the typical solvent for oligonucleotides in a pH-controlled buffer, whereas MeOH mimics a protic solvent 54 approximately the polarity of the inner part of double stranded DNA (DNA base stack). BP as an artificial nucleoside, allows selective excitation of its photochemically important 1 (np*) transition outside the typical nucleic acid absorption range (>300 nm), which is an important prerequisite to use the chromophore in photochemistry and photobiology.…”

An Isosteric and Fluorescent DNA Base Pair Consisting of 4‐aminophthalimide and 2,4‐diaminopyrimidine as C‐Nucleosides

“…As ac onsequence of switching the backbone from C6 to C5, the C1' À C1' distance of the central base pair is now 11.71 (compared to only 9.23 in DNA1-4). [20] With 1 [20] With 2 DNA2-4 forms aw ell-defined B-DNAs tructure,a lthough with aslightly wider center around the central 4AP:DAP pair.…”

Microwave-promoted synthesis of cyclic imides

“…Cyclic imides have also a great number of applications in polymer and synthetic chemistry. 18,19 Maleimides (2) are a prominent class of substrates suitable for biological, pharmacological and chemical applications. The activity of maleimides as antifungal, antimicrobial and insecticide compounds has been reported.…”