Effect of Imino Group of a Linker Arm at the C5 Position of a Pyrimidine Nucleoside on the Thermal Stabilities of DNA/DNA and DNA/RNA Duplexes

Abstract

The modified ODN's bearing C5-substituted 2'-deoxyuridine derivative were synthesized by a post-synthetic modification with an unsymmetrical triamine. The effect of the C5-substituent on the duplex formation with complementary DNA or RNA differed with the position of an imino group in the linker-arms.

Polyamine–Oligonucleotide Conjugates: A Promising Direction for Nucleic Acid Tools and Therapeutics

“…It is, therefore, unsurprising that the C-5 position of pyrimidines has been extensively used for conjugation of linear and branched polyamines ( Table 3; substructures 21-31) [18,[65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][83][84][85][96][97][98]100], predominately via amide linkers. Interestingly, the genome of the bacteriophage ΦW-14 contains a thymine with a putrescinyl-substitution at its C-5 position, which enhances local DNA duplex stability and provides added resistance against endo-and exonucleases [101][102][103].…”

“…In stark contrast, branched triamines conjugated via carbamoyl or alkyl linkers to C-5 sites stabilized ODN-DNA and ODN-RNA duplexes substantially (ΔT M = +1-4°C and +1-3°C per modification, respectively) ( Table 3; structures 22, 27 and 30) [74,[76][77][80][81]. Furthermore, enhanced nuclease resistance was observed for both terminally and internally modified ODNs [76][77]83], whereas RNase H activity was not attenuated [77,81] and an improved antisense activity of an ODN targeting the art/tris region of HIV-1 was demonstrated ( Table 3; structure 22) [82].…”

“…All of the modifications, however, showed increased nuclease resistance, and as a likely consequence, when tested, an increased silencing activity. • Conjugation of single amino groups or branched polyamines to the nucleobases appears most useful at the C-5 position of pyrimidines: 5-(N-aminoethyl)carbamoyl, 5-(N-aminohexyl)carbamoyl or triamine substituents were all found to increase nuclease resistance and most of them stabilized duplex ODN-DNA and ODN-RNA structures [70][71][73][74][76][77][78][79][80][81][82]. Increased thermal stability was observed for other spermine conjugates, particularly at the C-4 position.…”

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

“…Similarly, the more reactive 5-cyanomethoxycarbonylmethyl-2'-deoxyuridine monomer has been used [27]. The reactivity of the above-mentioned chemical groups has enabled the attachment of various amine-functionalized groups onto the 5-position of pyrimidines via both the modified monomeric building blocks and post-synthetic ON chemistry [27,28,[31][32][33][34][35][36][37][38][39][40][41]. The structures of some of the uridine derivatives are shown in Table 1.…”

5‐Substituted Nucleosides in Biochemistry and Biotechnology

“…The earliest studies appended amino groups on saturated alkanes (15b-d) [64][65][66] which were not particularly stabilizing. However, the majority of amino-substituted side chains contain an amide functionality (15e-n, r) [10,[67][68][69][70][71], which in many cases does enhance stabilization, an effect that to some degree reflects the ability of the appended amide group to stack with neighboring bases. In compounds 15e-h [8,70], the carbonyl is directly conjugated to the ring, and an electron-withdrawing group would be expected to increase the acidity of the N-3 proton.…”