Major-Groove-Halogenated DNA: The Effects of Bromo and Iodo Substituents Replacing H−C(7) of 8-Aza-7-deazapurine-2,6-diamine or H−C(5) of Uracil Residues

Abstract

Oligonucleotides containing halogenated purine and pyrimidine bases were synthesized. Bromo and iodo substituents were introduced at the 7-position of 8-aza-7-deazapurine-2,6-diamine (see 2b,c) or at the 5-position of uracil residues (see 3b,c). Phosphoramidites were synthesized after protection of 2b with the isobutyryl residue and of 2c with the benzoyl group. Duplexes containing the residues 2b or 2c gave always higher T m values than those of the nonmodified counterparts containing 2'-deoxyadenosine, the purine-2,6-diamine 2'-deoxyribonucleoside (1), or 2a at the same positions. Six 2b residues replacing dA in the duplex 5'-d(TAGGTCAATACT)-3' (11)´5'-d(AGTATTGACCTA)-3' (12) raised the T m value from 48 to 758 (4.58 per modification ( Table 3)). Contrary to this, incorporation of the 5-halogenated 2'-deoxyuridines 3b or 3c into oligonucleotide duplexes showed very little influence on the thermal stability, regardless of which purine nucleoside was located opposite to them (Tables 4 and 5). The positive effects on the thermal stability of duplexes observed in DNA were also found in DNA´RNA hybrids or in DNA with parallel chain orientation (Tables 8 and 9, resp.).Introduction. ± The thermal stability of oligonucleotide duplexes increases when 7-substituted 8-aza-7-deazapurines ( pyrazolo[3,4-d]pyrimidines) replace purines [1] [2]. This effect is particularly strong when the heterocyclic base is an 8-aza-7-deazaguanine and carries a halogeno substituent at the 7-position [1] [3] [4]. Recent studies on the substitution of purine-2,6-diamine by the 7-bromo derivative of 8-aza-7-deazapurine-2,6-diamine have shown that this modified purine derivative forms as stable base a pair with thymine as guanine does with cytosine [5]. In contrast, the base pair of the structurally related purine-2,6-diamine 2'-deoxyribonucleoside (1; n 2 A d ) with thymidine is rather weak when introduced into duplex DNA [5] [6].

Nucleosides and Oligonucleotides with Diynyl Side Chains: Base Pairing and Functionalization of 2′‐Deoxyuridine Derivatives by the Copper(I)‐Catalyzed AlkyneAzide ‘Click’ Cycloaddition

“…pyrimidines show very little influence or even no effect on the DNA duplex stability [18]. A significant stabilization is observed when alkynyl residues are introduced.…”

Synthesis and properties of DNA oligomers containing stereopure phosphorothioate linkages and C-5 modified deoxyuridine derivatives

“…The crude product was puried by RP-HPLC to afford pure stereoregulated PS/PO-chimeric DNA oligomers. The synthesized DNA oligomers were quantied by their UV absorbance and predicted extinction coefficients at 260 nm, 19,45 except for 4e. The quantication of 4e was performed by the high temperature UV absorbance and predicted extinction coefficients at 280 nm.…”

“…C5-Modied deoxyuridine derivatives have been studied to improve the properties of nucleic acids such as the affinity to their complementary RNAs and the nuclease resistance. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] C5-Modied deoxycytidine derivatives have also been explored for similar purposes, 21,24,26 while 5-methyl cytosine has been used to inhibit immune responses derived from CpG sequences. 30,31 In this study, we focused on the combination of stereoregulated PS linkages and C-5 modied uracil nucleobases using 5-methyl deoxyuridine, known as thymidine, 5-bromo deoxyuridine (d Br U), 5-iodo deoxyuridine (d I U), and 5-propynyl deoxyuridine (d pr U) units ( Fig.…”

Exploring purine N7 interactions via atomic mutagenesis: The group I ribozyme as a case study

“…In contrast, substitutions that did not diminish binding had little or no effect on duplex stability. DNA duplexes with a single 7-methylguanine were as stable as the unmodified ones (Ezaz-Nikpay and Verdine 1992), and those containing two 8-aza-7-deaza guanine residues were also similar in stability to the unmodified duplexes (0.3 kcal/mol more stable) (Becher et al 2001). Differences in stacking and solvation could explain this trend, as discussed below.…”