7‐Deazaguanine DNA: Oligonucleotides with hydrophobic or cationic side chains

Abstract

Dedicated to Prof. Dr. H . Seliger on the occasion of his 60th birthday (2. v. 97) The phosphoramidites 6b and 9 as well as the phosphonate 6 a derived from 7-(hex-l-ynyl)-and 7-[5-(triflu0roacetamido)pent-1-ynyll-substituted 7-deaza-2'-deoxyguanosines 1 and 10, respectively, were prepared (Scheme 1). They were employed in solid-phase oligodeoxynucleotide synthesis of the alternating octamers d(hxy7c7G-C), (12), d(C-hxy7c7G), (13), and d(npey7c7G-C), (15) as well as of other oligonucleotides (see 22-25; Table 2; hxy = hex-I-ynyl, npey = 5-aminopent-I-ynyl). The T, values and the thermodynamic data of duplex formation were determined and correlated with the major-groove modification of the DNA fragments. A hexynyl side chain introduced into the 7-position of a 7-deazaguanine residue (see 1) was found to fit into the major groove without any protrusion. The incorporation of the (5-aminopent-l-ynyl)-modified 7-deaza-2'-deoxyguanosine 2 into single-stranded oligomers of the type 24 and 25 did not lead to change in duplex stability compared to the parent oligonucleotides. The self-complementary oligomer 15 with alternating npey7c7G, (2) and dC units did not lead to a cooperative melting, either due to orientational disorder or interaction of the 5-aminopent-1-ynyl moiety with a base or with phosphate residues nearby or on the opposite strand.Introduction. -Much efforts have been made in the design of antisense oligonucleotides by replacing the negatively charged phosphodiester group of the DNA backbone while leaving the remainder of the structure chemically unchanged [I] [2]. A different strategy of design was described neutralizing the phosphate negative charge by attaching a cationic group on a lipophilic spacer to each nucleotide base [3]. It was reported that oligonucleotides bearing w-aminohexyl groups at the 5-position of the natural pyrimidine residues bind to natural DNA as well or even better than does natural DNA with itself. This appeared even when all of the nucleotide residues in a given single strand were rendered zwitterionic. Interestingly, nature has implemented a design of this general type in bacteriophage DNA where half of the thymidine residues are replaced by positively

pH‐Independent Recognition of the dG ⋅ dC Base Pair in Triplex DNA: 9‐Deazaguanine N7‐(2′‐Deoxyribonucleoside) and Halogenated Derivatives Replacing Protonated dC

“…These results are in line with observations reported for other halogenated 7-deazapurine and 8-aza-7-deazapurine 2'-deoxyribonucleosides [23 -28]. However, the stabilization by the halogeno substituents in a base pair of 7-functionalized 7-deazapurine nucleosides with regular glycosylation sites is slightly higher than those of the uncommonly glycosylated analogs [26]. Regarding the basepair motifs formed between 1a -c and m 5 iC d , we suggest a similar motif as it was proposed for the purine analog 2 (motif II) [35].…”

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

“…± To investigate the discrimination of the iodo nucleoside 2c towards the four canonical DNA constituents, hybridization experiments were performed according to Table 7. As expected, the base pair 2c´dT is the strongest (112 1, T m 578), while those of the duplexes forming mismatches melt at a significantly 5'-d( TAG G3cC AA3c ACT )-3' (28) 50 À 90.58 À 254.11 À 11.77 3'-d( ATC C2aG TT2a TGA )-5' (14) lower temperature ( Table 7). The discrimination of the iodo nucleoside 2c is similar to that of the canonical nucleosides, except that the duplex 33´21 (T m 508) shows a 78 lower T m value than the duplex 11´21 (T m 578), while duplex 33´12 (T m 468) has almost the same stability as the parent duplex 11´12 (T m 488).…”

“…From the CD spectra of Fig. 3, b it can be seen that the DNA´RNA hybrids adopt the A-form [28]. 2.5.…”

DNA Containing Side Chains with Terminal Triple Bonds: Base‐Pair Stability and Functionalization of Alkynylated Pyrimidines and 7‐Deazapurines

“…Oligonucleotides containing the nucleoside residues 1a -4a carrying propynyl groups have been already synthesized using the phosphoramidites 5a -8a as educts [5 -8]. As the chain length increased from propynyl to hexynyl groups, there is an unfavorable effect on the duplex stability, which is most likely due to the increasing hydrophobic character of the alkynyl chain [9]. As the hydrophobic character is decreased by the incorporation of additional triple bonds into the side chain, this principle was now used for the modification of oligonucleotides with long linker arms.…”