Methylated DNA: The influence of 7‐deaza‐7‐methylguanine on the structure and stability of oligonucleotides

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

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“…Apparently, both 7-iodo-and 7-(hex-l-ynyl) substituents stabilize the duplex structure (see 20 . 21 and 22 .…”

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confidence: 98%

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

Ramzaeva¹,

Mittelbach²,

Seela³

1997

Helvetica Chimica Acta

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“…2, a). According to earlier results, the oligonucleotides I1 and 13 containing either 7-deazaguanine or 7-deaza-7-methylguanine show sigmoidal melting profiles indicating highly ordered single strands [12]. According to the C D spectrum of 14, this oligonucleotide apparently shows more conformational flexibility than d[(c7G),-GI.…”

mentioning

confidence: 87%

“…Part). Some earlier data which used another program are now revised [10] [12] [13]. According to Table 2, the duplex d(msc7G-C), (18; T, 47") is enthalpically destabilized compared to d(c7G-C), (16; T, 52") and also to the 7-methylated d(m7c7G-C), (17).…”

Section: -2bmentioning

confidence: 99%

7‐Deazapurine Oligodeoxyribonucleotides: The effects of 7‐deaza‐8‐methylguanine on dna structure and stability

Seela

Chen

Mittelbach

1998

Helvetica Chimica Acta

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Oligodeoxyribonucleotides containing 7-deaza-2'-deoxy-8-methylguanosine (mRc7G,; 2b) were prepared. For this purpose, the phosphonate 3a and the phosphoramidite 3b were synthesized and employed in solidphase oligodeoxyribonucleotide synthesis. The structures and the thermodynamic data of duplex formation of oligodeoxyribonucleotides containing 2b were investigated by temperature-dependent C D and UV spectra and compared with those containing 7-deaza-2'-deoxy-7-methylguanosine (m7c7G,) or 7-deaza-2'-deoxyguanosine (c,G,: 2a). In general. compound 2b reduces the duplex stability. In case of the sequence d(m8c7G-C), (IS), the B + Z transition was facilitated by the incorporation of 2b. Moreover, a single 7-deaza-8-methylguanine residue present in a n oiigodeoxyribonucleotide tract of guanine residues destabilizes the dG quadruplex significantly. This destabilization is more pronounced than in the case of 7-deazaguanine or 7-deaza-7-methylguanine.Introduction. -The purine residues bearing alkyl or halogen substituents at C(8) have a strong influence on the nucleoside conformation and ultimately on the structure of D N A [I-81. Single-crystal X-ray analysis has shown that the orientation around the N-glycosylic bond is often biased towards SJW in the case of 8-substituted guanine ribonucleosides [I -41. This is the result of steric repulsion between the 8-substituents and the sugar moiety. In the solid state, these nucleosides show a C(2')-endo pucker ('TJ and an intramolecular 0(5')-H. . N(3) H-bond [I -41. The 8-methylguanosine (la) and 2'-deoxy-8-methylguanosine (1 b) have been incorporated into oligonucleotides. These residues markedly stabilize the Z-conformation of the oligonucleotide duplex, even at low salt concentration [5-81. In such a Z-DNA structure, the guanine residues adopt the syn/C(3')-endo conformation. The 8-substituents are located in the periphery of the left-handed helix and exposed to the solvent [5] [6].Earlier, the role of 7-substituted 7-deazapurine nucleosides on the D N A structure and stability was studied [9-321. It was found that substituents at the 7-position have steric freedom within the major groove of B-DNA, thereby stabilizing the duplex. Now, the 8-substituted 7-deazapurine derivative, 7-deaza-2'-deoxy-8-methy1guanosine (m8c7G,; 2b), is incorporated [I 31 into oligonucleotides. For this molecule, a single-crystal X-ray structure has been reported which is the first solid-state structure of an 8-substituted purine 2'-deoxyribonucleoside related to 2'-deoxyguanosine. This structure shows a peculiarity. The glycosylic-bond orientation is anti and not syn as observed for 8-substituted guanine ribonucleosides [I 41. This manuscript reports on the structure and stability of oligonucleotides containing compound 2b within various sequence patterns which were obtained by solid-phase synthesis using phosphonate 3a or phosphoramidite 3b. The structural changes of single-stranded oligonucleotide chains, duplexes, and

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“…Deprotection and displacement of the 6-chloro group yielded the 6-methoxy compound 10e, which was transformed afterwards with 2N NaOH to the 2'-deoxyguanosine analogue 11e [56]. The synthesis of 7-deaza-2'-deoxy-7-methylguanosine (12) shown in Scheme 18 made use of the unprotected base 42 which was glycosylated ( 43) and transformed into 12 by a similar route as described for the 7-fluoronucleoside 11e [58].…”

Section: Synthesis Of 7-deazapurine 2'-deoxyribonucleosides Related Tmentioning

confidence: 98%

Advances in the Synthesis of 7-Deazapurine - Pyrrolo[2,3-d]pyrimidine 2-Deoxyribonucleosides Including D- and L-Enantiomers, Fluoro Derivatives and 2,3-Dideoxyribonucleosides

Seela¹,

Peng²,

Budow

2007

COC

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Methylated DNA: The influence of 7‐deaza‐7‐methylguanine on the structure and stability of oligonucleotides

Cited by 16 publications

References 30 publications

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

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

7‐Deazapurine Oligodeoxyribonucleotides: The effects of 7‐deaza‐8‐methylguanine on dna structure and stability

Advances in the Synthesis of 7-Deazapurine - Pyrrolo[2,3-d]pyrimidine 2-Deoxyribonucleosides Including D- and L-Enantiomers, Fluoro Derivatives and 2,3-Dideoxyribonucleosides

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