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

Abstract

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

G‐Quartets 40 Years Later: From 5′‐GMP to Molecular Biology and Supramolecular Chemistry

“…Mizusawa et al showed that 7-deazaG (4) enables accurate nucleotide sequencing of G-rich DNA. [106] Later, Seela and Mersmann demonstrated that disaggregation of the RNA G-quadruplex [r(UGGGGU)] 4 could be effected by sequentially replacing G with 7-deazaG (4), [107,108] which indicates that removal of the N(7) atom of guanosine gives a system that does not form stable Gquadruplexes. A decreased propensity to form G-quadruplexes was also observed for oligonucleotides containing 6-thioG (5).…”

40 Jahre G‐Quartetts: von 5′‐GMP zur Molekularbiologie und Supramolekularen Chemie

“…[106] Später gelang Seela und Mersmann der Nachweis, dass der RNA-G-Quadruplex [r(UGGGGU)] 4 zerfällt, wenn G stufenweise durch 7-desazaG (4) ersetzt wird. [107,108] Durch das fehlende N7-Atom von Guanosin entsteht demnach ein System, das keine stabilen G-Quadruplexe bildet. Auch bei Oligonucleotiden, die 6-thioG (5) enthalten, nimmt die Tendenz zur Bildung von G-Quadruplexen ab.…”

Stability of Hoogsteen‐Type Triplexes – Electrostatic Attraction between Duplex Backbone and Triplex‐Forming Oligonucleotide (TFO) Using an Intercalating Conjugate

“…Therefore, a novel possibility for the design of strongly binding TFOs with good discriminating properties between matched and mismatched triplexes was developed, and this may be useful in the antigene strategy. To avoid the complication of quadruplex formation of G-rich TFOs, we consider it possible to optimize the 7-deaza-2'-deoxyguanosine approach by using our compatible intercalator approach in a proper combination [17]. In this context, it could also be interesting to use 7-(aminoalkynyl)-7-deaza-2'-deoxyguanosine to take advantage of a possible ion-pair stabilization [18].…”