Duplex Stabilization of DNA: Oligonucleotides containing 7‐substituted 7‐deazaadenines

Abstract

The oligonucleotide building blocks 4b-d derived from 7-bromo-, 7-chloro-, and 7-methyl-substituted 7-deaza-2'-deoxyadenosines 3bd were prepared. They were employed in the solid-phase synthesis of the oligonucleotides 7-25. The dA residues of the homomer d(A12), the alternating d[(A-T),], and the palindromic d(G-T-A-G-A-A-T-T-C-T-A-C) were replaced by 3 M as well as by the parent 7-deaza-2'-deoxyadenosine (3a). The melting profiles and CD spectra of oligonucleotide duplexes, showing this major groove modification: were measured, and the T,,, values as well as the thermodynamic data were determined. It was found that small substituents such as Br, CI, or Me introduced in the 7-position of a 7-deazaadenine residue increase the duplex stability compared to oligonucleotides containing adenine.

Preorganization of DNA: Design Principles for Improving Nucleic Acid Recognition by Synthetic Oligonucleotides

“…[50][51][52][53][54][55][56][57][58][59] All the substituents shown are stabilizing relative to deoxyuridine (which has hydrogen at the C-5 position), including the C-5 methyl group of thymidine (1). Structures of deoxycytidine (9) and some modified deoxycytidine nucleosides which have increased surface area by addition of extra rings (10)(11)(12).…”

Oligonucleotides Containing 7-Deazaadenines: The Influence of the 7-Substituent Chain Length and Charge on the Duplex Stability

“…In this case, it was not possible to obtain a sigmoidal melting profile, probably due to counter-ion condensation of the ammonium-ion-tethered oligomer. On the other hand, the duplex 46´48 containing ethynyl residues exhibited an increased stability that was superior to that of the parent 46´47 [32].…”

Pyrazolo[3,4-d]pyrimidine Nucleic Acids: Adjustment of the dA-dT to the dG-dC Base Pair Stability

“…Earlier our laboratory has shown that 7-substituents of 7-deazapurines as well as of 8-aza-7-deazapurines are well accommodated in the major groove of DNA (12)(13)(14)(15). In particular, halogen substituents show favorable properties with regard to duplex stability.…”

“…This problem was approached by replacing the purine moiety of compound 1 by other heterocyclic bases. 7-Deazapurines (pyrrolo [2,3-d]pyrimidines) (purine numbering is used throughout Results and Discussion) and 8-aza-7-deazapurines (pyrazolo [3,4-d]pyrimidines) have already been used in the case of adenine and guanine nucleosides to alter duplex stability (12)(13)(14)(15). These heterocycles mimic the shapes of the purines and can substitute for purine bases in Watson-Crick base pairs.…”

“…In the case of analogs of 2′-deoxyadenosine it has been observed that the 7-deaza-2′-deoxyadenosine-dT base pair is less stable than a dA-dT pair while the 8-aza-7-deaza-2′-deoxyadenine-dT pair shows the same stability. Furthermore, it was found that the 7-halogen substituents increase base pair stability significantly (13,14,16). However, it was not possible to increase the stability of the bidentate dA-dT pair to the level of a tridentate dG-dC pair when a modified base was substituted for a regular one.…”