Synthesis of C-Nucleosides Designed To Participate in Triplex Formation with Native DNA:  Specific Recognition of an A:T Base Pair in DNA

Abstract

[structure: see text] We have previously described a system of 2-aminoquinoline- and 2-aminoquinazoline-based C-deoxynucleosides (TRIPsides) that are designed to be incorporated into oligomers that can specifically bind in the major groove via Hoogsteen base pairing to any sequence of native DNA. The four TRIPsides are termed antiGC, antiCG, antiTA, and antiAT with respect to the Watson-Crick base pair targets that they bind. The first three TRIPsides have been prepared, characterized, and shown to form stable and sequence-specific triplexes. In the present study, we describe the preparation of two molecules, 2-amino-4-(2'-deoxy-beta-D-ribofuranosyl)quinazoline (7) and 2-amino-6-fluoro-4-(2'-deoxy-beta-D-ribofuranosyl)quinoline (14), that can serve as the remaining antiAT TRIPside. The phosphoramidites of 7 and 14 were prepared, but only the latter was successfully incorporated into DNA oligomers. It is demonstrated using UV-visible melting experiments that 14 forms sequence-specific intramolecular triplets with A:T base pairs at physiological pH.

Unnatural bases for recognition of noncoding nucleic acid interfaces

“…Gold designed a series of neutral 2-aminoquinazoline and protonated 2-aminoquinoline bases called "TRIPsides" to address an inherent limitation of triplex formation that requires the non-WC strand to target a poly-purine stretch. [123][124][125] Simultaneous binding to purines on both strands of the duplex requires that the third strand traverse the major groove, significantly complicating design of a repeat unit. By altering the site of C-glycosidation on the bicyclic bases, Gold and coworkers designed a system that would allow the synthetic backbone to remain near the center of the major groove, while the bases contact purines on both duplex strands.…”

Towards the Sequence‐Selective Recognition of Double‐Stranded DNA Containing Pyrimidine‐Purine Interruptions by Triplex‐Forming Oligonucleotides

“…However, when a long (30-mer), random and non-alternating α,β-oligodeoxycytidylate was used as a TFO, α-and β-protonated C (C + H) was able to bind to TA and AT base pairs, respectively. [85][86][87][88] The nucleobases in the TRIPsides preferentially adopted anti conformations due to steric hindrance between the nucleobases and the sugar moieties. [82] Leumann's group, on the other hand, examined hypoxanthin-7-yl, 2-aminopurin-7-yl or 2-aminopurin-9-yl nucleobases in a similar approach.…”

Recent highlights in modified oligonucleotide chemistry

“…The most recent of Gold's syntheses is that of the fluorinated antiAT phosphoramidite precursor 25 which was able to be incorporated into an oligonucleotide, unlike the nonfluorinated version. 11 The synthesis was achieved by coupling the 4-fluoroaniline salt 22 with ethyl cyanoacetate to generate 23. This was converted to bromide 24 and glycosidated via a Heck coupling and reduction as described previously (Scheme 3).…”