Dibenzotetraaza[14]annulene–adenine conjugate recognizes complementary poly dT among ss-DNA/ss-RNA sequences

Abstract

First published on the web Xth XXXXXXXXX 200X DOI:Among three novel DBTAA derivatives only DBTAA-propyl-adenine conjugate 1 showed recognition of the consecutive oligo dT sequence by increased affinity and specific induced chirooptical response in comparison to other single stranded RNA and DNA; whereby of particular 10 importance is up until now unique efficient differentiation between dT and rU. At variance, its close analogue DBTAA-hexyl-adenine 2 did not reveal any selectivity among ss-DNA/RNA pointing out to the important role of steric factors (linker length); moreover non-selectivity of the reference compound (3, lacking adenine) stressed the importance of adenine interactions in the 1 selectivity. 15 IntroductionBoth, DNA and RNA exhibit a wide range of structural topologies, among which different single stranded (ss-) sequences are quite numerous. While ss-sequences are ubiquitous part of the RNA folding landscape, there are fewer 20 observations of stable ss-DNA cases, such as hairpins 1 or abasic sites, 2 to name some of them. Since ds-DNA is protected from reaction with a number of chemical and biological nucleases, 3 many studies have been aimed at exploiting the vulnerable ss-DNA. A number of small 25 molecules were synthesized that bind specifically at abasic lesions with an idea to inhibit the DNA repair system and in that way pronounce the action of antitumor drugs. 4 Moreover, recently many research groups have explored the potential of the DNA as a template for arraying multichromophoric 30 systems, among which non-covalent ss-DNA-associated dyes attracted considerable attention. 5 Until now, aryl-nucleobase conjugates efficiently recognized complementary nucleobases by affinity increase, 4 Zn-cyclene derivatives showed highly selective interactions 35 with uracil and thymine caused by specific coordination of Zn with two keto-groups. 6 Very recently, abasic sites and single base bulges in DNA were efficiently recognized by metalloinsertors, 7 or small-ligand-immobilized biosensor was applied for detecting thymine-related single-nucleotide 40 polymorphisms (SNPs). 8 However, longer oligo-dT sequences were not specifically recognised until now, especially in respect to closely related uracil analogues. Within the last decade we showed that small modifications in structure of aryl-nucleobase conjugates can control their selectivity toward 45 various ss-and ds-polynucleotide sequences. 9 On the other hand, for the dibenzotetraaza [14]annulene (DBTAA) derivatives we recently showed that the interactions of side-chains can finely tune selectivity toward various DNA/RNA and consequently control their biological 50 activity. 10a Specific properties of the DBTAA moiety, such as larger aromatic surface than the most of until now used arylmoieties and pronounced out-of-plane flexibility, offered intriguing possibilities in design of novel aryl-nucleobase conjugates. The very last generation of DBTAA derivatives 55 showed high (sub-micromolar) DNA/RNA affinity and selectivity toward dA-d...

Molecular recognition of AT-DNA sequences by the induced CD pattern of dibenzotetraaza[14]annulene (DBTAA)–adenine derivatives

“…Changes of the UV–vis spectra in response to temperature increases of up to 95 °C were negligible, and the reproducibility of the UV–vis spectra upon cooling back to 25 °C was excellent. The UV–vis spectra of new compounds ( AP3am , AP5 ) were similar to previously studied analogues [11] (Supporting Information File 1). …”

“…Previous studies [11] revealed intriguing recognition of single stranded DNA dT sequences by AP3 (but not AP6 , APH ), whereby intercalation of AP3 , AP6 , APH in double stranded ct-DNA was excluded. Here, we studied in more detail the interactions of AP3 , AP6 , APH as well as the novel AP3am and AP5 with a series of synthetic double-stranded polynucleotides.…”

“…Previous studies also revealed the advantage of nucleobase incorporation in small molecule structures for the recognition of complementary nucleotides/polynucleotides [8–10]. Recent studies of the novel DBTAA-adenine conjugates AP3 and AP6 (Scheme 1) showed a highly selective binding of only AP3 to poly dT among all other ss-DNA/RNA, as characterized by the induction of a specific CD band response [11]. Observed oligo dT specificity provoked the intriguing question of whether such a specificity would be observed in double-stranded AT-DNA sequences.…”

“…The results were compared with the reference APH (lacking adenine) and previously studied DP77 [12] (Scheme 1), which, having pyridinium instead of adenine, can also be regarded as a reference structure. Double-stranded DNA/RNA targets chosen for this study are long (<100 base pairs) synthetic polynucleotides poly dG–poly dC, poly dA–poly dT, poly dAdT–poly dAdT and poly rA–poly rU, each associated with specific structural properties of the minor/major groove as the anticipated binding site ( APH , AP3 , AP6 didn’t intercalate into ct-DNA [11]). Namely, parameters such as the groove width and depth, steric obstructions like the amino groups of guanine, H-bonding patterns, as well as polynucleotide charge density and the curvature of the ds-helix backbone all differ significantly across the double stranded examples mentioned above (Table S1, Supporting Information File 1).…”

“…Studied DBTAA–adenine conjugates ( AP3 , AP3am , AP5 , AP6 ) [11], and the reference compounds lacking adenine ( APH [11], DP77 [12–13]).…”