Targeting abasic site-containing DNA with annelated quinolizinium derivatives: the influence of size, shape and substituents

Abstract

The interactions of regular DNA and abasic site-containing DNA (AP-DNA) with quinolizinium (1a), the linearly fused benzo[b]quinolizinium (2a), the angularly fused benzo[a]quinolizinium (3a), benzo[c]quinolizinium (4a), and dibenzo[a,f]quinolizinium (5a) as well as derivatives thereof were studied with photometric and viscosimetric titrations (regular DNA), fluorimetric titrations and thermal DNA denaturation experiments (regular DNA and AP-DNA). Whereas the parent quinolizinium ion (1a) and the benzo-annelated derivatives 2a, 3a and 4a exhibit no significant affinity to AP-DNA, additional benzo-annelation in 5a leads to an increased selective stabilization of AP-DNA by this ligand. Hence, the latter compound represents the first example of a ligand that does not require ancillary substituents for efficient AP-DNA stabilization. In addition, studies of derivatives with varied substitution patterns revealed an impact of substituents on the stabilization of the AP-DNA. We discovered that a chloro substituent affects the propensity of a ligand to bind to AP-DNA in a similar way as the methyl substituent and may be employed complementary to the known methyl effect to increase the binding affinity of a ligand.

Interaction of Functionalized Naphthalenophanes with Abasic Sites in DNA: DNA Cleavage, DNA Cleavage Inhibition, and Formation of Ligand–DNA Adducts

“…Beyond covalent trapping of AP sites with reactive drugs, such as MX or analogues, several classes of noncovalent ligands were shown to selectively bind to AP sites in DNA and potentially hinder their recognition and processing by APE1 . Along these lines, polyazacyclophanes, such as bis‐acridine BisA , and bis‐naphthalenes 2,7‐BisNP‐O and 2,7‐BisNP‐NH (Figure ) bind to AP sites with high affinity and selectivity, outperforming other known ligands .…”

Selective Stabilization of Abasic Site‐Containing DNA by Insertion of Sterically Demanding Biaryl Ligands

“…[14] Some evidence for the proposed binding mode is provided by the comparison between the benzo[b]quinolizinium derivatives 1 a and 1 b with the quinolizinium 1 c. Presumably, the steric hindrance of the phenanthridine unit does not allow the quinolizinium to insert as deeply into the binding pocket as the linearly expanded benzo[b]quinolizinium ligand. As a result, the quinolizinium in 1 c has a smaller overlap with the bases next to the AP site.…”

“…Along these lines, several ligands have been shown to bind to AP sites, for example, naphthyridine derivatives, [8] nucleic-base intercalator conjugates, [9,10] aminoalkyl-substituted DNA intercalators, [11,12] DNA intercalators such as proflavine, [13] annelated quinolizinium derivatives, [14] or berberine, [15] cyclic bisacridines, [16] or metalloinsertors with sterically expansive ligands. [17] Most substituted heterocyclic ligands accomplish the selective association with AP-DNA by hydrogen bonding of the ligand with the remaining nucleobase in the abasic site.…”

8-Styryl-substituted coralyne derivatives as DNA binding fluorescent probes

“…This behaviour is in agreement with the observation that a chloro substituent affects the DNA binding properties of a ligand in a similar manner as a methyl substituent. 34 The results of the spectrometric titrations of DNA to 4b indicate, on the one side, a preferred binding to duplex DNA over G4 DNA because a significant bathochromic shift of the absorbance maximum was only detected in the presence of ct DNA (Fig. 3A1 and A2).…”