Triggering G‐Quadruplex Conformation Switching with [7]Helicenes

Abstract

The dynamic interplay between two types of chiral structures; fully conjugated racemic hetero[7]helicenes and DNA strands prone to fold into G‐quadruplex structures is described. Both the [7]helicenes and the G‐quadruplex DNA structures exist in more than one conformation in solution. We show that the structures interact with and stabilise each other, mutually amplifying and stabilising certain conformations at increased temperatures. The [7]helicene ligands L1 and L2 stabilise the parallel conformation of k‐ras significantly, whereas hybrid (K+) and antiparallel (Na+) h‐telo G‐quadruplexes are stabilised upon conformational switching into altered G‐quadruplex conformations. Both L1 and L2 induce parallel G‐quadruplexes from hybrid structures (K+) and L1 induces hybrid G‐quadruplexes from antiparallel conformations (Na+). Enantioselective binding of one helicene enantiomer is observed for helicene ligand L2, and VTCD melting experiments are used to estimate the racemisation barrier of the helicene.

Deciphering the Binding Insights of Novel Disubstituted Anthraquinone Derivatives with G‐Quadruplex DNA to Exhibit Selective Cancer Cell Cytotoxicity

“…Thiazole orange displacement assay. [29] At first, the fluorescence spectrum of thiazole orange (TO, 1 μM) in 10 mM TrisÀ HCl, 0.1 M KCl was recorded with excitation wavelength 501 nm. Then, DNA (G-quadruplex DNA 0.5 μM, CT DNA 0.33 μM) was added to the TO solution, which provided the spectrum for TOÀ DNA complex (1 μM TO + 0.5 μM G4 DNA; 1 μM TO + 0.33 μM CT DNA).…”

“…Further to compare the binding affinity of the compounds with different G-Quadruplex DNA, binding constants (Table 1 and Table S3, Supporting Information) are calculated from the absorption spectral data using the linear Scatchard equation r/C f = K a (nÀ r) following the previously reported protocol. [27][28][29][30]44] The anthraquinone compound where morpholine groups (1, AM) are directly attached to both sides had negligible interaction with all the G-quadruplex DNA (~0.2-0.4 × 10 6 M À 1 ). When piperazine (2, AP) and N-methyl piperazine (3, APNMe) groups attached compounds were used, the binding constants increased (~0.5-0.6 × 10 6 M À 1 ) with the G-Quadruplexes probably because of the presence of more available H-bonding sites, but the observed selectivity was very poor (Table S3, Supporting Information).…”

“…[18][19][20][21][22][23] To target specific G-quadruplex DNA structures, various small molecules have been designed and synthesized in recent years. [24][25][26][27][28][29][30][31][32] Generally, a small molecule with an aromatic pharmacophore that can stack on the G-tetrad and cationic side chains can interact with the loop/ groove comprises the key strategy in the design of small molecule G-quadruplex binders. [33][34][35][36] One approach to synthesize these molecules is to take advantage of the previous literature precedents and select some chromophores which are known to interact with the duplex DNA.…”

[5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity

“…The best examples of helicenes designed for medicinal chemistry aim to address DNA topologies, including selective binding of helicenes to B/Z-DNA , and G-quadruplex DNA. ,, It is worth noting, however, that despite simple analogies between the helical form of both DNA and the helicenes, there is a large mismatch in helix dimensions: The helical pitch of [ n ]-helicenes with n = 6–11 is 3.21 vs 33.2 Å for B-DNA . As such, helicene recognition of DNA is likely based on conventional mechanisms of binding, such as intercalation, rather than more specific shape complementarity.…”

Azepine-Embedded Seco-Hexabenzocoronene-Based Helix Nanographenes: Access to Modification of the Core by N–H Functionalization

“…On the other hand, the introduction of a secondary amine at the core of the polyaromatics can alter their intrinsic properties and serve as a reactive site for further modifying the N−H bond orthogonally. 9 As a result, PAHs bearing the NH group on the backbone facilitate the functionalization of polycyclic aromatics by installation of versatile substituents. Recently, our group reported an azocine-embedded [5]helicene-containing NG formed by insertion of an electronwithdrawing imine into the HBC backbone (Figure 1c).…”