Bifunctional Zn(ii) complexes for recognition of non-canonical thymines in DNA bulges and G-quadruplexes

Abstract

Six Zn(II) complexes of derivatives of 1,4,7,10-tetraazacyclododecane (cyclen) were studied for binding to DNA sequences containing non-canonical thymines, including a hairpin with a single thymine bulge (T-bulge) and a G-quadruplex (H-telo) containing thymine loops. The cyclen-based macrocycles contained pendents with either two fused rings to give planar groups including quinolinone (QMC), coumarin (MCC) and quinoline (CQC) derivatives or a non-planar dansyl group (DSC). Macrocyclic complexes with three fused rings including an anthraquinone pendent (ATQ) were also studied. All Zn(II) complexes were stable in solution at micromolar concentrations and neutral pH with the Zn(L)(OH2) species prevailing for L = QMC and CQC at pH 7.5 and 100 mM NaCl. Immobilized T-bulge or H-telo G-quadruplex was used to study binding of the complexes by surface plasmon resonance (SPR) for several of the complexes. For the most part, data matched well with that obtained by isothermal calorimetry (ITC) and, for fluorescent complexes, by fluorescence titrations. Data showed that Zn(II) complexes containing planar aromatic pendents with two fused rings bound to T-bulge more tightly than complexes with non-planar pendents such as DSC. The H-telo DNA exhibited multiple binding sites for all complexes containing aromatic pendents. The complexes with two fused rings bound with low micromolar dissociation constants and two binding sites whereas a complex with three fused rings (ATQ) bound to three sites. This study shows that different pendent groups on Zn(II) cyclen complexes impart selectivity for recognition of non-canonical DNA structures.

G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs

“…17 Other examples of bimetallic complexes with homogeneous or heterogeneous metal centres reported as G4-ligands; 122,123 Monometallic Zn(II) macrocyclic complexes utilize the thymine residues as the primary mode of recognition. [124][125][126] for binding with G4 over duplex DNA. These complexes can induce and stabilize antiparallel hTel G4 (ΔT m = 12-24°C) in the presence or absence of K + with 1 : 1 stoichiometry, leading to promising inhibition effects on telomerase activity and cancer cell proliferation.…”

“…123 In addition, Morrow et al reported two Zn(II) macrocyclic complexes 190-191, the structures of which were similar to the monometallic counterparts of complex 186 with the nonplanar dansyl group and acridine group pendents, respectively. [124][125][126] Complex 190 shows 110-fold selectivity in binding to hTel G4 over duplex DNA, evidenced by an increase in the fluorescence and a simultaneous shift in emission upon G4 interaction. ITC, fluorescence and NMR spectroscopy give a complex/G4 stoichiometry of 2 : 1 and indicate one complex binding to two spaced thymines within two separate loops in the hTel G4.…”

Combining a Ru(II) “Building Block” and Rapid Screening Approach to Identify DNA Structure-Selective “Light Switch” Compounds

“…In recent reports, the loop regions have been essential for the binding of certain metal complexes, specifically Zn 2+ , where they interact with the thymidines within the loop region rather than with the G-tetrad. 58–60 We hypothesize that the loop regions are also important for recognition by the Ru(II) dppz complexes by either preventing binding to the G-tetrad or by shielding the phenazine nitrogens. Seq27 lacks loops, whereas Seq28–Seq30 each have 3 loop regions (see Figure 7).…”

Synthesis and Study in Solution of a New Dansyl-Modified Azacryptand

“…For these reasons, many cation sensors have been described and synthesized; fluorescent chemosensors, in particular, are very intriguing thanks to the low detection limits of the fluorescence technique [7][8][9][10][11]. Functionalized polyamine macrocycles and macrobicycles are often used as receptors; however, by introducing fluorescent signaling units in the molecular skeleton (e.g., anthracene or naphthalene), they can be also converted into efficient chemosensors [12][13][14][15]. In this field, bistren azacryptands have been deeply investigated, due to the possibility of modulating their cavity shape [16][17][18][19][20][21][22].…”