Dimeric Metal-Salphen Complexes Which Target Multimeric G-Quadruplex DNA

Abstract

G-Quadruplex DNA structures have attracted increasing attention due to their biological roles and potential as targets for the development of new drugs. While most guanine-rich sequences in the genome have the potential to form monomeric G-quadruplexes, certain sequences have enough guanine-tracks to give rise to multimeric quadruplexes. One of these sequences is the human telomere where tandem repeats of TTAGGG can lead to the formation of two or more adjacent G-quadruplexes. Herein we report on the modular synthesis via click chemistry of dimeric metal-salphen complexes (with NiII and PtII) bridged by either polyether or peptide linkers. We show by circular dichroism (CD) spectroscopy that they generally have higher selectivity for dimeric vs monomeric G-quadruplexes. The emissive properties of the PtII-salphen dimeric complexes have been used to study their interactions with monomeric and dimeric G-quadruplexes in vitro as well as to study their cellular uptake and localization.

Synthesis of cNDI‐Peptide‐Dimer as a G4 Cluster‐Selective Binder and its Interaction with G4 Dimer

“…In fact, the binding constant of metalÀ salphen dimers linked by peptides increased as the number of linker peptides increased. [6] Furthermore, the binding constant tended to increase with the introduction of lysine compared to arginine. Therefore, the lysine introduced into 1 may also have an effective effect on G1 and G2T1.…”

“…This seems to be influenced by the size of the compound itself and its charge. MetalÀ salphen dimers also do not exhibit cytotoxicity, [6] which seems to be a problem that should be solved with peptide dimers. In the future, by devising the method of cell introduction, we can expect it to have potential as an anticancer drug.…”

“…[14] Regarding stabilization of G2T1 by 1, when compared with MetalÀ Salphen dimer having a similar peptide linker, these had an similar stabilizing effect at about 15 °C. [6] A TRAP assay was performed to evaluate the telomerase inhibitory ability of 1. The results are shown in Figure 5a and b.…”

“…Peptides are used as linking parts for ligands such as MetalÀ Salphen dimers. [6] Naphthalene diimides with unique structures such as monomers, dimers, and polymers have been reported, [7] Iverson et al reported NDI dimers [8] and tetramers [9] linked by peptides. In these examples, it was reported that NDI intercalates into double-stranded DNA and the lysine within the peptide linker interacts with the phosphate backbone.…”

Therapeutic Use of G4-Ligands in Cancer: State-of-the-Art and Future Perspectives

“…Recently, high-resolution structural analyses of G4s complexed with small molecules have unveiled that loops and grooves can represent distinctive G4 elements that can be exploited for selective recognition by specific ligands [ 56 ]. In this context, an attractive strategy to enhance selectivity is represented by the possibility of targeting multimeric-G4s, two or more consecutive structures that, while introducing structural complexity to the basic G4 scaffold, can be selectively targeted [ 31 , 57 ]. Recently, some unconventional G4 structures have been described within the human genome.…”