Three new polyether‐tethered dinickel–salphen complexes (2 a–c) have been synthesized and fully characterized by NMR spectroscopy, mass spectrometry, and elemental analyses. The binding affinity and selectivity of these complexes and of the parent mono‐nickel complex (1) towards dimeric quadruplex DNA have been determined by UV/Vis titrations, fluorescence spectroscopy, CD spectroscopy, and electrophoresis. These studies have shown that the dinickel–salphen complex with the longest polyether linker (2 c) has higher binding affinity and selectivity towards dimeric quadruplexes (over monomeric quadruplexes) than the dinickel–salphen complexes with the shorter polyether linkers (2 a and 2 b). Complex 2 c also has higher selectivity towards human telomeric dimeric quadruplexes with one TTA linker than the monometallic complex 1. Based on the spectroscopic data, a possible binding mode between complex 2 c and the dimeric G‐quadruplex DNA under study is proposed.

Three polyether-tethered berberine dimers (1a-c) were studied for their binding affinity, selectivity and thermal stabilization towards human telomeric dimeric quadruplex DNA (G2T1). Compound 1a with the shortest polyether linker showed the highest affinity (K > 10 M) and 76-508-fold higher selectivity for mixed-type G2T1 over antiparallel G2T1 and three monomeric G-quadruplexes, which are human telomeric monomeric quadruplex G1, c-kit 1 and c-kit 2. Compound 1a induced the formation of quadruplex structures and showed higher thermal stabilization for mixed-type G2T1 than for anti-parallel G2T1, G1 and ds DNA. Spectroscopic studies suggest that compound 1a could bind to mixed-type G2T1 via end-stacking and external binding modes. These results suggest that the polyether linkers in these compounds play an important role in regulating the binding affinity and selectivity towards mixed-type G2T1 and that compound 1a could target mixed-type G2T1 at other genome regions with antiparallel G2T1 and monomeric G-quadruplexes. These results may provide useful guidance for the rational design of selective multimeric G-quadruplex binders and potential anticancer agents.

Three new polyether-tethered bisquinolinium dimers (3 a-c) were synthesized, and their binding affinities, selectivities, and thermal stabilization towards dimeric G-quadruplex DNA (G2T1) in human telomeric regions were studied. The bisquinolinium dimer with a medium-length polyether linker (3 b) showed 30-425-fold higher binding affinity and selectivity towards antiparallel G2T1 than towards monomeric quadruplexes, which included human telomeric monomeric G-quadruplexes (G1), c-kit 1, c-kit 2, and c-myc. In addition, compound 3 b induced the formation of quadruplexes and displayed the highest level of thermal stabilization (ΔT >28.1 °C) among all reported multimeric G-quadruplex binders. Compound 3 b also displayed a higher selectivity towards antiparallel G2T1 than monomer 360 A and bisquinolinium dimers 3 a and c. In contrast with our recent research on the analogous berberine dimer 1 b and dinickel-salphen complex 2 c, polyether linkers and their monomeric G-quadruplex binders in these dimeric G-quadruplex binders play a crucial role in regulating the binding affinities, selectivities, and thermal stabilization towards G2T1. More interestingly, these dimeric G-quadruplex compounds bind through end-stacking with the two adjacent G-quadruplex units in G2T1, and they showed high selectivity towards antiparallel G2T1 rather than mixed-type G2T1. In addition, compound 3 b, which displayed high selectivity towards antiparallel G2T1, showed strong telomerase inhibition and potent anticancer activities against HeLa and MCF-7 cells.

By adjusting the length of the polyether linkers, pyridostatin (PDS) dimers displayed higher binding selectivities and thermal stabilization towards human telomere antiparallel and mixed-type G-quadruplex dimers (G2T1).