Arylsulfanyl groups - Suitable side chains for 5-substituted 1,10-phenanthroline and nickel complexes as G4 ligands and telomerase inhibitors

Use of neomycin as a structured amino‐containing side chain motif for phenanthroline‐based G‐quadruplex ligands and telomerase inhibitors

“…Both neomycin and Phen could not stabilize G1 under this condition. Phen did not increase the T m value of G1, which is consistent with previous studies ( Liu et al, 2017). In the presence of 7 at 10 μM, the T m value was 66.6 ± 0.3°C, a 5.6°C increment as compared with that of G1.…”

“…It is noteworthy that these values are much lower than those obtained for other 5-substituted phenanthroline derivatives (10 and 11, Scheme 1) that contain amino side chains. The G4 DC 50 values for 10 and 11 are 83.2 and 72.3 µM, respectively, as previously reported (Liu et al, 2017). The significant difference in G4 DC 50 values among 7, 10, and 11 suggested that the structured amino-containing binding motif (neomycin) can significantly enhance the binding with G-quadruplex DNA.…”

“…Initial surveys suggested that over 300,000 putative G-quadruplex forming sequences are present in the human genome (Huppert & Balasubramanian, 2005;Todd, Johnston, & Neidle, 2005), and recent studies predicted an even higher G4 prevalence when considering G4s with long loops (Bedrat, Lacroix, & Mergny, 2016) and G4s in some large genes (Chambers et al, 2015), implying that a structure-function relationship may exist. In recent years, G4s have emerged as a target of considerable interest because they are not native substrates for binding of nucleic acid processing enzymes (e.g., telomerase and polymerase); therefore, inducing G4 formation has been recognized as a promising approach to regulate enzymatic functions (Neidle, 2017;Rhodes & Lipps, 2015;Tian, Chen, Wang, & Zhou, 2018), for instance, inhibition of human telomerase activity (De Cian et al, 2008;Liu, Wang, Dotsenko, Samoshin, & Xue, 2017;Wang et al, 2019) and regulation of oncogene expression (Balasubramanian, Hurley, & Neidle, 2011;Nishikawa, Kuwano, Takahara, Nishida, & Rokutan, 2019).…”

“…When Phen coordinates with metal ions such as Ni 2+ and Pt 2+ , the resulting complex becomes a potent G4 ligand due to the enlarged aromatic stacking surface. In a recent study of 5-substituted phenanthrolines, we reported that aromatic side chains (arylsulfanyl group) at the 5-position of Phen provide the best selectivity for G4 over duplex DNA (Liu et al, 2017). On the other hand, amino-containing side chains (piperidine, pyrrolidine) showed enhanced binding affinity but decreased binding selectivity for G4 over duplex DNA.…”

“…Most of the G4 ligands developed so far contain a large aromatic surface that effectively stacks with G-quartet(s) at the ends of G4s (end-stacking mode) (Burger et al, 2005;Chitranshi & Xue, 2011;De Cian, Delemos, Mergny, Teulade-Fichou, & Monchaud, 2007). Phenanthroline derivatives are examples of G4 ligands that have been extensively studied (Amato et al, 2014;Beauvineau, Guetta, Teulade-Fichou, & Mahuteau-Betzer, 2017;Bhasikuttan & Mohanty, 2015;Chung, Heddi, Hamon, Teulade-Fichou, & Phan, 2014;Liu et al, 2017;Medeiros-Silva et al, 2017;Wu et al, 2016). 1,10-Phenanthroline (Phen) alone does not bind to G4s.…”