Arylsulfanyl groups – suitable side chains for 5-substituted 1,10- phenanthroline metal complexes as G4 ligands and telomerase inhibitors

Telomerase is pivotal to the survival of 80-90% tumor cells where its activity overcomes the Hayflick limit related to cellular aging, but it is virtually absent in normal somatic cells. Such difference in presence has made it a promising anticancer target in recent years. Inducing G- quadruplex formation in G-rich telomeric DNA regions inhibits telomerase activity because telomerase only efficiently binds to DNA single strands. Formation of G-quadruplexes occurs in the presence of monovalent cations such as Na+ and K+under physiological conditions, which could be further enhanced by small molecules known as G4 ligands. A conventional G4 ligand has a large aromatic surface area that maximizes - stacking interaction with the end G-quartet(s) in a G-quadruplex. Ligand side chains also play an important role in inducing G-quadruplex formation and inhibiting human telomerase activity. Phenanthroline derivatives are examples of G4 ligands that form a large aromatic surface by coordinating with metal ions and preferentially bind to G-quadruplex over duplex DNA. Most of the phenanthroline-based G4 ligands are modified at the 4 position or inner arc (2 and/or 9 positions). To the best of our knowledge, the effect of side chains of phenanthrolines has not been extensively studied