Title

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

Poster Number

7

Lead Author Affiliation

Chemistry

Lead Author Status

Doctoral Student

Introduction

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.

Purpose

We recently reported a facile synthesis of 5-substituted phenanthroline derivatives, providing us a perfect scaffold to investigate the side chain effect on G-quadruplex recognition. When phenanthroline-metal complexes stack on top of a G-quartet, side chains at the outer arc (5position) could conveniently interact with G-quartet surface or grooves of G-quadruplexes and thus enhance the binding.

Method

We studied the binding of 5-substituted phenanthroline derivatives with various side chains to telomeric G-quadruplex DNA using several biophysical methods including CD thermal denaturation, CD titration, and FID assay. In vitro telomerase inhibition effect was evaluated using TRAP assay and cytotoxicity against cancer cells was examined using MTT assay.

Results

Phen-Ni complexes containing various side chains bind to G-quadruplex DNA with sub-micromolar G4DC50 values. Arylsulfanyl groups at the 5 position of 1,10-phenanthroline are the best side chains in terms of binding affinity and selectivity towards G-quadruplex DNA. Most of the G-quadruplex binding Phen-Ni complexes can inhibit telomerase activity in vitro as indicated by the TRAP assay and exhibited cytotoxicity against cancer cells.

Significance

Our results suggest that rather than cationic diethyl amine and piperdine, small aromatic rings could be used as a better side chain motif for developing selective telomerase inhibitors based on 5-substituted 1,10-phenanthroline. Moreover, due to their ease of preparation, 5-substituted phenanthrolines can be a very useful scaffold to fast screen various side chains for G-quadruplex recognition.

Location

DUC Ballroom A&B

Format

Poster Presentation

Poster Session

Afternoon

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Apr 29th, 1:00 PM Apr 29th, 3:00 PM

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

DUC Ballroom A&B

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.