File(s) under permanent embargo

Reason: Restricted by author. A copy can be supplied under Section 51(2) of the Australian Copyright Act 1968 by submitting a document delivery request through your library or by emailing

Novel anti-cancer agents targeting G-quadruplex DNA

posted on 09.02.2017, 02:39 by Ping, Lucy
The unique G-quadruplex secondary structures formed from guanine-rich DNA are implicated as anti-cancer targets for their ability to inhibit overactive DNA polymerase and aberrant gene expression. As the body's natural on-off switch for controlling cell life cycles, stabilisation of G-quadruplex by external ligands can reduce cellular dysfunction. Despite the extensive research on G-quadruplex stabilising agents, few ligands have reached clinical trials and moved further onto the market. Selectivity and potency issues can hinder this process. Through rational design, we developed three series of ligands to enhance potency, selectivity, and cell permeability: two aromatic planar series targeting G-tetrads, and one groove-binding series targeting a c-kit G-quadruplex groove site. For the first series, we used Schrodinger's Glide molecular docking software and an arbitrary selection of ligands from an extensive ligand database to perform a virtual screen on the ckit1 groove site. Results showed triangular ligands such as triarylpyridines and triarylpyrimidines were potent groove-binding ligands. From these docking results, we synthesised two 4'-substituted 2,2:6,2"-terpyridine derivatives and purchased three 2,2:6,2"-terpyridine ligands with reported low G-quadruplex selectivity as negative controls for surface plasmon resonance (SPR) analysis. In the second series, the parallel synthesis of linear, crescent, and triangular-shaped arylcarboxamides through amide coupling allowed the development of an extensive ligand library to ascertain the best pharmacophore for specific G-quadruplex structures. Initial attempts to synthesise a crescent 1-(4-aminophenyl)guanidine derivative was successful, however the method used was not transferrable to the linear and triangular counterparts. Following an alternate literature method, aniline and 3-aminopyridine derivatives were synthesised through isolation from a reagent, sym-collidine, appeared difficult. Using this method the linear 1-(4-aminophenyl)guanidine derivative was synthesised, though only intermediates were isolated for triangular derivative. The third series, we postulated triazolophane macrocycles to bind to G-tetrad surface due to its high planarity and aromaticity. A rationally designed triazolophane was devised with a pyridyl-based core featuring propylguanidine groups through ester and ether appendages for enhanced binding with the DNA backbone. The multistep synthesis of phenyl diazide and pyridyl dialkyne building blocks has thus far been fruitless as ideal "click" conditions are yet to be discovered for full triazolophane synthesis. Finally, SPR analysis of a model triazolophane, the crescent guanidine-based arylcarboxamide, and the five terpyridine ligands provided the impetus for further G-quadruplex ligand development. The terpyridine series showed no selectivity for cki1 and its groove site, or preference for G-quadruplex DNA - alternative molecular docking programs are required to determine an ideal ckitl-specific groove binding agent. Both the arylcarboxamide and model triazolophane displayed G-quadruplex selective binding - these positive results supports the full development of our arylcarboxamide ligand database and further analysis for the development of triazolophane macrocycles. While further research is needed to complete our goals, these intitial binding studies reveal two novel classes of anti-cancer agents targeting G-quadruplex DNA.


Campus location


Principal supervisor

Philip Thompson

Year of Award


Department, School or Centre

Medicinal chemistry

Degree Type



Faculty of Pharmacy and Pharmaceutical Sciences