Quadruplex nucleic acids can be formed in telomeric regions of chromosomal DNA as well as in promoter and other regulatory sequences of a number of genes involved in human cancer. Quadruplexes can be stabilised by a wide range of small molecules and the resulting complexes can act as impediments to effective telomere maintenance, to transcription or translation, depending on their genomic location. In practice, polyquadruplex targeting may be both an effective and feasible way of exploiting quadruplex genomics information since it is straightforward to devise compounds with selectivity for quadruplex over duplex DNA, but far more challenging to create compounds that effectively discriminate between different quadruplexes in favour of a single one.  It is now sixteen years since the initial publication of the concept that a disubstituted amidoanthraquinone can stabilise a human telomeric quadruplex sequence and inhibit the action of the telomerase enzyme (Sun et al, J Med Chem, 1977). A very large number of these polyheterocyclic compounds, usually with attached cationic side-chains compounds have subsequently been reported, although rather few have been evaluated in human cancer cell lines. Some such as the naphthalene diimides, are exceptionally potent, with an ability to inhibit cell growth at the nM level. In vivo and mode of action data will be presented for a lead compound in this class, optimised by structure-based methods, and which is currently undergoing development for the treatment of pancreatic cancer. Evidence will be presented that a primary mode of action involves binding to telomeric DNA single-stranded ends and induction of quadruplex formation, although other genomic quadruplex targets may also be implicated.

Design and development of quadruplex-targeted agents in human cancer

247th National Meeting (2014)

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