A new class of targeted anticancer drugs could soon be developed thanks to researchers from France who have prepared cyclic macromolecules that selectively bind four stranded DNA structures.

 Quadruplex-binding molecules, like the macrocycles developed by Marie-Paul Teulade-Fichou at the College de France in Paris, and co-workers, combat cancer by targeting the end section of DNA called the telomere. Telomeres carry no genetic information but are essential for DNA replication. Quadruplex-binding molecules can induce the telomere to fold up into a four-stranded quadruplex and the structure formed is known as G quadruplex DNA. The quadruplex structure impairs DNA replication and consequently the cells' ability to divide, limiting the increase of cancer cells.

The macrocycles prepared are a radical departure from the flat aromatic compounds typically used for DNA quadruplex binding. The macrocycles consist of an aminoglycoside tethered at each end to an aromatic platform to form a ring. Teulade-Fichou wanted to combine the nucleic acid-binding properties of aminoglycosides with the ability of aromatic molecules to insert into the DNA strand.

The cyclic nature of the molecules causes the aminoglycoside components to be curved like a dome, which binds within the loops of the folded quadruplex DNA structure. The dome-like shape also results in the macrocycle having a low affinity for normal linear DNA.

Having shown that the new macrocycles can bind pre-formed quadruplexes, the next step will be to test their ability to induce quadruplexes to form from single strand DNA. The new molecules are 'attractive structural scaffolds for further developments aimed at the discovery of new and more selective anticancer agents,' said Teulade-Fichou.

James Mitchell Crow