G-quadruplexes as therapeutic targets

The ends of chromosomes (telomeres) consist of tandem repeats of guanine‐rich sequences. In eukaryotics, telomeric DNA is single stranded for the final few hundred bases. These single‐stranded sequences can fold into a variety of four‐stranded structures (quadruplexes) held together by quartets of hydrogen‐bonded guanine bases. The reverse transcriptase enzyme telomerase is responsible for maintaining telomeric DNA length in over 85% of cancer cells by catalyzing the synthesis of further telomeric repeats. Its substrate is the single‐stranded 3′‐telomeric end. Inhibition of telomere maintenance can be achieved by stabilization of a quadruplex structure for the telomere end. A variety of small molecules have been devised to achieve this, ranging from anthraquinones to porphyrins, acridines, and complex polycyclic systems. Structural and mechanistic aspects of these quadruplex complexes are reviewed here, together with a discussion of the issues of selectivity/potency for quadruplex DNAs vs duplex DNA. © 2001 John Wiley & Sons, Inc. Biopoly (Nucleic Acid Sci) 56: 195–208, 2001