A G-Quadruplex Ligand with 10000-Fold Selectivity over Duplex DNA

摘要

There is considerable interest in the design of small molecules that selectively target telomeric DNA sequences and G-quadruplexes owing to their possible role as antitumor chemotherapeutic agents. The single-stranded overhang of the human G-rich telomeric DNA sequence, made of TTAGGG repeats, is able to fold into a quadruplex DNA structure in vitro. Quadruplex DNA structures have also been detected in vivo. Since each cell division is accompanied by an erosion of the telomeres, critical telomere shortening induces replicative senescence and apoptose, whereas maintaining the telomeres above a certain length confers a cell the capacity to divide a large number of times. Telomerase, a ribonucleoprotein that maintains telomere length, is active in more than 85% of cancer cells and this is one of the important features of their malignant character. Consequently, the inhibition of telomerase has been identified as an attractive target for cancer therapy. Stabilization of G-quadruplex structures by small molecules prevents telomerase elongation of telomeres by disrupting the interaction between the enzyme and its substrate, the unfolded G-rich single strand. In addition, in view of testing these molecules as potential antitumor drugs, their toxicity toward healthy cells has to be as low as possible and this requires at least a good selectivity for quadruplex over duplex DNA.