Utilizing G-quadruplex formation to target 8-oxoguanine in telomeric sequences

Abstract

Utilizing G-quadruplex specific ligands that can induce/bind G-quadruplex DNA in human telomeric regions has recently become an attractive means for cancer chemotherapy because the formation of G-quadruplex structures inhibits the activity of telomerase, a reverse transcriptase mainly expressed in cancer cells. In the present work, we synthesized a type of bifunctional molecules that selectively bind to telomeric DNA via G-quadruplex formation and subsequently react with proximate OxodG in the presence of one-electron oxidant. Such molecules could be useful for telomerase inhibition. Perylene derivatives (7 and 9) containing 1,3-diamino moieties were prepared for demonstration. The binding of 7 with G-quadruplex DNA was determined using UV thermal denaturation and the corresponding binding constant was derived from UV titration. The interactions of 7 with G-quadruplex DNA containing OxodG were characterized using circular dichroism. Gel electrophoresis revealed that 7 can form more adducts with OxodG in G-quadruplex regions than that in duplex DNA.