Formation of Unimolecular G-Quadruplex Macrocycles from N9-Modified Guanine Derivatives

Abstract

Our genetic information is protected by single-stranded, guanine-rich DNA sequences called telomeres, which have been shown to form guanine quadruplex structures in vivo. When stabilized, G-quadruplexes inhibit the activity of telomerase, an enzyme that contributes to the immortality of cancer cells. Due to recent interest in the anticancer potential of guanine quadruplexes, the need exists for understanding their self-assembly. As such, recent studies have focused on the formation of these structures from guanine derivatives. We have successfully synthesized G-quadruplex forming subunits from the coupling of N2-acetylguanine and 3,5-di-substituted benzylbromide derivatives followed by amide deprotection. Upon addition of potassium salts, these subunits were confirmed, though nuclear magnetic resonance (NMR) analysis, to form G-quartets. Following cation-templated ring-closing metathesis using Grubb’s 2nd generation catalyst, G-quadruplex macrocycles were successfully formed. Future studies will investigate the macrocycles\u27 ability to bind G-quadruplex stabilizing ligands and determine their potential to serve as model G-quadruplexes and aid in the search for new anti-cancer drugs