Targeting G-Quadruplex DNA with Small Molecules

Abstract

Despite a recent explosion of interest in G-quadruplex DNA, most fundamental questions regarding the possible presence and function of these intriguing structures in vivo remain unanswered. Cell-permeable G-quadruplex specific probes should provide researchers with new tools for studying these alternately folded DNA structures and their potential involvement in gene expression, chromosome stability, viral integration, and recombination. In this review, a survey of the binding affinity, specificity, and biological/pharmacological activities of some well-characterized G-quadruplex ligands is presented along with the potential importance of G-quadruplex DNA in vivo.134 CHIMIA 2009, 63, No. 3 Young AcAdemics in switzerlAnd PArt ii doi:10.2533doi:10. /chimia.2009doi:10. .134 Chimia 63 (2009 Despite a recent explosion of interest in G-quadruplex DNA, most fundamental questions regarding the possible presence and function of these intriguing structures in vivo remain unanswered. Cell-permeable Gquadruplex specific probes should provide researchers with new tools for studying these alternately folded DNA structures and their potential involvement in gene expression, chromosome stability, viral integration, and recombination. In this review, a survey of the binding affinity, specificity, and biological/pharmacological activities of some well-characterized G-quadruplex ligands is presented along with the potential importance of G-quadruplex DNA in vivo.

Noncovalent binding and fluorogenic response of cyanine dyes to DNA homoquadruplex and PNA-DNA heteroquadruplex structures

“…[1][2][3] Quadruplex-binding ligands might find applications in chemical biology, where they could report the presence or perturb the biological function of a quadruplex. 4,5 Clinical applications of drug-like small molecules targeted to G-quadruplexes are also envisioned. 6 Small molecules bind to G-quadruplexes primarily through shape-based recognition.…”

Insights into the Relative DNA Binding Affinity and Preferred Binding Mode of Homologous Compounds Using Isothermal Titration Calorimetry (ITC)

“…[21][22][23][24][25] Stabilization of DNA triplexes formed when oligonucleotides (normally referred to as triplex formation oligonucleotide or TFO) bind to DNA duplexes, have been explored in anti-gene therapeutics where expression of deleterious DNA sequences are suppressed by the binding and stabilization of complimentary TFO sequences. [15,21] Formation of transient G-quadruplexes in G-rich sequences have been found to be prominent in telomeres, G-rich ends on chromosomes that protects indispensable genes from being depleted, as well as preventing unwanted chromosomal fusions.…”

“…[15,21] Formation of transient G-quadruplexes in G-rich sequences have been found to be prominent in telomeres, G-rich ends on chromosomes that protects indispensable genes from being depleted, as well as preventing unwanted chromosomal fusions. [23][24][25] As a result, some compounds (e.g., certain NDI derivatives) can bind to and stabilize these telomeric G-quadruplexes can block access to these sequences by telomerase enzymes, which are responsible for extending and protecting telomeres and have been found to be over-expressed in 80% of cancers cells. [24,25] G-quadruplexes have also been found to be prominent in promoter regions, especially in the promoters of oncogenes such as the c-myc and Ras genes, were, found to be directly linked to the formation of certain cancers.…”

“…[23][24][25] As a result, some compounds (e.g., certain NDI derivatives) can bind to and stabilize these telomeric G-quadruplexes can block access to these sequences by telomerase enzymes, which are responsible for extending and protecting telomeres and have been found to be over-expressed in 80% of cancers cells. [24,25] G-quadruplexes have also been found to be prominent in promoter regions, especially in the promoters of oncogenes such as the c-myc and Ras genes, were, found to be directly linked to the formation of certain cancers. [24,25] Stabilization of these G-quadruplexes in oncogene promoter regions can block access by RNA polymerase, and ultimately blocking expression of these deleterious genes.…”

“…[24,25] G-quadruplexes have also been found to be prominent in promoter regions, especially in the promoters of oncogenes such as the c-myc and Ras genes, were, found to be directly linked to the formation of certain cancers. [24,25] Stabilization of these G-quadruplexes in oncogene promoter regions can block access by RNA polymerase, and ultimately blocking expression of these deleterious genes. It is therefore important that we continue to probe ligands systems in order to increase our understanding of the driving force behind ligand-DNA interactions, and to use this knowledge to control their preferred binding mode and sequence.…”