Biaryl polyamides as a new class of DNA quadruplex-binding ligands (original) (raw)
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Cancer Research, 2016
Guanine-rich nucleic acids can fold into distinctive four-stranded G-quadruplex structures which are found in telomeric DNA repeats as well as in sequences in the promoter and other regulatory regions of genes, especially those involved in cellular proliferation. Small molecules that can selectively bind and stabilize the G-quadruplex structure have become of significant interest to researchers, and are gaining momentum as a possible new class of anticancer agents. We recently reported a series of novel biaryl polyamides with significant selectively toward G-quadruplex compared to duplex DNA. Using a distamycin scaffold as a starting point, we introduced biaryl building blocks in place of pyrroles to switch preference from duplex to G-quadruplex DNA. This alteration in shape ensured that the molecules had low affinity for duplex DNA while increasing their interaction with a G-quadruplex structure. We have now used a molecular modeling approach to modify the structure of the previous...
G-quadruplexes as targets for drug design
Pharmacology & …, 2000
G-quadruplexes are a family of secondary DNA structures formed in the presence of monovalent cations that consist of four-stranded structures in which Hoogsteen base-pairing stabilizes G-tetrad structures. These structures are proposed to exist in vivo, although direct confirmatory evidence is lacking. Guanine-rich regions of DNA capable of forming G-quadruplex structures are found in a variety of chromosomal regions, including telomeres and promoter regions of DNA. In this review, we describe the design of three separate groups of G-quadruplex-interactive compounds and their interaction with G-quadruplex DNA. Using the first group of compounds (anthraquinones), we describe experiments that provide the proof of concept that a G-quadruplex is required for inhibition of telomerase. Using the second group of compounds (perylenes), we describe the structure of a G-quadruplex-ligand complex and its effect on the dynamics of formation and enzymatic unwinding of the quadruplex. For the third group of compounds (porphyrins), we describe the experiments that relate the biological effects to their interactions with G-quadruplexes.
Bioorganic & Medicinal Chemistry Letters, 2012
Keywords: G-quadruplex Duplex DNA Ligands NCI Diversity Set High throughput screen FRET-based assay Drug-likeness a b s t r a c t Thirteen compounds with diverse chemical structures have been identified as selective telomeric G-quadruplex-binding ligands through screening the NCI Diversity Set II, the NCI Natural Products Set II and the NCI Mechanistic Diversity Set libraries containing a total of 2307 members against a human telomeric G-quadruplex using a FRET-based DNA melting assay. These compounds show significant selectivity towards a telomeric G-quadruplex compared to duplex DNA, fall within a molecular weight range of 327-533, and are generally consistent with the Lipinski Rule of Five for drug-likeness. Thus they provide new chemical scaffolds for the development of novel classes of G-quadruplex-targeting agents.
DNA quadruplex : a potential target for anticancer therapy
2018
Cancer is one of the most important health problems and very common in different populations in the world. The main objective of newly synthesized molecules has selectivity against tumor cells with low-toxic effect. The use of different methods and molecules depends on the stage and type of cancer. This process defines the compounds containing planar aromatic or hetero aromatic ring systems embedded between adjacent base pairs perpendicularly to the axis of the helix and without disturbing the overall arranging pattern due to Watson–Crick hydrogen bonding. Last few years, fluorescence intercalating agents, fluorescence probe and sensor in biophysical chemistry and molecular biology, photosensitized molecule in fluorescence-decay reactions as DNA strainers became very important. G-quadruplex structures and epigenetic enzymes have raised much interest as potential anticancer targets. Several agents acting on DNA are clinically used, but the severe driving side effects limit their ther...
Biochimie, 2009
Human DNA sequences consisting of tandem guanine (G) nucleotides can fold into a four-stranded structure named G-quadruplex via Hoogsteen hydrogen bonding. As the sequences forming G-quadruplex exist in essential regions of eukaryotic chromosomes and are involved in many important biological processes, the study of their biological functions has currently become a hotspot. Compounds selectively binding and stabilizing G-quadruplex structures have the potential to inhibit telomerase activity or alter oncogene expression levels and thus may act as antitumor agents. Most of reported G-quadruplex ligands generally have planar structures which stabilize G-quadruplex by p-p stacking.
Quadruplex Ligands in Cancer Therapy
Cancers, 2021
Nucleic acids can adopt alternative secondary conformations including four-stranded structures known as quadruplexes. To date, quadruplexes have been demonstrated to exist both in human chromatin DNA and RNA. In particular, quadruplexes are found in guanine-rich sequences constituting G-quadruplexes, and in cytosine-rich sequences forming i-Motifs as a counterpart. Quadruplexes are associated with key biological processes ranging from transcription and translation of several oncogenes and tumor suppressors to telomeres maintenance and genome instability. In this context, quadruplexes have prompted investigations on their possible role in cancer biology and the evaluation of small-molecule ligands as potential therapeutic agents. This review aims to provide an updated close-up view of the literature on quadruplex ligands in cancer therapy, by grouping together ligands for DNA and RNA G-quadruplexes and DNA i-Motifs.
Organic & Biomolecular Chemistry, 2011
A series of novel 2,4,6-triarylpyridines have been synthesized and their interactions with intramolecular G-quadruplexes have been measured by Förster Resonance Energy Transfer (FRET) melting and Fluorescent Intercalator Displacement (FID) assays. A few of these compounds exhibit stabilization of G4-DNA that is comparable to other benchmark G4-DNA ligands with fair to excellent G4-DNA vs. duplex selectivity and significant cytotoxicity towards HeLa cells. The nature of the 4-aryl substituents along with side chain length governs the G4-DNA stabilization ability of the compounds. In addition, we demonstrate that there is a strong correlation between the ability of the compounds to stabilize the same G4-DNA sequence in K + and Na + conditions and a strong correlation between the ability of the compounds to stabilize different G4-DNA sequences in K + or Na + buffer.