scholarly journals Metal-Based G-Quadruplex Binders for Cancer Theranostics

2021 ◽  
Vol 14 (7) ◽  
pp. 605
Author(s):  
Elisa Palma ◽  
Josué Carvalho ◽  
Carla Cruz ◽  
António Paulo
Keyword(s):  
Nuclear Medicine ◽  
Metal Complexes ◽  
Small Molecules ◽  
Significant Progress ◽  
Comprehensive Overview ◽  
Dna Structures ◽  
Potential Interest ◽  
G Quadruplex ◽  
Theranostic Agents ◽  
Cancer Theranostics

The ability of fluorescent small molecules, such as metal complexes, to selectively recognize G-quadruplex (G4) structures has opened a route to develop new probes for the visualization of these DNA structures in cells. The main goal of this review is to update the most recent research efforts towards the development of novel cancer theranostic agents using this type of metal-based probes that specifically recognize G4 structures. This encompassed a comprehensive overview of the most significant progress in the field, namely based on complexes with Cu, Pt, and Ru that are among the most studied metals to obtain this class of molecules. It is also discussed the potential interest of obtaining G4-binders with medical radiometals (e.g., 99mTc, 111In, 64Cu, 195mPt) suitable for diagnostic and/or therapeutic applications within nuclear medicine modalities, in order to enable their theranostic potential.

scholarly journals N-methyl mesoporphyrin IX as a highly selective light-up probe for G-quadruplex DNA

2019 ◽  
Vol 23 (11n12) ◽  
pp. 1195-1215 ◽  
Author(s):  
Ariana Yett ◽  
Linda Yingqi Lin ◽  
Dana Beseiso ◽  
Joanne Miao ◽  
Liliya A. Yatsunyk
Keyword(s):  
Optical Properties ◽  
Small Molecules ◽  
Genomic Stability ◽  
Water Soluble ◽  
Biological Processes ◽  
Binding Properties ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
G Quadruplex ◽  
High Fluorescence

[Formula: see text]-methyl mesoporphyrin IX (NMM) is a water-soluble, non-symmetric porphyrin with excellent optical properties and unparalleled selectivity for G-quadruplex (GQ) DNA. G-quadruplexes are non-canonical DNA structures formed by guanine-rich sequences. They are implicated in genomic stability, longevity, and cancer. The ability of NMM to selectively recognize GQ structures makes it a valuable scaffold for designing novel GQ binders. In this review, we survey the literature describing the GQ-binding properties of NMM as well as its wide utility in chemistry and biology. We start with the discovery of the GQ-binding properties of NMM and the development of NMM-binding aptamers. We then discuss the optical properties of NMM, focusing on the light-switch effect — high fluorescence of NMM induced upon its binding to GQ DNA. Additionally, we examine the affinity and selectivity of NMM for GQs, as well as its ability to stabilize GQ structures and favor parallel GQ conformations. Furthermore, a portion of the review is dedicated to the applications of NMM-GQ complexes as biosensors for heavy metals, small molecules ([Formula: see text] ATP and pesticides), DNA, and proteins. Finally and importantly, we discuss the utility of NMM as a probe to investigate the roles of GQs in biological processes.

Differences in affinity of arylstilbazolium derivatives to tetraplex structures

2011 ◽  
Vol 65 (2) ◽  
Author(s):  
Izabella Czerwinska ◽  
Bernard Juskowiak
Keyword(s):  
Small Molecules ◽  
Therapeutic Agent ◽  
Equilibrium Dialysis ◽  
Structural Features ◽  
Acid Number ◽  
Strong Interactions ◽  
Dna Structures ◽  
G Quadruplex ◽  
Preferential Binding ◽  
Important Field

AbstractResearch into the interactions of small molecules (ligands) with DNA is a very important field of biochemistry. A ligand interacts with a DNA structure in many ways, depending on the structural features of the ligand (the presence of rings, substituent groups, length of bonds, etc.) or nucleic acid (number and association of strands, base sequence etc.). This study reports on an investigation of the preferential binding of arylstilbazolium ligands to a four-stranded DNA. For this purpose, an equilibrium dialysis was used. Equilibrium dialysis is a versatile method which enables many DNA structures to be investigated at the same time. A dozen different DNA structures of (single-stranded, double-stranded (duplex), triple-stranded (triplex), and four-stranded (tetraplex)) were involved in experiments with each ligand. Following the dissociation of DNA-ligand complexes by SDS, the concentration of the ligand bound was calculated from fluorescence and absorbance calibration curves. As a result, the amount of the ligand bound was directly related to the ligand-binding affinity. Equilibrium dialysis was used as a powerful tool to indicate which of the arylstilbazolium ligands investigated was the best therapeutic agent targeting G-quadruplex. Arylstilbazolium derivatives demonstrated strong interactions with the DNA samples used in the assay. The most interesting finding was a selective, preferential binding of anthryl derivative to c-MYC DNA (c-MYC is a DNA sequence that appears in an oncogene). Furthermore, as this derivative binds preferentially to one of the triplexes investigated, it can find an application in the TFO-triplex forming oligonucleotides which are used in gene therapy.

scholarly journals Transcription-associated topoisomerase 2α activity is a major effector of cytotoxicity induced by G-quadruplex ligands

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Madeleine Bossaert ◽  
Angélique Pipier ◽  
Jean-Francois Riou ◽  
Céline Noirot ◽  
Linh-Trang Nguyễn ◽  
...  
Keyword(s):  
Small Molecules ◽  
Double Strand Breaks ◽  
Transcriptional Elongation ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Dna Structures ◽  
Topoisomerase 1 ◽  
G Quadruplex ◽  
Topoisomerase 2 ◽  
Topoisomerase 2 Alpha

G-quadruplexes (G4) are non-canonical DNA structures found in the genome of most species including human. Small molecules stabilizing these structures, called G4 ligands, have been identified and, for some of them, shown to induce cytotoxic DNA double-strand breaks. Through the use of an unbiased genetic approach, we identify here topoisomerase 2-alpha (TOP2A) as a major effector of cytotoxicity induced by two clastogenic G4 ligands, pyridostatin and CX-5461, the latter molecule currently undergoing phase I/II clinical trials in oncology. We show that both TOP2 activity and transcription account for DNA break production following G4 ligand treatments. In contrast, clastogenic activity of these G4 ligands is countered by topoisomerase 1 (TOP1), which limits co-transcriptional G4 formation, and by factors promoting transcriptional elongation. Altogether our results support that clastogenic G4 ligands act as DNA structure-driven TOP2-poisons at transcribed regions bearing G4 structures.

scholarly journals DNA G-quadruplexes for native mass spectrometry in potassium: a database of validated structures in electrospray-compatible conditions

2021 ◽  
Author(s):  
Anirban Ghosh ◽  
Eric Largy ◽  
Valérie Gabelica
Keyword(s):  
Mass Spectrometry ◽  
Drug Targets ◽  
Native Mass Spectrometry ◽  
Drug Binding ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
Nmr Structures ◽  
G Quadruplex ◽  
Screening Assays

Abstract G-quadruplex DNA structures have become attractive drug targets, and native mass spectrometry can provide detailed characterization of drug binding stoichiometry and affinity, potentially at high throughput. However, the G-quadruplex DNA polymorphism poses problems for interpreting ligand screening assays. In order to establish standardized MS-based screening assays, we studied 28 sequences with documented NMR structures in (usually ∼100 mM) potassium, and report here their circular dichroism (CD), melting temperature (Tm), NMR spectra and electrospray mass spectra in 1 mM KCl/100 mM trimethylammonium acetate. Based on these results, we make a short-list of sequences that adopt the same structure in the MS assay as reported by NMR, and provide recommendations on using them for MS-based assays. We also built an R-based open-source application to build and consult a database, wherein further sequences can be incorporated in the future. The application handles automatically most of the data processing, and allows generating custom figures and reports. The database is included in the g4dbr package (https://github.com/EricLarG4/g4dbr) and can be explored online (https://ericlarg4.github.io/G4_database.html).

scholarly journals Marine Exopolysaccharide Complexed With Scandium Aimed as Theranostic Agents

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1143 ◽  
Author(s):  
Mattia Mazza ◽  
Cyrille Alliot ◽  
Corinne Sinquin ◽  
Sylvia Colliec-Jouault ◽  
Pascal E. Reiller ◽  
...  
Keyword(s):  
Nuclear Medicine ◽  
Light Scattering ◽  
Molar Mass ◽  
Field Flow Fractionation ◽  
High Concentration ◽  
New Class ◽  
Free Ion ◽  
Theranostic Agents ◽  
The Stability ◽  
Drug Reference

(1) Background: Exopolysaccharide (EPS) derivatives, produced by Alteromonas infernus bacterium, showed anti-metastatic properties. They may represent a new class of ligands to be combined with theranostic radionuclides, such as 47Sc/44Sc. The goal of this work was to investigate the feasibility of such coupling. (2) Methods: EPSs, as well as heparin used as a drug reference, were characterized in terms of molar mass and dispersity using Asymmetrical Flow Field-Flow Fractionation coupled to Multi-Angle Light Scattering (AF4-MALS). The intrinsic viscosity of EPSs at different ionic strengths were measured in order to establish the conformation. To determine the stability constants of Sc with EPS and heparin, a Free-ion selective radiotracer extraction (FISRE) method has been used. (3) Results: AF4-MALS showed that radical depolymerization produces monodisperse EPSs, suitable for therapeutic use. EPS conformation exhibited a lower hydrodynamic volume for the highest ionic strengths. The resulting random-coiled conformation could affect the complexation with metal for high concentration. The LogK of Sc-EPS complexes have been determined and showing that they are comparable to the Sc-Hep. (4) Conclusions: EPSs are very promising to be coupled with the theranostic pair of scandium for Nuclear Medicine.

Structural Insights into the Recognition of DNA Defects by Small Molecules

2021 ◽  
Author(s):  
David Dayanidhi Paul Elisa Sundar ◽  
Vaidyanathan Ganesan
Keyword(s):  
Nucleic Acids ◽  
Metal Complexes ◽  
Small Molecules ◽  
Chemical Properties ◽  
Biological Applications ◽  
Binding Interaction ◽  
Structural Insights

Studies on the binding interaction of small molecules and nucleic acids have been explored for their biological applications. With excellent photophysical/chemical properties, numerous metal complexes have been studied as structural...

scholarly journals Subtle structural alterations in G-quadruplex DNA regulate site specificity of fluorescence light-up probes

2020 ◽  
Vol 48 (3) ◽  
pp. 1108-1119 ◽  
Author(s):  
Rajendra Kumar ◽  
Karam Chand ◽  
Sudipta Bhowmik ◽  
Rabindra Nath Das ◽  
Snehasish Bhattacharjee ◽  
...  
Keyword(s):  
Rational Design ◽  
Dna Structure ◽  
Biological Processes ◽  
Chemical Research ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
Future Studies ◽  
G4 Dna ◽  
G Quadruplex ◽  
Fluorescence Light

Abstract G-quadruplex (G4) DNA structures are linked to key biological processes and human diseases. Small molecules that target specific G4 DNA structures and signal their presence would therefore be of great value as chemical research tools with potential to further advance towards diagnostic and therapeutic developments. However, the development of these types of specific compounds remain as a great challenge. In here, we have developed a compound with ability to specifically signal a certain c-MYC G4 DNA structure through a fluorescence light-up mechanism. Despite the compound's two binding sites on the G4 DNA structure, only one of them result in the fluorescence light-up effect. This G-tetrad selectivity proved to originate from a difference in flexibility that affected the binding affinity and tilt the compound out of the planar conformation required for the fluorescence light-up mechanism. The intertwined relation between the presented factors is likely the reason for the lack of examples using rational design to develop compounds with turn-on emission that specifically target certain G4 DNA structures. However, this study shows that it is indeed possible to develop such compounds and present insights into the molecular details of specific G4 DNA recognition and signaling to advance future studies of G4 biology.

Nanoporous Gold Disks Functionalized with Stabilized G-Quadruplex Moieties for Sensing Small Molecules

2016 ◽  
Vol 8 (44) ◽  
pp. 29968-29976 ◽  
Author(s):  
Suyan Qiu ◽  
Fusheng Zhao ◽  
Oussama Zenasni ◽  
Jingting Li ◽  
Wei-Chuan Shih
Keyword(s):  
Small Molecules ◽  
Nanoporous Gold ◽  
G Quadruplex
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