scholarly journals G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs

2017 ◽  
Vol 4 (1) ◽  
pp. 10-32 ◽  
Author(s):  
Qian Cao ◽  
Yi Li ◽  
Eva Freisinger ◽  
Peter Z. Qin ◽  
Roland K. O. Sigel ◽  
...  
Keyword(s):  
Metal Complexes ◽  
Anticancer Drugs ◽  
Quadruplex Dna ◽  
G4 Dna ◽  
G Quadruplex

This review summarizes the recent development of G4 DNA targeted metal complexes and discusses their potential as anticancer drugs.

Recent Progress and Future Potential for Metal Complexes as Anticancer Drugs Targeting G-quadruplex DNA

2012 ◽  
Vol 19 (18) ◽  
pp. 2957-2975 ◽  
Author(s):  
J. Zhang ◽  
F. Zhang ◽  
H. Li ◽  
C. Liu ◽  
J. Xia ◽  
...  
Keyword(s):  
Metal Complexes ◽  
Anticancer Drugs ◽  
Recent Progress ◽  
Quadruplex Dna ◽  
G Quadruplex ◽  
Future Potential

scholarly journals ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-Ching Teng ◽  
Aishwarya Sundaresan ◽  
Ryan O’Hara ◽  
Vincent U. Gant ◽  
Minhua Li ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Genome Stability ◽  
Helicase Domain ◽  
Quadruplex Dna ◽  
Heterochromatin Formation ◽  
Replicative Stress ◽  
G4 Dna ◽  
Mutation Burden ◽  
G Quadruplex ◽  
Dna Replication Stress

AbstractATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with a number of the MCM replication complex subunits and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease.

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.

scholarly journals Selective Interactions with Various G-Quadruplex DNA Forming Sequences by Berberine and Palmatine Analogues

2018 ◽  
Author(s):  
Marco Franceschin ◽  
Lorenzo Cianni ◽  
Massimo Pitorri ◽  
Emanuela Micheli ◽  
Stefano Cacchione ◽  
...  
Keyword(s):  
Anticancer Drugs ◽  
Natural Compounds ◽  
Side Chains ◽  
Quadruplex Dna ◽  
G Quadruplex ◽  
Quadruplex Formation ◽  
Selective Interactions

In this article/review, the selective interactions of several berberine and palmatine derivatives with various DNA G-quadruplex structures are reported. These derivatives were constructed starting from two natural compounds, berberine and palamatine, through specific synthetic passages following two different schemes for each of them and using several substituents. The details of these synthesis are also described. Indeed, the study of the interactions of these derivative compounds with various G-quadruplex forming sequences was carried out by means of various structural and biochemical techniques. The results show that the presence of suitable side chains are very useful to improve the interaction of the ligands with G-quadruplex structures. Thus, since G-quadruplex formation is promoted by these compounds, which have never been reported before, these may be tested as potential anticancer drugs.

scholarly journals G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma

2018 ◽  
Author(s):  
Yuxiang Wang ◽  
Jie Yang ◽  
Wei Wu ◽  
Rachna Shah ◽  
Carla Danussi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Malignant Glioma ◽  
Model Systems ◽  
Copy Number Alterations ◽  
Molecular Alteration ◽  
Quadruplex Dna ◽  
G4 Dna ◽  
G Quadruplex

AbstractMutational inactivation of ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma. Yet the pathogenic consequences of ATRX deficiency remain unclear, as do tractable mechanisms for its therapeutic targeting. Here we report that ATRX loss in isogenic glioma model systems induces replication stress and DNA damage by way of G-quadruplex (G4) DNA secondary structure. Moreover, these effects are associated with the acquisition of disease-relevant copy number alterations over time. We then demonstrate, both in vitro and in vivo, that ATRX deficiency selectively enhances DNA damage and cell death following chemical G4 stabilization. Finally, we show that G4 stabilization synergizes with other DNA-damaging therapies, including ionizing radiation, in the ATRX-deficient context. Our findings reveal novel pathogenic mechanisms driven by ATRX deficiency in glioma, while also pointing to tangible strategies for drug development.

scholarly journals Macrocyclization of bis-indole quinolines for selective stabilization of G-quadruplex DNA structures

2020 ◽  
Vol 11 (38) ◽  
pp. 10529-10537 ◽  
Author(s):  
Rabindra Nath Das ◽  
Måns Andréasson ◽  
Rajendra Kumar ◽  
Erik Chorell
Keyword(s):  
Quadruplex Dna ◽  
Dna Structures ◽  
G4 Dna ◽  
Selective Stabilization ◽  
G Quadruplex

Macrocyclization improves the selectivity, affinity, and ability to stabilize G4 DNA structures.

scholarly journals Human Rev1 polymerase disrupts G-quadruplex DNA

2013 ◽  
Vol 42 (5) ◽  
pp. 3272-3285 ◽  
Author(s):  
Sarah Eddy ◽  
Amit Ketkar ◽  
Maroof K. Zafar ◽  
Leena Maddukuri ◽  
Jeong-Yun Choi ◽  
...  
Keyword(s):  
Genome Maintenance ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
G4 Dna ◽  
G Quadruplex ◽  
Steady State Rate ◽  
Dna Substrates ◽  
Successful Replication ◽  
Y Family

Abstract The Y-family DNA polymerase Rev1 is required for successful replication of G-quadruplex DNA (G4 DNA) in higher eukaryotes. Here we show that human Rev1 (hRev1) disrupts G4 DNA structures and prevents refolding in vitro. Nucleotidyl transfer by hRev1 is not necessary for mechanical unfolding to occur. hRev1 binds G4 DNA substrates with Kd,DNA values that are 4–15-fold lower than those of non-G4 DNA substrates. The pre-steady-state rate constant of deoxycytidine monophosphate (dCMP) insertion opposite the first tetrad-guanine by hRev1 is ∼56% as fast as that observed for non-G4 DNA substrates. Thus, hRev1 can promote fork progression by either dislodging tetrad guanines to unfold the G4 DNA, which could assist in extension by other DNA polymerases, or hRev1 can prevent refolding of G4 DNA structures. The hRev1 mechanism of action against G-quadruplexes helps explain why replication progress is impeded at G4 DNA sites in Rev1-deficient cells and illustrates another unique feature of this enzyme with important implications for genome maintenance.

Spectroscopic Studies on the Binding Properties of Ofloxacin and Human Telomeric G-Quadruplex DNA

2013 ◽  
Vol 634-638 ◽  
pp. 1062-1065 ◽  
Author(s):  
Xu Jian Luo ◽  
Qi Pin Qin ◽  
Yu Lan Li ◽  
Yan Yang
Keyword(s):  
Spectral Analysis ◽  
Fluorescence Emission ◽  
Spectroscopic Studies ◽  
Binding Properties ◽  
Quadruplex Dna ◽  
G4 Dna ◽  
G Quadruplex ◽  
Shoulder Peak ◽  
Binding Intensity ◽  
Dna Complex

The binding of ofloxacin with human telomeric G-quadruplex DNA, Htel-G4-DNA and Htel-3-G4-DNA were examined by Fluorescence and CD spectroscopic methods. In the Fluorescence emission spectral analysis, the addition of ofloxacin induced significant quenching on the fluorescence emission of TO-G4-DNA complex. The fluorescence spectral analysis indicated that ofloxacin exhibited higher binding affinity and binding intensity to Htel-G4-DNA than Htel-3-G4-DNA. In the CD spectral analysis, the interaction with ofloxacin did not disturb the characteristic absorption of Htel-G4-DNA at 290 nm corresponding to its antiparallel form, and only slightly increased the positive absorption at 270 nm as shoulder peak, which suggests the antiparallel structure of G-quadruplex can remain stable in the presence of ofloxacin

scholarly journals MN4-based G4-Ligands as Potential Antitumor Agents: A Review

2021 ◽  
Vol 12 (3) ◽  
pp. 3977-3988
Keyword(s):  
Metal Complexes ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Genomic Dna ◽  
Rational Design ◽  
Structural Engineering ◽  
Antitumor Agents ◽  
Medical Field ◽  
G Quadruplex ◽  
Potential Antitumor

Cisplatin-based metal drugs have been widely used clinically as anticancer agents. However, these drugs also harm ordinary tissues because cisplatin kills cancer cells by attacking genomic DNA. Therefore, it has been shown that cisplatin-based metal drugs have some serious side effects that cannot be avoided. In order to replace the target site of genomic DNA, G-quadruplex nucleic acid is considered to be an alternative and attractive target for anticancer agents because G-quadruplex always folds into a parallel topology and is, therefore, more important than DNA. This review discussed the recent advancements in the rational design and the development of metal complexes containing anticancer drugs to interact and stabilize or cleave the G4 structure selectively. Further, we also highlighted the G4-interacting transition metal complexes, interacting modes, and their potentials to serve as anticancer drugs in the medical field. The significance of this survey lies in designing the metallodrugs from the most fundamental characteristic of electronic structural engineering to an increasingly reasonable dimension of bio-science.

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