scholarly journals Small Molecule Fluorescent Probes for G- Quadruplex Visualization as Potential Cancer Theranostic Agents

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 752 ◽  
Author(s):  
Pallavi Chilka ◽  
Nakshi Desai ◽  
Bhaskar Datta
Keyword(s):  
Small Molecule ◽  
Fluorescent Probes ◽  
Cancer Prognosis ◽  
Fluorescence Signal ◽  
Physiological Relevance ◽  
G Quadruplex ◽  
Small Molecule Ligands ◽  
Recent Developments ◽  
Theranostic Agents

G-quadruplexes have gained prominence over the past two decades for their role in gene regulation, control of anti-tumour activity and ageing. The physiological relevance and significance of these non-canonical structures in the context of cancer has been reviewed several times. Putative roles of G-quadruplexes in cancer prognosis and pathogenesis have spurred the search for small molecule ligands that are capable of binding and modulating the effect of such structures. On a related theme, small molecule fluorescent probes have emerged that are capable of selective recognition of G-quadruplex structures. These have opened up the possibility of direct visualization and tracking of such structures. In this review we outline recent developments on G-quadruplex specific small molecule fluorescent probes for visualizing G-quadruplexes. The molecules represent a variety of structural scaffolds, mechanism of quadruplex-recognition and fluorescence signal transduction. Quadruplex selectivity and in vivo imaging potential of these molecules places them uniquely as quadruplex-theranostic agents in the predominantly cancer therapeutic context of quadruplex-selective ligands.

scholarly journals Investigation of Transcription Repression and Small-Molecule Responsiveness by TetR-Like Transcription Factors Using a Heterologous Escherichia coli-Based Assay

2007 ◽  
Vol 189 (18) ◽  
pp. 6655-6664 ◽  
Author(s):  
Sang Kyun Ahn ◽  
Kapil Tahlan ◽  
Zhou Yu ◽  
Justin Nodwell
Keyword(s):  
Escherichia Coli ◽  
Transcription Factors ◽  
Small Molecule ◽  
Target Genes ◽  
Streptomyces Coelicolor ◽  
Targeted Mutagenesis ◽  
E Coli ◽  
Small Molecule Ligands

ABSTRACT The SCO7222 protein and ActR are two of ∼150 TetR-like transcription factors encoded in the Streptomyces coelicolor genome. Using bioluminescence as a readout, we have developed Escherichia coli-based biosensors that accurately report the regulatory activity of these proteins and used it to investigate their interactions with DNA and small-molecule ligands. We found that the SCO7222 protein and ActR repress the expression of their putative target genes, SCO7223 and actII-ORF2 (actA), respectively, by interacting with operator sequence in the promoters. The operators recognized by the two proteins are related such that O 7223 (an operator for SCO7223) could be bound by both the SCO7222 protein and ActR with similar affinities. In contrast, Oact (an operator for actII-ORF2) was bound tightly by ActR and more weakly by the SCO7222 protein. We demonstrated ligand specificity of these proteins by showing that while TetR (but not ActR or the SCO7222 protein) interacts with tetracyclines, ActR (but not TetR or the SCO7222 protein) interacts with actinorhodin and related molecules. Through operator-targeted mutagenesis, we found that at least two nucleotide changes in O 7223 were required to disrupt its interaction with SCO7222 protein, while ActR was more sensitive to changes on Oact . Most importantly, we found that the interaction of each protein with wild-type and mutant operator sequences in vivo and in vitro correlated perfectly. Our data suggest that E. coli-based biosensors of this type should be broadly applicable to TetR-like transcription factors.

Benzothiazole hydrazones of furylbenzamides preferentially stabilize c-MYC and c-KIT1 promoter G-quadruplex DNAs

2016 ◽  
Vol 14 (24) ◽  
pp. 5779-5793 ◽  
Author(s):  
Sushree Prangya Priyadarshinee Pany ◽  
Praneeth Bommisetti ◽  
K. V. Diveshkumar ◽  
P. I. Pradeepkumar
Keyword(s):  
Small Molecule ◽  
Anticancer Agents ◽  
Next Generation ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
G Quadruplex ◽  
Small Molecule Ligands

The stabilization of G-quadruplex DNA structures by using small molecule ligands having simple structural scaffolds has the potential to be harnessed for developing next generation anticancer agents.

A G-Quadruplex-Interactive Potent Small-Molecule Inhibitor of Telomerase Exhibiting in Vitro and in Vivo Antitumor Activity

2002 ◽  
Vol 61 (5) ◽  
pp. 1154-1162 ◽  
Author(s):  
Sharon M. Gowan ◽  
John R. Harrison ◽  
Lisa Patterson ◽  
Melanie Valenti ◽  
Martin A. Read ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
In Vivo Antitumor Activity ◽  
Molecule Inhibitor ◽  
G Quadruplex

Synthetic Small Molecules Targeting G-Quadruplexes and their Application

2015 ◽  
Vol 1088 ◽  
pp. 507-513
Author(s):  
Hui Yu ◽  
Yan Li Wang ◽  
Xiao Yin Zhao ◽  
Wen Zhang
Keyword(s):  
Drug Design ◽  
Small Molecules ◽  
Small Molecule ◽  
Binding Mode ◽  
Current Understanding ◽  
Promising Target ◽  
G Quadruplex ◽  
Small Molecule Ligands

G-quadruplex is expected to be a promising target for drug design. The manually synthesized small-molecule compounds are able to induce the formation of and stabilize G-quadruplexes. In this paper, we summarize the current understanding of the structure of G-quadruplexes, the binding mode of G-quadruplexes and small-molecule ligands, and important synthesized small molecules targeting G-quadruplexes as potential drugs.

Selectivity of small molecule ligands for parallel and anti-parallel DNA G-quadruplex structures

2009 ◽  
Vol 7 (20) ◽  
pp. 4194 ◽  
Author(s):  
Thomas P. Garner ◽  
Huw E. L. Williams ◽  
Katarzyna I. Gluszyk ◽  
Stephen Roe ◽  
Neil J. Oldham ◽  
...  
Keyword(s):  
Small Molecule ◽  
G Quadruplex ◽  
Small Molecule Ligands

scholarly journals Multimerization Increases Tumor Enrichment of Peptide–Photosensitizer Conjugates

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 817 ◽  
Author(s):  
Jisi Zhao ◽  
Shuang Li ◽  
Yingying Jin ◽  
Jessica Wang ◽  
Wenjing Li ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Tumor Targeting ◽  
Integrin Αvβ3 ◽  
Rgd Peptide ◽  
Therapeutic Modality ◽  
In Vivo Experiments ◽  
Small Molecule Ligands ◽  
Pyropheophorbide A

Photodynamic therapy (PDT) is an established therapeutic modality for the management of cancers. Conjugation with tumor-specific small molecule ligands (e.g., short peptides or peptidomimetics) could increase the tumor targeting of PDT agents, which is very important for improving the outcome of PDT. However, compared with antibody molecules, small molecule ligands have a much weaker affinity to their receptors, which means that their tumor enrichment is not always ideal. In this work, we synthesized multimeric RGD ligand-coupled conjugates of pyropheophorbide-a (Pyro) to increase the affinity through multivalent and cluster effects to improve the tumor enrichment of the conjugates. Thus, the dimeric and trimeric RGD peptide-coupled Pyro conjugates and the monomeric one for comparison were efficiently synthesized via a convergent strategy. A short polyethylene glycol spacer was introduced between two RGD motifs to increase the distance required for multivalence. A subsequent binding affinity assay verified the improvement of the binding towards integrin αvβ3 receptors after the increase in the valence, with an approximately 20-fold improvement in the binding affinity of the trimeric conjugate compared with that of the monomeric conjugate. In vivo experiments performed in tumor-bearing mice also confirmed a significant increase in the distribution of the conjugates in the tumor site via multimerization, in which the trimeric conjugate had the best tumor enrichment compared with the other two conjugates. These results indicated that the multivalence interaction can obviously increase the tumor enrichment of RGD peptide-conjugated Pyro photosensitizers, and the prepared trimeric conjugate can be used as a novel antitumor photodynamic agent with high tumor enrichment.

scholarly journals Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3465
Author(s):  
Guanhui Wu ◽  
Desiree Tillo ◽  
Sreejana Ray ◽  
Ta-Chau Chang ◽  
John S. Schneekloth ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Targets ◽  
Large Scale ◽  
High Specificity ◽  
Binding Selectivity ◽  
Large Scale Assessment ◽  
G Quadruplex ◽  
Flanking Sequences ◽  
Fluorescence Binding

G-quadruplexes (G4) are considered new drug targets for human diseases such as cancer. More than 10,000 G4s have been discovered in human chromatin, posing challenges for assessing the selectivity of a G4-interactive ligand. 3,6-bis(1-Methyl-4-vinylpyridinium) carbazole diiodide (BMVC) is the first fluorescent small molecule for G4 detection in vivo. Our previous structural study shows that BMVC binds to the MYC promoter G4 (MycG4) with high specificity. Here, we utilize high-throughput, large-scale custom DNA G4 microarrays to analyze the G4-binding selectivity of BMVC. BMVC preferentially binds to the parallel MycG4 and selectively recognizes flanking sequences of parallel G4s, especially the 3′-flanking thymine. Importantly, the microarray results are confirmed by orthogonal NMR and fluorescence binding analyses. Our study demonstrates the potential of custom G4 microarrays as a platform to broadly and unbiasedly assess the binding selectivity of G4-interactive ligands, and to help understand the properties that govern molecular recognition.

scholarly journals Recent Developments in Small-Molecule Ligands of Medicinal Relevance for Harnessing the Anticancer Potential of G-Quadruplexes

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 841
Author(s):  
Loukiani Savva ◽  
Savvas N. Georgiades
Keyword(s):  
Clinical Trials ◽  
Critical Discussion ◽  
Affinity Ligands ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Anticancer Effects ◽  
G Quadruplex ◽  
Small Molecule Ligands ◽  
Recent Developments ◽  
Further Development

G-quadruplexes, a family of tetraplex helical nucleic acid topologies, have emerged in recent years as novel targets, with untapped potential for anticancer research. Their potential stems from the fact that G-quadruplexes occur in functionally-important regions of the human genome, such as the telomere tandem sequences, several proto-oncogene promoters, other regulatory regions and sequences of DNA (e.g., rDNA), as well as in mRNAs encoding for proteins with roles in tumorigenesis. Modulation of G-quadruplexes, via interaction with high-affinity ligands, leads to their stabilization, with numerous observed anticancer effects. Despite the fact that only a few lead compounds for G-quadruplex modulation have progressed to clinical trials so far, recent advancements in the field now create conditions that foster further development of drug candidates. This review highlights biological processes through which G-quadruplexes can exert their anticancer effects and describes, via selected case studies, progress of the last few years on the development of efficient and drug-like G-quadruplex-targeted ligands, intended to harness the anticancer potential offered by G-quadruplexes. The review finally provides a critical discussion of perceived challenges and limitations that have previously hampered the progression of G-quadruplex-targeted lead compounds to clinical trials, concluding with an optimistic future outlook.

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