Xanthene and Xanthone Derivatives as G-Quadruplex Stabilizing Ligands

G-quadruplex (G4) structures have emerged as singular therapeutic targets for cancer and neurodegeneration. Autophagy is a housekeeping cellular homeostatic mechanism and deregulation of autophagy is common in cancer and in neurodegenerative diseases. In this study, we identified the presence of 46 putative G4 sequences in the MTOR gene by use of QGRS mapper tool. We sought to connect these putative G4 sequences to a functional context by leveraging G4-targeting ligands. A G4-selective dimeric carbocyanine dye Bis-4,3 and the porphyrin TMPyP4 were used to affect the replication, transcription and translation of the MTOR gene. The ligand-induced induction of autophagic pathway via MTOR gene regulation was monitored upon treatment of HeLa and SHSY-5Y cells with G4-targeting ligands. The use of Bis-4,3 was compared with the known G4-stabilizing activity of TMPyP4. Our results show that treatment with G4-selective ligands downregulates mTOR activity and leads to the induction of excessive autophagy. This is first report on effect of G4-selective ligands on MTOR regulation and mTOR expression. mTOR being the key negative regulator of autophagy, the current work suggests potential of G4 stabilizing ligands towards induction of autophagy through the downregulation of mTOR.

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Discovery of G-quadruplex stabilizing ligands through direct ELISA of a one-bead-one-compound library

Organic & Biomolecular Chemistry ◽

10.1039/b611716c ◽

2006 ◽

Vol 4 (23) ◽

pp. 4364 ◽

Cited By ~ 11

Author(s):

James E. Redman ◽

Sylvain Ladame ◽

Anthony P. Reszka ◽

Stephen Neidle ◽

Shankar Balasubramanian

Keyword(s):

Compound Library ◽

G Quadruplex ◽

Direct Elisa ◽

Stabilizing Ligands

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Enhancement Effect of Zn-Arsenazo III Complex for G-quadruplex DNA Stability of Proto-oncogene Promoter Telomeres

Letters in Drug Design & Discovery ◽

10.2174/1570180816666191112154141 ◽

2020 ◽

Vol 17 (7) ◽

pp. 858-866

Author(s):

Liyuan Zou ◽

Hongbo Li ◽

Mingbin Liu ◽

Weihua Zhao ◽

Suqin Wang

Keyword(s):

Enhancement Effect ◽

Antitumor Therapy ◽

Quadruplex Dna ◽

G Quadruplex ◽

Cellular Context ◽

Different Temperatures ◽

Nucleic Acid Stain ◽

Reciprocal Method ◽

Growth Of Tumor ◽

Stabilizing Ligands

Background: Controlling the structure of proto-oncogene telomeres is very important in antitumor therapy. There are relationships between G-quadruplex DNA and the growth of tumor cell. Methods: In this study, spectroscopic, cyclic voltammetry and viscosity methods were employed to investigate the interaction between Zn-Arsenazo Ⅲ complex and G-quadruplex DNA by using 4S Green Plus Nucleic Acid Stain as a spectral probe in PBS buffer. The binding ratios were n Arsenazo Ⅲ : n Zn(Ⅱ) = 5:1 for Zn-Arsenazo Ⅲ complex and n Zn- Arsenazo Ⅲ : n G-quadruplex DNA = 8:1 for Zn-Arsenazo Ⅲ-G-quadruplex DNA. The bonding constants (Kθ 298.15K=4.44x105 L·mol-1, Kθ 308.15K= 1.00x105 L·mol-1, Kθ 318.15K= 1.04x106 L·mol-1) were obtained by double reciprocal method at different temperatures, Which was found that the interaction between Zn-Arsenazo Ⅲ complex and Gquadruplex DNA was driven by enthalpy. Furthermore, the research further confirmed that the interaction mode between Zn-Arsenazo Ⅲ complex and G-quadruplex DNA was a mixed binding which involved intercalation and non-intercalation interaction. Results and Conclusion: Together these findings also have corroborated the application of stabilizing ligands and intervening with their function for target G-quadruplexes in a cellular context.

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Tetramethylpyridiniumporphyrazines — A New Class of G-Quadruplex Inducing and Stabilizing Ligands.

ChemInform ◽

10.1002/chin.200710133 ◽

2007 ◽

Vol 38 (10) ◽

Author(s):

Diana P. N. Goncalves ◽

Raphael Rodriguez ◽

Shankar Balasubramanian ◽

Jeremy K. M. Sanders

Keyword(s):

New Class ◽

G Quadruplex ◽

Stabilizing Ligands

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Control of the polyamine biosynthesis pathway by G2-quadruplexes

eLife ◽

10.7554/elife.36362 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 11

Author(s):

Helen Louise Lightfoot ◽

Timo Hagen ◽

Antoine Cléry ◽

Frédéric Hai-Trieu Allain ◽

Jonathan Hall

Keyword(s):

Feedback Loops ◽

Polyamine Biosynthesis ◽

Biophysical Characterization ◽

Cellular Assays ◽

Naturally Occurring ◽

Genome Wide ◽

G Quadruplex ◽

Stabilizing Ligands ◽

Influence Gene Expression

G-quadruplexes are naturally-occurring structures found in RNAs and DNAs. Regular RNA G-quadruplexes are highly stable due to stacked planar arrangements connected by short loops. However, reports of irregular quadruplex structures are increasing and recent genome-wide studies suggest that they influence gene expression. We have investigated a grouping of G2-motifs in the UTRs of eight genes involved in polyamine biosynthesis, and concluded that several likely form novel metastable RNA G-quadruplexes. We performed a comprehensive biophysical characterization of their properties, comparing them to a reference G-quadruplex. Using cellular assays, together with polyamine-depleting and quadruplex-stabilizing ligands, we discovered how some of these motifs regulate and sense polyamine levels, creating feedback loops during polyamine biosynthesis. Using high-resolution 1H-NMR spectroscopy, we demonstrated that a long-looped quadruplex in the AZIN1 mRNA co-exists in salt-dependent equilibria with a hairpin structure. This study expands the repertoire of regulatory G-quadruplexes and demonstrates how they act in unison to control metabolite homeostasis.

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Molecular docking based screening of triterpenoids as potential G-quadruplex stabilizing ligands with anti-cancer activity

Bioinformation ◽

10.6026/97320630013284 ◽

2017 ◽

Vol 13 (09) ◽

pp. 284-292 ◽

Cited By ~ 7

Author(s):

Sittichai Sillapapongwarakorn ◽

◽

Somchai Yanarojana ◽

Darawan Pinthong ◽

Amnuay Thithapandha ◽

...

Keyword(s):

Molecular Docking ◽

Anti Cancer ◽

G Quadruplex ◽

Stabilizing Ligands ◽

Cancer Activity

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Synthesis and evaluation of 9-O-substituted berberine derivatives containing aza-aromatic terminal group as highly selective telomeric G-quadruplex stabilizing ligands

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2009.05.030 ◽

2009 ◽

Vol 19 (13) ◽

pp. 3414-3417 ◽

Cited By ~ 52

Author(s):

Yan Ma ◽

Tian-Miao Ou ◽

Jia-Heng Tan ◽

Jin-Qiang Hou ◽

Shi-Liang Huang ◽

...

Keyword(s):

Terminal Group ◽

G Quadruplex ◽

Berberine Derivatives ◽

Stabilizing Ligands

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E. coli Rep helicase and RecA recombinase unwind G4 DNA and are important for resistance to G4-stabilizing ligands

Nucleic Acids Research ◽

10.1093/nar/gkaa442 ◽

2020 ◽

Vol 48 (12) ◽

pp. 6640-6653 ◽

Cited By ~ 1

Author(s):

Tapas Paul ◽

Andrew F Voter ◽

Rachel R Cueny ◽

Momčilo Gavrilov ◽

Taekjip Ha ◽

...

Keyword(s):

Atp Hydrolysis ◽

Cellular Toxicity ◽

Dna Structures ◽

E Coli ◽

G4 Dna ◽

G Quadruplex ◽

Physical Barriers ◽

Stabilizing Ligands

Abstract G-quadruplex (G4) DNA structures can form physical barriers within the genome that must be unwound to ensure cellular genomic integrity. Here, we report unanticipated roles for the Escherichia coli Rep helicase and RecA recombinase in tolerating toxicity induced by G4-stabilizing ligands in vivo. We demonstrate that Rep and Rep-X (an enhanced version of Rep) display G4 unwinding activities in vitro that are significantly higher than the closely related UvrD helicase. G4 unwinding mediated by Rep involves repetitive cycles of G4 unfolding and refolding fueled by ATP hydrolysis. Rep-X and Rep also dislodge G4-stabilizing ligands, in agreement with our in vivo G4-ligand sensitivity result. We further demonstrate that RecA filaments disrupt G4 structures and remove G4 ligands in vitro, consistent with its role in countering cellular toxicity of G4-stabilizing ligands. Together, our study reveals novel genome caretaking functions for Rep and RecA in resolving deleterious G4 structures.

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