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15 pages, 3227 KiB

Open AccessArticle

Ligand Selectivity in the Recognition of Protoberberine Alkaloids by Hybrid-2 Human Telomeric G-Quadruplex: Binding Free Energy Calculation, Fluorescence Binding, and NMR Experiments

by Nanjie Deng, Junchao Xia, Lauren Wickstrom, Clement Lin, Kaibo Wang, Peng He, Yunting Yin and Danzhou Yang

Molecules 2019, 24(8), 1574; https://doi.org/10.3390/molecules24081574 - 21 Apr 2019

Cited by 11 | Viewed by 3822

Abstract

The human telomeric G-quadruplex (G4) is an attractive target for developing anticancer drugs. Natural products protoberberine alkaloids are known to bind human telomeric G4 and inhibit telomerase. Among several structurally similar protoberberine alkaloids, epiberberine (EPI) shows the greatest specificity in recognizing the human [...] Read more.

The human telomeric G-quadruplex (G4) is an attractive target for developing anticancer drugs. Natural products protoberberine alkaloids are known to bind human telomeric G4 and inhibit telomerase. Among several structurally similar protoberberine alkaloids, epiberberine (EPI) shows the greatest specificity in recognizing the human telomeric G4 over duplex DNA and other G4s. Recently, NMR study revealed that EPI recognizes specifically the hybrid-2 form human telomeric G4 by inducing large rearrangements in the 5′-flanking segment and loop regions to form a highly extensive four-layered binding pocket. Using the NMR structure of the EPI-human telomeric G4 complex, here we perform molecular dynamics free energy calculations to elucidate the ligand selectivity in the recognition of protoberberines by the human telomeric G4. The MM-PB(GB)SA (molecular mechanics-Poisson Boltzmann/Generalized Born) Surface Area) binding free energies calculated using the Amber force fields bsc0 and OL15 correlate well with the NMR titration and binding affinity measurements, with both calculations correctly identifying the EPI as the strongest binder to the hybrid-2 telomeric G4 wtTel26. The results demonstrated that accounting for the conformational flexibility of the DNA-ligand complexes is crucially important for explaining the ligand selectivity of the human telomeric G4. While the MD-simulated (molecular dynamics) structures of the G-quadruplex-alkaloid complexes help rationalize why the EPI-G4 interactions are optimal compared with the other protoberberines, structural deviations from the NMR structure near the binding site are observed in the MD simulations. We have also performed binding free energy calculation using the more rigorous double decoupling method (DDM); however, the results correlate less well with the experimental trend, likely due to the difficulty of adequately sampling the very large conformational reorganization in the G4 induced by the protoberberine binding. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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17 pages, 3354 KiB

Open AccessArticle

Importance of Chiral Recognition in Designing Metal-Free Ligands for G-Quadruplex DNA

by Dora M. Răsădean, Samuel W. O. Harrison, Isobel R. Owens, Aucéanne Miramont, Frances M. Bromley and G. Dan Pantoș

Molecules 2019, 24(8), 1473; https://doi.org/10.3390/molecules24081473 - 15 Apr 2019

Cited by 3 | Viewed by 5308

Abstract

Four pairs of amino acid-functionalized naphthalenediimide enantiomers (d- and l-lysine derived NDIs) were screened toward G-quadruplex forming sequences in telomeres (h-TELO) and oncogene promoters: c-KIT1, c-KIT2, k-RAS and BCL-2. This is the first study to address the effect of point [...] Read more.

Four pairs of amino acid-functionalized naphthalenediimide enantiomers (d- and l-lysine derived NDIs) were screened toward G-quadruplex forming sequences in telomeres (h-TELO) and oncogene promoters: c-KIT1, c-KIT2, k-RAS and BCL-2. This is the first study to address the effect of point chirality toward G-quadruplex DNA stabilization using purely small organic molecules. Enantioselective behavior toward the majority of ligands was observed, particularly in the case of parallel conformations of c-KIT2 and k-RAS. Additionally, N_ε-Boc-l-Lys-NDI and N_ε-Boc-d-Lys-NDI discriminate between quadruplexes with parallel and hybrid topologies, which has not previously been observed with enantiomeric ligands. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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26 pages, 7207 KiB

Open AccessArticle

Binding of BRACO19 to a Telomeric G-Quadruplex DNA Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

by Babitha Machireddy, Holli-Joi Sullivan and Chun Wu

Molecules 2019, 24(6), 1010; https://doi.org/10.3390/molecules24061010 - 13 Mar 2019

Cited by 46 | Viewed by 5280

Abstract

Although BRACO19 is a potent G-quadruplex binder, its potential for clinical usage is hindered by its low selectivity towards DNA G-quadruplex over duplex. High-resolution structures of BRACO19 in complex with neither single-stranded telomeric DNA G-quadruplexes nor B-DNA duplex are available. In this study, [...] Read more.

Although BRACO19 is a potent G-quadruplex binder, its potential for clinical usage is hindered by its low selectivity towards DNA G-quadruplex over duplex. High-resolution structures of BRACO19 in complex with neither single-stranded telomeric DNA G-quadruplexes nor B-DNA duplex are available. In this study, the binding pathway of BRACO19 was probed by 27.5 µs molecular dynamics binding simulations with a free ligand (BRACO19) to a DNA duplex and three different topological folds of the human telomeric DNA G-quadruplex (parallel, anti-parallel and hybrid). The most stable binding modes were identified as end stacking and groove binding for the DNA G-quadruplexes and duplex, respectively. Among the three G-quadruplex topologies, the MM-GBSA binding energy analysis suggested that BRACO19′s binding to the parallel scaffold was most energetically favorable. The two lines of conflicting evidence plus our binding energy data suggest conformation-selection mechanism: the relative population shift of three scaffolds upon BRACO19 binding (i.e., an increase of population of parallel scaffold, a decrease of populations of antiparallel and/or hybrid scaffold). This hypothesis appears to be consistent with the fact that BRACO19 was specifically designed based on the structural requirements of the parallel scaffold and has since proven effective against a variety of cancer cell lines as well as toward a number of scaffolds. In addition, this binding mode is only slightly more favorable than BRACO19s binding to the duplex, explaining the low binding selectivity of BRACO19 to G-quadruplexes over duplex DNA. Our detailed analysis suggests that BRACO19′s groove binding mode may not be stable enough to maintain a prolonged binding event and that the groove binding mode may function as an intermediate state preceding a more energetically favorable end stacking pose; base flipping played an important role in enhancing binding interactions, an integral feature of an induced fit binding mechanism. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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11 pages, 2024 KiB

Open AccessArticle

Practical Microwave Synthesis of Carbazole Aldehydes for the Development of DNA-Binding Ligands

by Agata Głuszyńska and Bernard Juskowiak

Molecules 2019, 24(5), 965; https://doi.org/10.3390/molecules24050965 - 9 Mar 2019

Cited by 4 | Viewed by 3785

Abstract

Microwave formylation of carbazole derivatives was investigated and 3-monoaldehydes were obtained in high yield. A potential DNA-binding ligand, 3-[(3-ethyl)-2-vinylbenzothiazolium]-9-N-ethyl carbazole iodide, was synthesized and characterized including spectral properties (UV-Vis absorption and fluorescence spectra). The binding selectivity and affinity of three carbazole [...] Read more.

Microwave formylation of carbazole derivatives was investigated and 3-monoaldehydes were obtained in high yield. A potential DNA-binding ligand, 3-[(3-ethyl)-2-vinylbenzothiazolium]-9-N-ethyl carbazole iodide, was synthesized and characterized including spectral properties (UV-Vis absorption and fluorescence spectra). The binding selectivity and affinity of three carbazole ligands for double-stranded and G-quadruplex DNA structures were studied using a competitive dialysis method in sodium- and potassium-containing buffer solutions. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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9 pages, 1403 KiB

Open AccessArticle

Investigating the Effect of Mono- and Dimeric 360A G-Quadruplex Ligands on Telomere Stability by Single Telomere Length Analysis (STELA)

by In Pyo Hwang, Patrick Mailliet, Virginie Hossard, Jean-Francois Riou, Anthony Bugaut and Lauréline Roger

Molecules 2019, 24(3), 577; https://doi.org/10.3390/molecules24030577 - 6 Feb 2019

Cited by 9 | Viewed by 3860

Abstract

Telomeres are nucleoprotein structures that cap and protect the natural ends of chromosomes. Telomeric DNA G-rich strands can form G-quadruplex (or G4) structures. Ligands that bind to and stabilize G4 structures can lead to telomere dysfunctions by displacing shelterin proteins and/or by interfering [...] Read more.

Telomeres are nucleoprotein structures that cap and protect the natural ends of chromosomes. Telomeric DNA G-rich strands can form G-quadruplex (or G4) structures. Ligands that bind to and stabilize G4 structures can lead to telomere dysfunctions by displacing shelterin proteins and/or by interfering with the replication of telomeres. We previously reported that two pyridine dicarboxamide G4 ligands, 360A and its dimeric analogue (360A)_2A, were able to displace in vitro hRPA (a single-stranded DNA-binding protein of the replication machinery) from telomeric DNA by stabilizing the G4 structures. In this paper, we perform for the first time single telomere length analysis (STELA) to investigate the effect of G4 ligands on telomere length and stability. We used the unique ability of STELA to reveal the full spectrum of telomere lengths at a chromosome terminus in cancer cells treated with 360A and (360A)_2A. Upon treatment with these ligands, we readily detected an increase of ultrashort telomeres, whose lengths are significantly shorter than the mean telomere length, and that could not have been detected by other methods. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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19 pages, 3315 KiB

Open AccessFeature PaperArticle

Selectivity of Terpyridine Platinum Anticancer Drugs for G-quadruplex DNA

by Elodie Morel, Claire Beauvineau, Delphine Naud-Martin, Corinne Landras-Guetta, Daniela Verga, Deepanjan Ghosh, Sylvain Achelle, Florence Mahuteau-Betzer, Sophie Bombard and Marie-Paule Teulade-Fichou

Molecules 2019, 24(3), 404; https://doi.org/10.3390/molecules24030404 - 23 Jan 2019

Cited by 32 | Viewed by 6740

Abstract

Guanine-rich DNA can form four-stranded structures called G-quadruplexes (G4s) that can regulate many biological processes. Metal complexes have shown high affinity and selectivity toward the quadruplex structure. Here, we report the comparison of a panel of platinum (II) complexes for quadruplex DNA selective [...] Read more.

Guanine-rich DNA can form four-stranded structures called G-quadruplexes (G4s) that can regulate many biological processes. Metal complexes have shown high affinity and selectivity toward the quadruplex structure. Here, we report the comparison of a panel of platinum (II) complexes for quadruplex DNA selective recognition by exploring the aromatic core around terpyridine derivatives. Their affinity and selectivity towards G4 structures of various topologies have been evaluated by FRET-melting (Fluorescence Resonance Energy Transfert-melting) and Fluorescent Intercalator Displacement (FID) assays, the latter performed by using three different fluorescent probes (Thiazole Orange (TO), TO-PRO-3, and PhenDV). Their ability to bind covalently to the c-myc G4 structure in vitro and their cytotoxicity potential in two ovarian cancerous cell lines were established. Our results show that the aromatic surface of the metallic ligands governs, in vitro, their affinity, their selectivity for the G4 over the duplex structures, and platination efficiency. However, the structural modifications do not allow significant discrimination among the different G4 topologies. Moreover, all compounds were tested on ovarian cancer cell lines and normal cell lines and were all able to overcome cisplatin resistance highlighting their interest as new anticancer drugs. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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14 pages, 5006 KiB

Open AccessArticle

Synthesis and Telomeric G-Quadruplex-Stabilizing Ability of Macrocyclic Hexaoxazoles Bearing Three Side Chains

by Yue Ma, Keisuke Iida, Shogo Sasaki, Takatsugu Hirokawa, Brahim Heddi, Anh Tuân Phan and Kazuo Nagasawa

Molecules 2019, 24(2), 263; https://doi.org/10.3390/molecules24020263 - 11 Jan 2019

Cited by 18 | Viewed by 4745

Abstract

G-quadruplexes (G4s), which are structures formed in guanine-rich regions of DNA, are involved in a variety of significant biological functions, and therefore “sequence-dependent” selective G4-stabilizing agents are required as tools to investigate and modulate these functions. Here, we describe the synthesis of a [...] Read more.

G-quadruplexes (G4s), which are structures formed in guanine-rich regions of DNA, are involved in a variety of significant biological functions, and therefore “sequence-dependent” selective G4-stabilizing agents are required as tools to investigate and modulate these functions. Here, we describe the synthesis of a new series of macrocyclic hexaoxazole-type G4 ligand (6OTD) bearing three side chains. One of these ligands, 5b, stabilizes telomeric G4 preferentially over the G4-forming DNA sequences of c-kit and K-ras, due to the interaction of its piperazinylalkyl side chain with the groove of telomeric G4. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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13 pages, 4585 KiB

Open AccessArticle

Binding of Small Molecules to G-quadruplex DNA in Cells Revealed by Fluorescence Lifetime Imaging Microscopy of o-BMVC Foci

by Ting-Yuan Tseng, I-Te Chu, Shang-Jyun Lin, Jie Li and Ta-Chau Chang

Molecules 2019, 24(1), 35; https://doi.org/10.3390/molecules24010035 - 21 Dec 2018

Cited by 16 | Viewed by 4687

Abstract

G-quadruplex (G4) structures have recently received increasing attention as a potential target for cancer research. We used time-gated fluorescence lifetime imaging microscopy (FLIM) with a G4 fluorescent probe, 3,6-bis(1-methyl-2-vinylpyridinium) carbazole diiodide (o-BMVC), to measure the number of o-BMVC foci, which [...] Read more.

G-quadruplex (G4) structures have recently received increasing attention as a potential target for cancer research. We used time-gated fluorescence lifetime imaging microscopy (FLIM) with a G4 fluorescent probe, 3,6-bis(1-methyl-2-vinylpyridinium) carbazole diiodide (o-BMVC), to measure the number of o-BMVC foci, which may represent G4 foci, in cells as a common signature to distinguish cancer cells from normal cells. Here, the decrease in the number of o-BMVC foci in the pretreatment of cancer cells with TMPyP4, BRACO-19 and BMVC4 suggested that they directly bind to G4s in cells. In contrast, the increase in the number of o-BMVC foci in the pretreatment of cells with PDS and Hoechst 33258 (H33258) suggested that they do not inhabit the binding site of o-BMVC to G4s in cells. After the H33258 was removed, the gradual decrease of H33258-induced G4 foci may be due to DNA repair. The purpose of this work is to introduce o-BMVC foci as an indicator not only to verify the direct binding of potential G4 ligands to G4 structures but also to examine the possible effect of some DNA binding ligands on DNA integrity by monitoring the number of G4 foci in cells. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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13 pages, 2701 KiB

Open AccessArticle

Design and Properties of Ligand-Conjugated Guanine Oligonucleotides for Recovery of Mutated G-Quadruplexes

by Shuntaro Takahashi, Boris Chelobanov, Ki Tae Kim, Byeang Hyean Kim, Dmitry Stetsenko and Naoki Sugimoto

Molecules 2018, 23(12), 3228; https://doi.org/10.3390/molecules23123228 - 6 Dec 2018

Cited by 2 | Viewed by 3521

Abstract

The formation of a guanine quadruplex DNA structure (G4) is known to repress the expression of certain cancer-related genes. Consequently, a mutated G4 sequence can affect quadruplex formation and induce cancer progression. In this study, we developed an oligonucleotide derivative consisting of a [...] Read more.

The formation of a guanine quadruplex DNA structure (G4) is known to repress the expression of certain cancer-related genes. Consequently, a mutated G4 sequence can affect quadruplex formation and induce cancer progression. In this study, we developed an oligonucleotide derivative consisting of a ligand-containing guanine tract that replaces the mutated G4 guanine tract at the promoter of the vascular endothelial growth factor (VEGF) gene. A ligand moiety consisting of three types of polyaromatic hydrocarbons, pyrene, anthracene, and perylene, was attached to either the 3′ or 5′ end of the guanine tract. Each of the ligand-conjugated guanine tracts, with the exception of anthracene derivatives, combined with other intact guanine tracts to form an intermolecular G4 on the mutated VEGF promoter. This intermolecular G4, exhibiting parallel topology and high thermal stability, enabled VEGF G4 formation to be recovered from the mutated sequence. Stability of the intramolecular G4 increased with the size of the conjugated ligand. However, suppression of intermolecular G4 replication was uniquely dependent on whether the ligand was attached to the 3′ or 5′ end of the guanine tract. These results indicate that binding to either the top or bottom guanine quartet affects unfolding kinetics due to polarization in DNA polymerase processivity. Our findings provide a novel strategy for recovering G4 formation in case of damage, and fine-tuning processes such as replication and transcription. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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22 pages, 6354 KiB

Open AccessArticle

Binding Study of the Fluorescent Carbazole Derivative with Human Telomeric G-Quadruplexes

by Agata Głuszyńska, Bernard Juskowiak and Błażej Rubiś

Molecules 2018, 23(12), 3154; https://doi.org/10.3390/molecules23123154 - 30 Nov 2018

Cited by 15 | Viewed by 5184

Abstract

The carbazole ligand 3 was synthesized, characterized and its binding interactions with human telomeric (22HT) G-quadruplex DNA in Na⁺ and K⁺-containing buffer were investigated by ultraviolet-visible (UV-Vis) spectrophotometry, fluorescence, circular dichroism (CD) spectroscopy, and DNA melting. The results showed that [...] Read more.

The carbazole ligand 3 was synthesized, characterized and its binding interactions with human telomeric (22HT) G-quadruplex DNA in Na⁺ and K⁺-containing buffer were investigated by ultraviolet-visible (UV-Vis) spectrophotometry, fluorescence, circular dichroism (CD) spectroscopy, and DNA melting. The results showed that the studied carbazole ligand interacted and stabilized the intramolecular G-quadruplexes formed by the telomeric sequence in the presence of sodium and potassium ions. In the UV-Vis titration experiments a two-step complex formation between ligand and G-quadruplex was observed. Very low fluorescence intensity of the carbazole derivative in Tris HCl buffer in the presence of the NaCl or KCl increased significantly after addition of the 22HT G4 DNA. Binding stoichiometry of the ligand/G-quadruplex was investigated with absorbance-based Job plots. Carbazole ligand binds 22HT with about 2:1 stoichiometry in the presence of sodium and potassium ions. The binding mode appeared to be end-stacking with comparable binding constants of ~10⁵ M⁻¹ as determined from UV-Vis and fluorescence titrations data. The carbazole ligand is able to induce formation of G4 structure of 22HT in the absence of salt, which was proved by CD spectroscopy and melting studies. The derivative of carbazole 3 shows significantly higher cytotoxicity against breast cancer cells then for non-tumorigenic breast epithelial cells. The cytotoxic activity of ligand seems to be not associated with telomerase inhibition. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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26 pages, 5078 KiB

Open AccessFeature PaperArticle

Molecular Recognition of Parallel G-quadruplex [d-(TTGGGGT)]₄ Containing Tetrahymena Telomeric DNA Sequence by Anticancer Drug Daunomycin: NMR-Based Structure and Thermal Stability

by Ritu Barthwal and Zia Tariq

Molecules 2018, 23(9), 2266; https://doi.org/10.3390/molecules23092266 - 5 Sep 2018

Cited by 16 | Viewed by 4772

Abstract

The anticancer drug daunomycin exerts its influence by multiple strategies of action to interfere with gene functioning. Besides inhibiting DNA/RNA synthesis and topoisomerase-II, it affects the functional pathway of telomere maintenance by the telomerase enzyme. We present evidence of the binding of daunomycin [...] Read more.

The anticancer drug daunomycin exerts its influence by multiple strategies of action to interfere with gene functioning. Besides inhibiting DNA/RNA synthesis and topoisomerase-II, it affects the functional pathway of telomere maintenance by the telomerase enzyme. We present evidence of the binding of daunomycin to parallel-stranded tetramolecular [d-(TTGGGGT)]₄ guanine (G)-quadruplex DNA comprising telomeric DNA from Tetrahymena thermophilia by surface plasmon resonance and Diffusion Ordered SpectroscopY (DOSY). Circular Dichroism (CD) spectra show the disruption of daunomycin dimers, suggesting the end-stacking and groove-binding of the daunomycin monomer. Proton and phosphorus-31 Nuclear Magnetic Resonance (NMR) spectroscopy show a sequence-specific interaction and a clear proof of absence of intercalation of the daunomycin chromophore between base quartets or stacking between G-quadruplexes. Restrained molecular dynamics simulations using observed short interproton distance contacts depict interaction at the molecular level. The interactions involving ring A and daunosamine protons, the stacking of an aromatic ring of daunomycin with a terminal G6 quartet by displacing the T7 base, and external groove-binding close to the T1–T2 bases lead to the thermal stabilization of 15 °C, which is likely to inhibit the association of telomerase with telomeres. The findings have implications in the structure-based designing of anthracycline drugs as potent telomerase inhibitors. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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6 pages, 910 KiB

Open AccessArticle

HnRNPA1 Specifically Recognizes the Base of Nucleotide at the Loop of RNA G-Quadruplex

by Xiao Liu and Yan Xu

Molecules 2018, 23(1), 237; https://doi.org/10.3390/molecules23010237 - 22 Jan 2018

Cited by 20 | Viewed by 7326

Abstract

Human telomere RNA performs various cellular functions, such as telomere length regulation, heterochromatin formation, and end protection. We recently demonstrated that the loops in the RNA G-quadruplex are important in the interaction of telomere RNA with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Here, we [...] Read more.

Human telomere RNA performs various cellular functions, such as telomere length regulation, heterochromatin formation, and end protection. We recently demonstrated that the loops in the RNA G-quadruplex are important in the interaction of telomere RNA with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Here, we report on a detailed analysis of hnRNPA1 binding to telomere RNA G-quadruplexes with a group of loop variants using an electrophoretic mobility shift assay (EMSA) and circular dichroism (CD) spectroscopy. We found that the hnRNPA1 binds to RNA G-quadruplexes with the 2’-O-methyl and DNA loops, but fails to bind with the abasic RNA and DNA loops. These results suggested that hnRNPA1 binds to the loop of the RNA G-quadruplex by recognizing the base of the loop’s nucleotides. The observation provides the first evidence that the base of the loop’s nucleotides is a key factor for hnRNPA1 specifically recognizing the RNA G-quadruplex. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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2846 KiB

Open AccessFeature PaperArticle

Design, Synthesis and Biological Evaluation of New Substituted Diquinolinyl-Pyridine Ligands as Anticancer Agents by Targeting G-Quadruplex

by Rabindra Nath Das, Edith Chevret, Vanessa Desplat, Sandra Rubio, Jean-Louis Mergny and Jean Guillon

Molecules 2018, 23(1), 81; https://doi.org/10.3390/molecules23010081 - 30 Dec 2017

Cited by 18 | Viewed by 4958

Abstract

G-quadruplexes (G4) are stacked non-canonical nucleic acid structures found in specific G-rich DNA or RNA sequences in the human genome. G4 structures are liable for various biological functions; transcription, translation, cell aging as well as diseases such as cancer. These structures are therefore [...] Read more.

G-quadruplexes (G4) are stacked non-canonical nucleic acid structures found in specific G-rich DNA or RNA sequences in the human genome. G4 structures are liable for various biological functions; transcription, translation, cell aging as well as diseases such as cancer. These structures are therefore considered as important targets for the development of anticancer agents. Small organic heterocyclic molecules are well known to target and stabilize G4 structures. In this article, we have designed and synthesized 2,6-di-(4-carbamoyl-2-quinolyl)pyridine derivatives and their ability to stabilize G4-structures have been determined through the FRET melting assay. It has been established that these ligands are selective for G4 over duplexes and show a preference for the parallel conformation. Next, telomerase inhibition ability has been assessed using three cell lines (K562, MyLa and MV-4-11) and telomerase activity is no longer detected at 0.1 μM concentration for the most potent ligand 1c. The most promising G4 ligands were also tested for antiproliferative activity against the two human myeloid leukaemia cell lines, HL60 and K562. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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2287 KiB

Open AccessArticle

Investigation of ‘Head-to-Tail’-Connected Oligoaryl N,O-Ligands as Recognition Motifs for Cancer-Relevant G-Quadruplexes

by Natalia Rizeq and Savvas N. Georgiades

Molecules 2017, 22(12), 2160; https://doi.org/10.3390/molecules22122160 - 6 Dec 2017

Cited by 13 | Viewed by 4521

Abstract

Oligomeric compounds, constituted of consecutive N,O-heteroaromatic rings, introduce useful and tunable properties as alternative ligands for biomolecular recognition. In this study, we have explored a synthetic scheme relying on Van Leusen oxazole formation, in conjunction with C–H activation of the [...] Read more.

Oligomeric compounds, constituted of consecutive N,O-heteroaromatic rings, introduce useful and tunable properties as alternative ligands for biomolecular recognition. In this study, we have explored a synthetic scheme relying on Van Leusen oxazole formation, in conjunction with C–H activation of the formed oxazoles and their subsequent C–C cross-coupling to 2-bromopyridines in order to assemble a library of variable-length, ‘head-to-tail’-connected, pyridyl-oxazole ligands. Through investigation of the interaction of the three longer ligands (5-mer, 6-mer, 7-mer) with cancer-relevant G-quadruplex structures (human telomeric/22AG and c-Myc oncogene promoter/Myc2345-Pu22), the asymmetric pyridyl-oxazole motif has been demonstrated to be a prominent recognition element for G-quadruplexes. Fluorescence titrations reveal excellent binding affinities of the 7-mer and 6-mer for a Na⁺-induced antiparallel 22AG G-quadruplex (K_D = 0.6 × 10⁻⁷ M⁻¹ and 0.8 × 10⁻⁷ M⁻¹, respectively), and satisfactory (albeit lower) affinities for the 22AG/K⁺ and Myc2345-Pu22/K⁺ G-quadruplexes. All ligands tested exhibit substantial selectivity for G-quadruplex versus duplex (ds26) DNA, as evidenced by competitive Förster resonance energy transfer (FRET) melting assays. Additionally, the 7-mer and 6-mer are capable of promoting a sharp morphology transition of 22AG/K⁺ G-quadruplex. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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Review

Jump to: Research

15 pages, 4508 KiB

Open AccessFeature PaperReview

Molecular Recognition of the Hybrid-Type G-Quadruplexes in Human Telomeres

by Guanhui Wu, Luying Chen, Wenting Liu and Danzhou Yang

Molecules 2019, 24(8), 1578; https://doi.org/10.3390/molecules24081578 - 22 Apr 2019

Cited by 15 | Viewed by 6243

Abstract

G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form [...] Read more.

G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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15 pages, 4835 KiB

Open AccessReview

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

by Pallavi Chilka, Nakshi Desai and Bhaskar Datta

Molecules 2019, 24(4), 752; https://doi.org/10.3390/molecules24040752 - 19 Feb 2019

Cited by 57 | Viewed by 6435

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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17 pages, 1664 KiB

Open AccessReview

Promise of G-Quadruplex Structure Binding Ligands as Epigenetic Modifiers with Anti-Cancer Effects

by Antara Sengupta, Akansha Ganguly and Shantanu Chowdhury

Molecules 2019, 24(3), 582; https://doi.org/10.3390/molecules24030582 - 6 Feb 2019

Cited by 31 | Viewed by 7569

Abstract

Evidences from more than three decades of work support the function of non-duplex DNA structures called G-quadruplex (G4) in important processes like transcription and replication. In addition, G4 structures have been studied in connection with DNA base modifications and chromatin/nucleosome arrangements. Recent work, [...] Read more.

Evidences from more than three decades of work support the function of non-duplex DNA structures called G-quadruplex (G4) in important processes like transcription and replication. In addition, G4 structures have been studied in connection with DNA base modifications and chromatin/nucleosome arrangements. Recent work, interestingly, shows promise of G4 structures, through interaction with G4 structure-interacting proteins, in epigenetics—in both DNA and histone modification. Epigenetic changes are found to be intricately associated with initiation as well as progression of cancer. Multiple oncogenes have been reported to harbor the G4 structure at regulatory regions. In this context, G4 structure-binding ligands attain significance as molecules with potential to modify the epigenetic state of chromatin. Here, using examples from recent studies we discuss the emerging role of G4 structures in epigenetic modifications and, therefore, the promise of G4 structure-binding ligands in epigenetic therapy. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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29 pages, 4440 KiB

Open AccessFeature PaperReview

Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy

by Sefan Asamitsu, Shunsuke Obata, Zutao Yu, Toshikazu Bando and Hiroshi Sugiyama

Molecules 2019, 24(3), 429; https://doi.org/10.3390/molecules24030429 - 24 Jan 2019

Cited by 220 | Viewed by 14233

Abstract

A G-quadruplex (G4) is a well-known nucleic acid secondary structure comprising guanine-rich sequences, and has profound implications for various pharmacological and biological events, including cancers. Therefore, ligands interacting with G4s have attracted great attention as potential anticancer therapies or in molecular probe applications. [...] Read more.

A G-quadruplex (G4) is a well-known nucleic acid secondary structure comprising guanine-rich sequences, and has profound implications for various pharmacological and biological events, including cancers. Therefore, ligands interacting with G4s have attracted great attention as potential anticancer therapies or in molecular probe applications. To date, a large variety of DNA/RNA G4 ligands have been developed by a number of laboratories. As protein-targeting drugs face similar situations, G-quadruplex-interacting drugs displayed low selectivity to the targeted G-quadruplex structure. This low selectivity could cause unexpected effects that are usually reasons to halt the drug development process. In this review, we address the recent research on synthetic G4 DNA-interacting ligands that allow targeting of selected G4s as an approach toward the discovery of highly effective anticancer drugs. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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26 pages, 16334 KiB

Open AccessFeature PaperReview

Naphthalene Diimides as Multimodal G-Quadruplex-Selective Ligands

by Valentina Pirota, Matteo Nadai, Filippo Doria and Sara N. Richter

Molecules 2019, 24(3), 426; https://doi.org/10.3390/molecules24030426 - 24 Jan 2019

Cited by 61 | Viewed by 8097

Abstract

G-quadruplexes are four-stranded nucleic acids structures that can form in guanine-rich sequences. Following the observation that G-quadruplexes are particularly abundant in genomic regions related to cancer, such as telomeres and oncogenes promoters, several G-quadruplex-binding molecules have been developed for therapeutic purposes. Among them, [...] Read more.

G-quadruplexes are four-stranded nucleic acids structures that can form in guanine-rich sequences. Following the observation that G-quadruplexes are particularly abundant in genomic regions related to cancer, such as telomeres and oncogenes promoters, several G-quadruplex-binding molecules have been developed for therapeutic purposes. Among them, naphthalene diimide derivatives have reported versatility, consistent selectivity and high affinity toward the G-quadruplex structures. In this review, we present the chemical features, synthesis and peculiar optoelectronic properties (absorption, emission, redox) that make naphtalene diimides so versatile for biomedical applications. We present the latest developments on naphthalene diimides as G-quadruplex ligands, focusing on their ability to bind G-quadruplexes at telomeres and oncogene promoters with consequent anticancer activity. Their different binding modes (reversible versus irreversible/covalent) towards G-quadruplexes and their additional use as antimicrobial agents are also presented and discussed. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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29 pages, 8049 KiB

Open AccessReview

Developing Novel G-Quadruplex Ligands: From Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction

by Zhi-Yin Sun, Xiao-Na Wang, Sui-Qi Cheng, Xiao-Xuan Su and Tian-Miao Ou

Molecules 2019, 24(3), 396; https://doi.org/10.3390/molecules24030396 - 22 Jan 2019

Cited by 101 | Viewed by 14720

Abstract

G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has [...] Read more.

G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has become a novel promising anti-tumor strategy. Different kinds of small molecules targeting the G-quadruplexes have been designed, synthesized, and identified as potential anti-tumor agents, including molecules directly bind to the G-quadruplex and molecules interfering with the binding between the G-quadruplex structures and related binding proteins. This review will explore the feasibility of G-quadruplex ligands acting as anti-tumor drugs, from basis to application. Meanwhile, since helicase is the most well-defined G-quadruplex-related protein, the most extensive research on the relationship between helicase and G-quadruplexes, and its meaning in drug design, is emphasized. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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19 pages, 1793 KiB

Open AccessReview

Natural Alkaloids and Heterocycles as G-Quadruplex Ligands and Potential Anticancer Agents

by Tong Che, Yu-Qing Wang, Zhou-Li Huang, Jia-Heng Tan, Zhi-Shu Huang and Shuo-Bin Chen

Molecules 2018, 23(2), 493; https://doi.org/10.3390/molecules23020493 - 23 Feb 2018

Cited by 45 | Viewed by 6804

Abstract

G-quadruplexes are four-stranded nucleic acid secondary structures that are formed in guanine-rich sequences. G-quadruplexes are widely distributed in functional regions of the human genome and transcriptome, such as human telomeres, oncogene promoter regions, replication initiation sites, and untranslated regions. Many G-quadruplex-forming sequences are [...] Read more.

G-quadruplexes are four-stranded nucleic acid secondary structures that are formed in guanine-rich sequences. G-quadruplexes are widely distributed in functional regions of the human genome and transcriptome, such as human telomeres, oncogene promoter regions, replication initiation sites, and untranslated regions. Many G-quadruplex-forming sequences are found to be associated with cancer, and thus, these non-canonical nucleic acid structures are considered to be attractive molecular targets for cancer therapeutics with novel mechanisms of action. In this mini review, we summarize recent advances made by our lab in the study of G-quadruplex-targeted natural alkaloids and their derivatives toward the development of potential anticancer agents. Full article

(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)

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