Expanding the Hoogsteen Edge of 2‘-Deoxyguanosine:  Consequences for G-Quadruplex Formation

Gubala, Vladimir; Betancourt, José E.; Rivera, José M.

doi:10.1021/ol048013v

Cited by 58 publications

(61 citation statements)

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“…Compound 1 was synthesized and purified as previously reported. 31 NMR spectra were recorded on spectrometers equipped with either a 5 mm BBO or a TXI probe, with nominal frequencies of 500.13 MHz for proton and 125 MHz for carbon respectively. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 procedure for the AMBER force field, as implemented in RED III.…”

Section: Methodsmentioning

confidence: 99%

“…30 The Davis group have also reported that a 4T-SGQ or hexadecamer could be form via the putative picrate- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 We have developed an alternative approach towards modulating the structure of SGQs that relies in replacing the H8 in the guanine moiety with a functionalized phenyl group. 31 The position of the functional group on the phenyl ring enables modulation of the molecularity and stability (thermal and kinetic) of the resulting supramolecules. For example, in the presence of potassium cations the mAG (metaacetylphenyl) scaffold promotes the formation of a four-tetrad (4T) SGQ or hexadecamer in both organic and aqueous environments.…”

Section: Introductionmentioning

confidence: 99%

“…33 In contrast, the isomeric derivative 3 (para-acetylphenyl) leads the formation of 2T-SGQs or octamers (Figure 1). 31 Herein we report NMR spectroscopic and molecular dynamics simulation (MDS) studies to determine the three-dimensional structure of various 4T-SGQs, in order to provide a detail molecular level explanation for these phenomena. We show that the balance between attractive and repulsive interactions is responsible for the self-terminating behavior and high stability of these supramolecules.…”

Section: Introductionmentioning

confidence: 99%

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Structural Studies of Supramolecular G-Quadruplexes Formed from 8-Aryl-2′-deoxyguanosine Derivatives

2016

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Self-assembly is a powerful tool for the construction of complex nanostructures. Despite advances in the field, the development of precise self-assembled structures remains a challenge. We have shown that, in the presence of suitably sized cations like K(+), 8-aryl-2'-deoxyguanosine (8ArG) derivatives self-assemble into sets of coaxially stacked planar tetramers, which we term supramolecular G-quadruplexes (SGQs). Previously, we reported that, when the 8-aryl group is a phenyl ring with a meta-carbonyl group, the resulting supramolecule is a hexadecamer, which is remarkably robust as illustrated by its isostructural assembly in both organic and aqueous environments. We report here a detailed three-dimensional structure of the SGQs formed by lipophilic, and hydrophilic, 8ArG derivatives with either 8-(meta-acetylphenyl), 8-(para-acetylphenyl), or 8-(meta-ethoxycarbonylphenyl) groups. The chirality and close contacts between the subunits impose different levels of steric and electrostatic constraints on opposite sides of the tetrads, which determine their preferred relative orientation. The balance between attractive noncovalent interactions juxtaposed with repulsive steric and electrostatic interactions explains the high cooperativity, fidelity, and stability of these SGQs. These structural studies, together with titration experiments and molecular dynamics simulations, provide insight into the mechanism of formation of these SGQs.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural Studies of Supramolecular G-Quadruplexes Formed from 8-Aryl-2′-deoxyguanosine Derivatives

2016

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“…We have shown that functional groups within an 8-phenyl ring can lead to supramolecular complexes with higher stability. 7 Since Shaughnessy's method 9 of using the easily prepared 8-bromo-2′-deoxyguanosine 10 and commercially available boronic acids had proven successful in the synthesis of 8-aromatic-2′-deoxyguanosine analogues (8-ArdG), 7 we decided to apply it to the synthesis of 8-(HetAr)dG targets. However, although the method is useful in the coupling of a variety of heterocycles vide infra, we quickly realized that we needed to use a different method to couple the 2-pyridyl moiety.…”

mentioning

confidence: 99%

Synthesis of 8-Heteroaryl-2′-deoxyguanosine Derivatives

Hobley¹,

Gubala²,

Rivera-Sánchez³

et al. 2008

Synlett

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We describe the synthesis of 8-heteroaromatic-2′-deoxyguanosine analogues using Suzuki-Miyaura or Stille conditions. Unprotected and protected 8-bromo-2′-deoxyguanosine was coupled with commercially available heteroarylboronic acids or the trialkyltin derivatives of 2-pyridylbromides either with or without microwave irradiation in good yields. KeywordsStille reaction; nucleosides; nucleobases; palladium; coupling The development of efficient strategies for the synthesis of nucleoside analogues is of great importance due to their potential uses in biological applications. For example, many nucleoside analogues have found uses as antibiotics and antivirals,1 as probes for nucleic acid structure2 and as chain terminators for DNA sequencing. 3 Our main interest is in guanine and its derivatives, which arises from the fact that they can self-associate to form macrocyclic, planar tetramers known as G-tetrads. These further associate through π-stacking interactions to form G-quadruplexes (GQs). These GQs can be formed from individual guanine subunits or from G-rich oligonucleotides that fold up into a variety of quadruplex structures. 4 The cation templated self-assembly of guanosines into G-quadruplexes has been recognized since the 1960's.5 More recent studies of G-quadruplex formation have been in diverse areas such as cancer research and nanotechnology.4 , 6 We have demonstrated the aggregation of 8-aromatic-2′-deoxyguanosine analogues in organic solvents 7 and have shown their selective binding of cations in some cases. 8 We are particularly interested in the synthesis of 8-heteroaromatic-2′-deoxyguanosine (8-(HetAr)dG) derivatives. Heteroatoms and functional groups in the heteroaryl moieties can be used to increase the number of H-bonds. We have shown that functional groups within an 8-phenyl ring can lead to supramolecular complexes with higher stability. 7 Since Shaughnessy's method 9 of using the easily prepared 8-bromo-2′-deoxyguanosine (8-BrdG) 10 and commercially available boronic acids had proven successful in the synthesis of 8-aromatic-2′-deoxyguanosine analogues (8-ArdG), 7 we decided to apply it to the synthesis of 8-(HetAr)dG targets. However, although the method is useful in the coupling of a variety of heterocycles vide infra, we quickly realized that we needed to use a different method to couple the 2-pyridyl moiety. Because of the expense, reported instability 11 and relative scarcity of commercially available, functionalized 2-pyridyl boronic acids we decided to use Stille conditions as an alternative method. 12 This is not without precedent since the Stille methodology has been used for 2-pyridylstannane couplings to various aromatic skeletons 13

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“…Through Hoogsteen hydrogen bonding, four nonadjacent guanines can associate with one another, forming a guanine tetrad. Furthermore, these guanine tetrads are capable of stacking upon one another, establishing a G-quadruplex (Gubala, 2004). These structures occur naturally throughout the human genome, most notably in telomeres, which are found at the ends of chromosomes, as well as in the promoter regions of an estimated 43% of all genes, including VEGF.…”

Section: Oligonucleotide Therapymentioning

confidence: 99%

The VEGF quadruplex-forming sequence inhibits lung cancer cell growth.

Muench

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ACKNOWLEDGEMENTSFirst off, I would like to thank Dr. Donald Miller for taking me on as a co-op student and introducing me to the vitally important and fascinating world of cancer research. He not only helped me discover my dream job, but he has also set an outstanding example of how to be an extraordinary physician scientist that I one day hope to take after. I also want to thank all of the members of the Miller/Bates lab who have helped me learn how fun life can be as a scientist and have inspired me to keep improving no matter what. Thank you to Sheila Thomas for her help with the stability experiments, and to Dr. Tariq Malik for his help with the in vivo imaging studies. Special thanks to Dr. Kara Sedoris, who had the patience and fortitude to work with me every day. I enjoyed every minute of it, and couldn't have done it without her! I also want to thank Dr. Frieboes and Dr. Panchapakesan for being part of my committee. I appreciate all of your hard work and advice which has been extremely helpful. I also want to thank Dr. Andre Gobin for being such a great professor and for sponsoring my independent study, which was a very enjoyable experience! To determine the biological role of VEGFq on non-small cell lung cancer in vivo, A549 cells were injected into nude mice and grown for 10 days prior to daily IP injections of 10 mg/kg VEGFq or the control vehicle for 14 days. Tumor progression was physically measured using calipers three times a week. Fluorescent imaging was used to detect the presence, stability, and distribution of Alexa Fluor 750-labeled VEGFq after injection into the mouse to ensure localization in the targeted tumor.These results demonstrate that A549 cells treated with VEGF quadruplex-forming oligonucleotides experience a dramatic decrease in cell proliferation, suggesting that VEGFq may have significant therapeutic implications for the treatment of non-small cell lung cancer.

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Expanding the Hoogsteen Edge of 2‘-Deoxyguanosine: Consequences for G-Quadruplex Formation

Cited by 58 publications

References 20 publications

Structural Studies of Supramolecular G-Quadruplexes Formed from 8-Aryl-2′-deoxyguanosine Derivatives

Structural Studies of Supramolecular G-Quadruplexes Formed from 8-Aryl-2′-deoxyguanosine Derivatives

Synthesis of 8-Heteroaryl-2′-deoxyguanosine Derivatives

The VEGF quadruplex-forming sequence inhibits lung cancer cell growth.

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