Synthesis and Molecular Modeling of Thermally Stable DNA G‐Quadruplexes with Anthraquinone Insertions

Gouda, Alaa S.; Amine, M. S.; Pedersen, Erik B.

doi:10.1002/ejoc.201700065

Cited by 5 publications

(4 citation statements)

References 69 publications

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“…The aptamers containing the 1,8-linker at G8 or T9 in the TGT loop had improved anticoagulant activity [ 218 ]. Gouda et al [ 219 ] also replaced the TT and TGT loops of the TBA GQ with novel 1,5- and 2,6-disubstituted anthraquinones. Single substitutions destabilized, while anthraquinones in two TT loops led to 1–18°C increase in T m of the parent GQ without changing the original topology.…”

Section: Stabilization or Destabilization Of A Gq By The Same Syntmentioning

confidence: 99%

In What Ways Do Synthetic Nucleotides and Natural Base Lesions Alter the Structural Stability of G-Quadruplex Nucleic Acids?

Sági¹

2017

Journal of Nucleic Acids

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Synthetic analogs of natural nucleotides have long been utilized for structural studies of canonical and noncanonical nucleic acids, including the extensively investigated polymorphic G-quadruplexes (GQs). Dependence on the sequence and nucleotide modifications of the folding landscape of GQs has been reviewed by several recent studies. Here, an overview is compiled on the thermodynamic stability of the modified GQ folds and on how the stereochemical preferences of more than 70 synthetic and natural derivatives of nucleotides substituting for natural ones determine the stability as well as the conformation. Groups of nucleotide analogs only stabilize or only destabilize the GQ, while the majority of analogs alter the GQ stability in both ways. This depends on the preferred syn or anti N-glycosidic linkage of the modified building blocks, the position of substitution, and the folding architecture of the native GQ. Natural base lesions and epigenetic modifications of GQs explored so far also stabilize or destabilize the GQ assemblies. Learning the effect of synthetic nucleotide analogs on the stability of GQs can assist in engineering a required stable GQ topology, and exploring the in vitro action of the single and clustered natural base damage on GQ architectures may provide indications for the cellular events.

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Section: Stabilization or Destabilization Of A Gq By The Same Syntmentioning

confidence: 99%

In What Ways Do Synthetic Nucleotides and Natural Base Lesions Alter the Structural Stability of G-Quadruplex Nucleic Acids?

Sági¹

2017

Journal of Nucleic Acids

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“…From the modern therapeutic organic synthesis point of view and our previous work to modify DNA, [4][5][6] synthesis of modified DNA bases guanosine 1 and adenosine 6 derivatives was carried out. The Sonogashira reaction was carried out on the 2-pent-4-ynyl-isoindole-1,3-dione 2 with bromoguanosine 1 and bromoadenosine 6 using copper iodide and tetrakis(triphenylphosphine) palladium(0) Pd(PPh3)4 in the presence of triethyl amine to synthesize compound 3 and 7 (Scheme 1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Modification of DNA and RNA oligonucleotides with new synthesized heterocyclic compounds have drawn significant interest owing to their ability to imitate new gene chemical probes that play an important role in the drug discovery process [1][2][3][4][5][6][7]. Gene-therapy in recent research was based on DNA and its modification [8][9][10].…”

Section: ■ Introductionmentioning

confidence: 99%

“…Gene-therapy in recent research was based on DNA and its modification [8][9][10]. The thymidine ring is a DNA building block that interests many researchers to focused their research on the synthesis of new pyrimidine rings as anti-cancer agents such as 5-fluorouracil [1][2][3][4][5][6][7][8][9][10][11][12][13][14], and anti-HIV like AZT, D4T, Nikavir [15][16][17][18][19][20][21], Lamivudina [22] and Emtricitabina [16,[23][24]. The Nitrogen containing heterocycles like pyrimidines and their derivatives have received great attention for their considerable exciting biological activities [25][26][27][28].…”

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis, Characterization and Docking Study of Novel Pyrimidine Derivatives as Anticancer Agents

et al. 2020

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New compounds 5 and 9 using DNA bases e.g. Adenine 1 and Guanine 6 derivatives have been synthesized. The use of simple methods to synthesize compounds 5 and 9 were done using pyrimidine as an alternative DNA base ring. Another design to synthesize new simple pyrimidine rings utilizing thiourea and ethylcyano acetate to afford 6-amino-2-thiouracil was adopted. The reaction of thiouracil 10 with chloro cyano or chloro ester and ketone, resulted in the formation of adduct compounds 18-21, rather than the formation of compound 17. All the synthesized compounds were subjected to docking study, in order to gain insights into their binding modes against cyclin-dependent protein kinase 2 (CDK-2) that is involved heavily in cell cycle regulation and receptor protein B-cell lymphoma 2 (BCL-2) which is involved in cell apoptosis. These targets were selected based on their key roles in cancer progression via the regulation of the cell cycle and DNA replication. Molecular-docking analyses showed that compound 14e was the best docked ligand against both targets, as it displayed the lowest binding energy, critical hydrogen bonds and hydrophobic interactions with the targets.

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Improved i-motif thermal stability by insertion of anthraquinone monomers

2017

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In order to gain insight into how to improve thermal stability of i-motifs when used in the context of biomedical and nanotechnological applications, novel anthraquinone-modified i-motifs were synthesized by insertion of 1,8-, 1,4-, 1,5- and 2,6-disubstituted anthraquinone monomers into the TAA loops of a 22mer cytosine-rich human telomeric DNA sequence. The influence of the four anthraquinone linkers on the i-motif thermal stability was investigated at 295 nm and pH 5.5. Anthraquinone monomers modulate the i-motif stability in a position-depending manner and the modulation also depends on the substitution pattern of the anthraquinone. The insertion of anthraquinone was found to stabilize the i-motif structure when replacing any one of the positions of the central TAA loop and the thermal stabilities were typically higher than those previously found for i-motifs containing pyrene-modified uracilyl unlocked nucleic acid monomers or twisted intercalating nucleic acid. The 2,6-disubstituted anthraquinone linker replacing T enabled a significant increase of i-motif thermal melting by 8.2 °C. A substantial increase of 5.0 °C in i-motif thermal melting was recorded when both A and T were modified with a double replacement by the 2,6-isomer into the TAA loops in the outer regions. The largest destabilization is observed for the 1,5-disubstituted anthraquinone linker upon the replacement of A. CD curves of anthraquinone-modified variants imply no structural changes in all cases under potassium buffer conditions compared with those of the native i-motif. Molecular modeling studies explained the increased thermal stabilities of anthraquinone-modified i-motifs.

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Synthesis and Molecular Modeling of Thermally Stable DNA G‐Quadruplexes with Anthraquinone Insertions

Cited by 5 publications

References 69 publications

In What Ways Do Synthetic Nucleotides and Natural Base Lesions Alter the Structural Stability of G-Quadruplex Nucleic Acids?

In What Ways Do Synthetic Nucleotides and Natural Base Lesions Alter the Structural Stability of G-Quadruplex Nucleic Acids?

Synthesis, Characterization and Docking Study of Novel Pyrimidine Derivatives as Anticancer Agents

Improved i-motif thermal stability by insertion of anthraquinone monomers

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