Fluorine in medicinal chemistry: β-fluorination of peripheral pyrrolidines attached to acridine ligands affects their interactions with G-quadruplex DNA

Campbell, N.H.; Smith, Daniel L.; Reszka, Anthony P.; Neidle, Stephen; O’Hagan, David

doi:10.1039/c0ob00886a

Cited by 63 publications

(42 citation statements)

References 34 publications

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“…Yet, judgments on these FIGURE 10-2 Structure of an Oxytricha nova quadruplex-ligand complex (Campbell et al, 2011 ), at 1.10 Å resolution, viewed into one of the grooves and showing the water molecules (as small spheres) in the 1st and 2nd coordination shell. Hydrogen bonds are designated by thin lines.…”

Section: Single-crystal Methodsmentioning

confidence: 99%

“…It should not be assumed though that the use of MPD, PEG or other crowding agents, either in the conditions of crystal growth or in solution, in itself produces an innate tendency for parallel structures. The bimolecular quadruplex from Oxytricha nova has been crystallized as a native structure (Haider, Parkinson & Neidle, 2002) and with a number of ligands (for example, Campbell et al, 2011), always in the presence of MPD. All these quadruplexes have an anti-parallel topology with diagonal loops, identical to that observed in solution by NMR methods in the absence of MPD (Schultze et al, 1999).…”

Section: Single-crystal Methodsmentioning

confidence: 99%

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The Determination of Quadruplex Structures

Neidle

2012

Therapeutic Applications of Quadruplex Nucleic Acids

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Section: Single-crystal Methodsmentioning

confidence: 99%

Section: Single-crystal Methodsmentioning

confidence: 99%

The Determination of Quadruplex Structures

Neidle

2012

Therapeutic Applications of Quadruplex Nucleic Acids

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“…For example, O’Hagan and co-workers investigated the pyrrolidine-containing molecules 9 and 10 (Fig. 3) as ligands of G-quadruplex DNA [22]. The non-fluorinated ligand 9 had some conformational disorder because the pyrrolidine rings were able to interconvert between exo and endo puckers.…”

Section: Reviewmentioning

confidence: 99%

Stereoselectively fluorinated N-heterocycles: a brief survey

Hu¹,

Hunter²

2013

Beilstein J. Org. Chem.

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SummaryThe stereoselective incorporation of fluorine atoms into N-heterocycles can lead to dramatic changes in the molecules’ physical and chemical properties. These changes can be rationally exploited for the benefit of diverse fields such as medicinal chemistry and organocatalysis. This brief review will examine some of the effects that fluorine substitution can have in N-heterocycles, including changes to the molecules’ stability, their conformational behaviour, their hydrogen bonding ability, and their basicity. Finally, some methods for the synthesis of stereoselectively fluorinated N-heterocycles will also be reviewed.

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“…By analyzing crystal (1L1H [107], 1PH4, 1PH6, 1PH8 [108], 1JB7 [103], 2HBN [109], 3EUM [106], 3NYP [110]) and NMR (156D [111], 230D [112], 1K4X [113], 2AKG [114]) structures we were able to construct a consensus conformational map (Figure 3(d) and (e)) showing the succession of conformers in the O. nova G-quadruplex. From the studied pool of structures, four (3EUM, 3NYP, 1L1H, and 3NZ7) represent a complex of the G-quadruplex with a drug acridine, while the rest are not complexed.…”

Section: Resultsmentioning

confidence: 99%

Automatic workflow for the classification of local DNA conformations

et al. 2013

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BackgroundA growing number of crystal and NMR structures reveals a considerable structural polymorphism of DNA architecture going well beyond the usual image of a double helical molecule. DNA is highly variable with dinucleotide steps exhibiting a substantial flexibility in a sequence-dependent manner. An analysis of the conformational space of the DNA backbone and the enhancement of our understanding of the conformational dependencies in DNA are therefore important for full comprehension of DNA structural polymorphism.ResultsA detailed classification of local DNA conformations based on the technique of Fourier averaging was published in our previous work. However, this procedure requires a considerable amount of manual work. To overcome this limitation we developed an automatic classification method consisting of the combination of supervised and unsupervised approaches. A proposed workflow is composed of k-NN method followed by a non-hierarchical single-pass clustering algorithm. We applied this workflow to analyze 816 X-ray and 664 NMR DNA structures released till February 2013. We identified and annotated six new conformers, and we assigned four of these conformers to two structurally important DNA families: guanine quadruplexes and Holliday (four-way) junctions. We also compared populations of the assigned conformers in the dataset of X-ray and NMR structures.ConclusionsIn the present work we developed a machine learning workflow for the automatic classification of dinucleotide conformations. Dinucleotides with unassigned conformations can be either classified into one of already known 24 classes or they can be flagged as unclassifiable. The proposed machine learning workflow permits identification of new classes among so far unclassifiable data, and we identified and annotated six new conformations in the X-ray structures released since our previous analysis. The results illustrate the utility of machine learning approaches in the classification of local DNA conformations.

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Fluorine in medicinal chemistry: β-fluorination of peripheral pyrrolidines attached to acridine ligands affects their interactions with G-quadruplex DNA

Cited by 63 publications

References 34 publications

The Determination of Quadruplex Structures

The Determination of Quadruplex Structures

Stereoselectively fluorinated N-heterocycles: a brief survey

Automatic workflow for the classification of local DNA conformations

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