Thread Insertion of a Bis(dipyridophenazine) Diruthenium Complex into the DNA Double Helix by the Extrusion of AT Base Pairs and Cross‐Linking of DNA Duplexes

Boer, Roeland; Wu, Lijuan; Lincoln, Per; Coll, Miquel

doi:10.1002/anie.201308070

Cited by 44 publications

(24 citation statements)

References 29 publications

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“…Conventional intercalators, such as acridine1 and ethidium234, bind into the DNA lattice by direct insertion of planar aromatic moieties between the base pairs, for which the primary rate limiting step is breathing of the DNA double helix. In contrast, unconventional intercalators require further DNA deformation during association in order to accommodate bulky non-intercalating moieties, for example fitting cyclic polypeptide chains in DNA grooves, or breaking base pairs to thread a bulky moiety through DNA, before reaching the final intercalated state567. This strong DNA deformation is the primary rate-limiting step, giving unconventional intercalators much slower binding and dissociation from the final intercalated state, which is a desirable property for many DNA applications, including anti-cancer drugs8910.…”

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confidence: 99%

DNA intercalation optimized by two-step molecular lock mechanism

Almaqwashi

Andersson

Lincoln

et al. 2016

Sci Rep

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The diverse properties of DNA intercalators, varying in affinity and kinetics over several orders of magnitude, provide a wide range of applications for DNA-ligand assemblies. Unconventional intercalation mechanisms may exhibit high affinity and slow kinetics, properties desired for potential therapeutics. We used single-molecule force spectroscopy to probe the free energy landscape for an unconventional intercalator that binds DNA through a novel two-step mechanism in which the intermediate and final states bind DNA through the same mono-intercalating moiety. During this process, DNA undergoes significant structural rearrangements, first lengthening before relaxing to a shorter DNA-ligand complex in the intermediate state to form a molecular lock. To reach the final bound state, the molecular length must increase again as the ligand threads between disrupted DNA base pairs. This unusual binding mechanism results in an unprecedented optimized combination of high DNA binding affinity and slow kinetics, suggesting a new paradigm for rational design of DNA intercalators.

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DNA intercalation optimized by two-step molecular lock mechanism

Almaqwashi

Andersson

Lincoln

et al. 2016

Sci Rep

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“…Barton's group has also discovered various types of Rh III compounds targeting A:A mismatches which eject mismatched adenosines into the major groove . On the other hand, the octahedral Ru‐dppz complexes have been found to intercalate into the DNA stack, accompanied with the extrusion of the terminal thymine and adenine residues . Interestingly, all of the above compounds are intercalators and not groove binders.…”

Section: Figurementioning

confidence: 99%

Induced‐Fit Recognition of CCG Trinucleotide Repeats by a Nickel–Chromomycin Complex Resulting in Large‐Scale DNA Deformation

Tseng

Chang

et al. 2017

Angewandte Chemie

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Small-molecule compounds targeting trinucleotide repeats in DNAh ave considerable potential as therapeutic or diagnostic agents against many neurological diseases.N i II -(Chro) 2 (Chro = chromomycin A3) binds specifically to the minor grooveof(CCG) n repeats in duplex DNA, with unique fluorescence features that mays erve as ap robe for disease detection. Crystallographic studies revealed that the specificity originates from the large-scale spatial rearrangement of the DNAs tructure,i ncluding extrusion of consecutive bases and backbone distortions,w ith as harp bending of the duplex accompanied by conformational changes in the Ni II chelate itself.T he DNAd eformation of CCG repeats upon binding forms aG GCC tetranucleotide tract, which is recognized by Ni II (Chro) 2 .T he extruded cytosine and last guanine nucleotides form water-mediated hydrogen bonds,whichaid in ligand recognition. The recognition can be accounted for by the classic induced-fit paradigm.

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“…[43][44][45] The best-characterisedsystems are those reported by Lincoln, etal.,i nw hichb ridging ligandsc ontaining linked dppz units have been used to create threading intercalators. [46][47][48][49][50] Due to the threading mechanism, [51] the resulting dinuclearc omplexes showe xtremelyh igh binding affinities (in the nanomolar range) [52] and ab inding preference for AT-rich sequences. [50,53] On the other hand, the multi-step syntheses of these complexes startingf rom classically resolved chiral metal complexs tartingm aterials are not trivial.…”

Section: Introductionmentioning

confidence: 99%

The Structure of Linkers Affects the DNA Binding Properties of Tethered Dinuclear Ruthenium(II) Metallo‐Intercalators

Saeed

Buurma

et al. 2017

Chemistry A European J

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With the long‐term aim of enhancing the binding properties of dinuclear RuII‐based DNA light‐switch complexes, a series of eight structurally related mono‐ and dinuclear systems are reported in which the linker of the bridging ligand has been modulated. These tethered systems have been designed to explore issues of steric demand at the binding site and the thermodynamic cost of entropy loss upon binding. Detailed spectroscopic and isothermal titration calorimetry (ITC) studies on the new complexes reveal that one of the linkers produces a dinuclear system that binds to duplex DNA with an affinity (Kb >107 m−1) that is higher than its corresponding monometallic complex and is the highest affinity for a non‐threading bis‐intercalating metal complex. These studies confirm that the tether has a major effect on the binding properties of dinuclear complexes containing intercalating units and establishes key design rules for the construction of dinuclear complexes with enhanced DNA binding characteristics.

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Thread Insertion of a Bis(dipyridophenazine) Diruthenium Complex into the DNA Double Helix by the Extrusion of AT Base Pairs and Cross‐Linking of DNA Duplexes

Cited by 44 publications

References 29 publications

DNA intercalation optimized by two-step molecular lock mechanism

DNA intercalation optimized by two-step molecular lock mechanism

Induced‐Fit Recognition of CCG Trinucleotide Repeats by a Nickel–Chromomycin Complex Resulting in Large‐Scale DNA Deformation

The Structure of Linkers Affects the DNA Binding Properties of Tethered Dinuclear Ruthenium(II) Metallo‐Intercalators

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