Insertion of a Bulky Rhodium Complex into a DNA Cytosine−Cytosine Mismatch:  An NMR Solution Study

Cordier, C.; Pierre, Valérie C.; Barton, Jacqueline K.

doi:10.1021/ja0739436

Cited by 62 publications

(73 citation statements)

References 49 publications

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“…Instead, the DNA accommodates the inserting ligand through the ejection of the mismatched bases out of the π-stack and into the major and minor grooves. This binding mode was verified with an additional crystal structure of the complex bound to an AA mismatch (Figure 4), as well as a solution NMR structure of the complex with DNA containing a CC mismatch [57,58]. This structure provides additional insight into why G-containing mismatches are not detected by metalloinsertors; these highly stable mismatches are not easily ejected from the base-stack, so chrysi cannot displace mismatches at these sites.…”

Section: Binding Of Rhodium Metalloinsertors To Dna Mismatchesmentioning

confidence: 74%

Targeting DNA mismatches with rhodium metalloinsertors

Boyle

Barton

2016

Inorganica Chimica Acta

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DNA has been exploited as a biological target of chemotherapeutics since the 1940s. Traditional chemotherapeutics, such as cisplatin and DNA-alkylating agents, rely primarily on increased uptake by rapidly proliferating cancer cells for therapeutic effects, but this strategy can result in off-target toxicity in healthy tissue. Recently, research interests have shifted towards targeted chemotherapeutics, in which a drug targets a specific biological signature of cancer, resulting in selective toxicity towards cancerous cells. Here, we review a family of complexes, termed rhodium metalloinsertors, that selectively target DNA base pair mismatches, a hallmark of mismatch-repair (MMR) deficient cancers. These rhodium metalloinsertors, bind DNA mismatches with high specificity and display high selectively in killing MMR-deficient versus MMR-proficient cells. This cell selectivity is unique for small molecules that bind DNA. Current generations of rhodium metalloinsertors have shown nanomolar potency along with high selectivity towards MMR-deficient cells, and show promise as a foundation for a new family of chemotherapeutics for MMR-deficient cancers.

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Section: Binding Of Rhodium Metalloinsertors To Dna Mismatchesmentioning

confidence: 74%

Targeting DNA mismatches with rhodium metalloinsertors

Boyle

Barton

2016

Inorganica Chimica Acta

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“…Recent structural studies show that this mismatch binding occurs not by intercalation, where the metal complex binds from the major groove, increasing the base pair rise through stacking within the helix, but rather by insertion, where the bulky ligand of the complex binds from the minor groove without increasing the base rise and ejects the mismatched base pairs into the major groove. 9,10 This insertion mode clearly reconciles the relationship between mismatch destabilization and site recognition: the more destabilized the mismatch, the easier the extrusion of the mismatched bases.The relationship between site destabilization and Rh(bpy) 2 -(chrysi) 3+ affinity has led us to investigate metalloinsertor recognition of two other common DNA defects: abasic sites and single base bulges. Abasic sites result from cleavage of the glycosidic bond and can arise spontaneously, as a result of exogenous carcinogens, or as an intermediate in repair.…”

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confidence: 69%

Targeting Abasic Sites and Single Base Bulges in DNA with Metalloinsertors

2008

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The site-specific recognition of abasic sites and single base bulges in duplex DNA by sterically expansive rhodium metalloinsertors has been investigated. Through DNA photocleavage experiments, Rh(bpy)2(chrysi)3+ is shown to bind both abasic sites and single base bulges site-specifically and, upon irradiation, to cleave the backbone of the defect-containing DNA. Photocleavage titrations reveal that the metal complex binds DNA containing an abasic site with high affinity (2.6(5) x 106 M-1), comparably to the metalloinsertor and a CC mismatch. The complex binds single base bulge sites with lower affinity (approximately 105 M-1). Analysis of cleavage products and the correlation of affinities with helix destabilization suggest that Rh(bpy)2(chrysi)3+ binds both lesions via metalloinsertion, as observed for Rh binding at mismatched sites, a binding mode in which the mismatched or unpaired bases are extruded from the helix and replaced in the base stack by the sterically expansive ligand of the metalloinsertor.

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“…6 We have recently elucidated how the complex [Rh(bpy) 2 (chrysi)] 3+ interacts with the mismatched sites in DNA by crystal structural determination and NMR analysis. 9,10 The binding mode of this complex to the mismatch site is not classical intercalation but rather insertion. The expansive chrysi ligand is deeply inserted into the mismatch site in the minor groove resulting in the complete ejection of mismatched nucleotides from the base stack.…”

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confidence: 99%

DNA Strand Cleavage near a CC Mismatch Directed by a Metalloinsertor

2007

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Reagents for recognition and efficient cleavage of mismatched DNA without photoactivation were designed. They contain a combination of a mismatch-directing metalloinsertor, [Rh (bpy) 2 (chrysi)] 3+ (chrysi = 5,6-chrysenequinone diimine), and an oxidative cleavage functionality, [Cu(phen) 2 ] + (Cu). Both unconjugated (Rh+Cu) and conjugated (Rh−Cu) frameworks of the Rh insertor and Cu were prepared. Compared to Cu, both constructs Rh+Cu and Rh−Cu exhibit efficient site-specific DNA scission only with mismatched DNA, confirmed by experiments with 32 P-labeled oligonucleotides. Furthermore, these studies indicate that DNA cleavage occurs near the mismatch in the minor groove and on both strands. Interestingly, the order of reactivity of the three systems with a CC mismatch is Rh+Cu > Rh−Cu ≫ Cu. Rh binding appears to direct Cu reactivity with or without tethering. These results illustrate advantages and disadvantages in bifunctional conjugation.Base pair mismatches in the genome can arise from damage by environmental agents (i.e. UV light), a wide range of genotoxic chemicals as well as errors made by DNA polymerase during synthesis. 1,2 These base mispairs are generally corrected by the mismatch repair machinery; if they are not repaired, however, mutations arise, which subsequently lead to increased cancer susceptibility. [1][2][3][4] To recognize DNA mismatches, we have developed rhodium complexes containing an intercalating ligand that is too bulky to insert at stable matched sites and instead preferentially binds to thermodynamically destabilized mismatched sites. [5][6][7][8] The complex [Rh (bpy) 2 (chrysi)] 3+ (Figure 1), designed by our laboratory, targets more than 80% of mismatches with high selectivity and promotes single-stranded cleavage of the DNA backbone next to the mismatch site upon photoactivation. [5][6][7] More interestingly, this Rh complex can detect and photocleave a single base mismatch in a linearized 2725 base pair plasmid. 6 We have recently elucidated how the complex [Rh(bpy) 2 (chrysi)] 3+ interacts with the mismatched sites in DNA by crystal structural determination and NMR analysis. 9,10 The binding mode of this complex to the mismatch site is not classical intercalation but rather insertion. The expansive chrysi ligand is deeply inserted into the mismatch site in the minor groove resulting in the complete ejection of mismatched nucleotides from the base stack.Recently, this mismatch-specific metalloinsertor has shown promise in cell-selective strategies for chemotherapeutic design. 11 The Rh complex selectively inhibits cellular proliferation in mismatch repair-deficient cells as compared to mismatch repair-proficient cells. In another possible chemotherapeutic approach, bifunctional conjugates that combine a metalloinsertor targeting DNA mismatches with a reactive species such as an aniline mustard or a cisplatin *To whom correspondence should be addressed. Email: jkbarton@caltech.edu. Supporting Information Available: Preparation of the conjugate Rh-Cu and Figures S1-S3. ...

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Insertion of a Bulky Rhodium Complex into a DNA Cytosine−Cytosine Mismatch: An NMR Solution Study

Cited by 62 publications

References 49 publications

Targeting DNA mismatches with rhodium metalloinsertors

Targeting DNA mismatches with rhodium metalloinsertors

Targeting Abasic Sites and Single Base Bulges in DNA with Metalloinsertors

DNA Strand Cleavage near a CC Mismatch Directed by a Metalloinsertor

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