Targeting DNA Bulged Microenvironments with Synthetic Agents

Xi, Zhen; Hwang, Geum‐Sook; Goldberg, Irving H.; Harris, Jeffrey L.; Pennington, William T.; Fouad, Farid; Qabaja, Ghassan; Wright, Justin M.; Jones, Graham B.

doi:10.1016/s1074-5521(02)00188-6

Cited by 47 publications

(81 citation statements)

References 25 publications

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“…Such considerations have led us to design and prepare small molecule analogues of NCSi-gb with more favorable binding properties (17,18). These analogues share the same key structural features of NCSi-gb: a wedge-shaped aglycon moiety, consisting of two aromatic ring systems held rigidly by a stable spirocyclic ring having a right-handed helical twist of 35°, and a pendant aminosugar moiety (17,18). Initial efforts led to the preparation of simple analogues in which an aminoglucose moiety was readily β-linked to the 5-membered spirocyclic ring (17) or to the BI ring (18).…”

Section: Introductionmentioning

confidence: 99%

“…The solution structures of the complexes formed between oligodeoxynucleotides containing a two-base bulge and the natural, as well as analogue ligands in which the aminosugar is β-linked to the spirocyclic ring (17), have been elucidated using high-resolution NMR spectroscopy and restrained molecular dynamic simulation (15,16,21,22). The structures of the complexes reveal, in important details, the differences in binding modes, which provide insight into the relationship between structure and binding affinity.…”

Section: Introductionmentioning

confidence: 99%

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Solution Structure of a Designed Spirocyclic Helical Ligand Binding at a Two-Base Bulge Site in DNA

et al. 2007

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The solution structure of the complex formed between an oligodeoxynucleotide containing a twobase bulge (5′-CCATCGTCTACCTTTGGTAGGATGG) and SCA-α2, a designed spirocyclic helical molecule, has been elucidated. SCA-α2, a close mimic of the metabolite, NCSi-gb, of the DNA bulge-specific enediyne antibiotic neocarzinostatin, differs in possessing a more stable spirocyclic ring system and in lacking certain bulky groupings that compromise bulged DNA binding. This study provides a detailed comparison of the binding modes of the two complexes and provides new insights into the importance of shape and space, as opposed to simple nucleotide sequence, in complex formation at the bulge site. The two rigidly held aromatic rings of SCA-α2 form a righthanded helical molecular wedge that specifically penetrates the bulge binding pocket and immobilizes the two bulge residues (GT), which point towards the minor groove, rather than the major groove as in the NCSi-gb•bulged DNA complex. The ligand aromatic ring systems stack on the DNA bulge-flanking base pairs that define the long sides of the triangular prism binding pocket. Like NCSi-gb, SCA-α2 possesses the natural N-methyl furanose moiety, α-linked to the benzindanol (BI) moiety. The aminosugar anchors in the major groove of the DNA and points toward the 3′-bulgeflanking base pair. Lacking the bulky cyclocarbonate of NCSi-gb, the SCA-α2•bulged DNA complex has a much less twisted and buckled 3'-bulge-flanking base pair (dG20·dC8), and the G20 residue stacks directly above the BI ring platform. Also, the absence of the methyl group and the free rotation of the methoxy group on the dihydronaphthanone (NA) moiety of SCA-α2 allow better stacking geometry of the NA ring above the 5′-bulge-flanking base pair dG21·dC5. These and other considerations help to explain why NCSi-gb binds very poorly to bulged RNA and are consistent with the recent observation of good binding with SCA-α2. Thus, although the two complexes resemble each other closely, they differ in important local environmental details. SCA-α2 has a better * To whom correspondence should be addressed: Irving H. Goldberg, Telephone: (617) (Table S1), proton chemical shift changes (ppm) of the bound form of SCA-α2 in the SCA-α2•bulged 25-mer DNA complex (in D 2 O at 25 °C) relative to the free form of SCA-α2 (in d4-MeOH at 25 °C) (Table S2), the exchangeable proton chemical shifts (ppm) of DNA components within the SCA-α2•bulged 25-mer DNA complex in H 2 O buffer at pH 6.8 and 10°C (Table S3 A), the non-exchangeable proton chemical shifts (ppm) of DNA components within the SCA-α2•bulged 25-mer DNA complex in D 2 O buffer at pH 6.8 and 10°C (Table S3 B), the titration of various amount of SCA-α2 into 25-mer bulged DNA as monitored by 1 H NMR spectra shown as expanded imino proton region ( Figure S1), the expanded NOESY (200 ms mixing time) contour plots of the SCA-α2•bulged 25mer DNA complex, focusing on the amino and aromatic proton regions ( Figure S2), the expanded NOESY (200 ms mixing time) contour plots for the b...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Solution Structure of a Designed Spirocyclic Helical Ligand Binding at a Two-Base Bulge Site in DNA

et al. 2007

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“…Because formation of the bulge structure might be important in DNA slippage [16], we speculate that the enhancement of repeat slippage by DDI-1A and DDI-1B might be caused by their specific recognition of bulge DNA. Accordingly, CD spectropolarimetry can be used to monitor conformational transitions as the ligand-nucleic acid complex is formed.…”

Section: Selective Binding Of Ddi-1a and Ddi-1b To Bulge Dnamentioning

confidence: 96%

“…Several groups have shown an interest in developing small molecules that possess specific effects for DNA triplet repeat strand slippage [14][15][16][17][18][19][20][21][22][23]. The most promising and successful bulge-specific agent discovered to date originated from studies on the enediyne natural product neocarzinostatin chromophore (NCS-chrom) [24].…”

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confidence: 99%

“…Molecules that mimic the wedge-shaped natural product have been designed and synthesized, with the expectation that they may be used to study the role of bulged structures in nucleic acid function [16]. For example, the compound double deck intercalater (DDI), which has an spirocyclic backbone almost identical to that of NCSi-gb (Scheme 1B), was able to enhance slippage synthesis of various repeat DNA strands [16,20,28].…”

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In vitro expansion of DNA triplet repeats with bulge binders and different DNA polymerases

Ouyang

Liu

et al. 2008

The FEBS Journal

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Triplet repeats are the most abundant simple sequence repeats in the coding and non-coding sequences of all known eukaryotic genomes [1]. The frequency of specific types of triplet repeats and their localization in genes vary significantly between genomes, reflecting their important role in genome evolution [1,2]. Expansions of DNA triplet repeat sequences are associated with 16 inherited neurological disorders known as triplet repeat expansion diseases [3][4][5], which can lead to total disability and death. The severity of a triplet repeat expansion disease is increased anticipatively and the age of onset is reduced with each successive generation [6,7]. The high mutation rate of triplet repeats makes them a rich source of quantitative genetic variation [8][9][10][11]. The tendency for repeating DNA strands to form hairpin loops or slipped conformations, and their inherent conformational properties, for example their high degree of flexibility, writhing and the stability of the hairpin formation, are important in the investigation of DNA slippage phenomena [3,11,12].Among the non-B-form DNA conformations formed by triplet repeats, simple bulged structures (one or more unpaired bases) have been postulated as intermediates in the synthesis of slipped DNA and are associated with the unstable expansion of triplet repeats on the basis of their entropy [13]. Several groups have shown an interest in developing small molecules that possess specific effects for DNA triplet repeat strand slippage [14][15][16][17][18][19][20][21][22][23]. The most promising and successful bulge-specific agent discovered to date originated from studies on the enediyne natural product neocarzinostatin chromophore (NCS-chrom) [24]. Its isostructural mimic, NCSi-gb (Scheme 1A) binds bulge DNA at sub-micromolar concentrations [25], and is also able to induce formation of the bulge-binding pocket by stacking between the base pairs that flank the bulge site in the oligonucleotide [26,27]. The expansion of DNA repeat sequences is associated with many genetic diseases in humans. Simple bulge DNA structures have been implicated as intermediates in DNA slippage within the DNA repeat regions. To probe the possible role of bulged structures in DNA slippage, we designed and synthesized a pair of simple chiral spirocyclic compounds [Xi Z, Ouyang D & Mu HT (2006) Bioorg Med Chem Lett 16, 1180-1184, DDI-1A and DDI-1B, which mimic the molecular architecture of the enediyne antitumor antibiotic neocarzinostatin chromophore. Both compounds strongly stimulated slippage in various DNA repeats in vitro. Enhanced slippage synthesis was found to be synchronous for primer and template. CD spectra and UV thermal stability studies supported the idea that DDI-1A and DDI-1B exhibited selective binding to the DNA bulge and induced a significant conformational change in bulge DNA. The proposed mechanism for the observed in vitro expansion of long DNA is discussed.Abbreviations DDI, Double Deck Intercalater; NCS-chrom, neocarzinostatin chromophore.

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DNA and RNA Binding Small Molecules

2011

Medicinal Chemistry of Nucleic Acids

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Targeting DNA Bulged Microenvironments with Synthetic Agents

Cited by 47 publications

References 25 publications

Solution Structure of a Designed Spirocyclic Helical Ligand Binding at a Two-Base Bulge Site in DNA

Solution Structure of a Designed Spirocyclic Helical Ligand Binding at a Two-Base Bulge Site in DNA

In vitro expansion of DNA triplet repeats with bulge binders and different DNA polymerases

DNA and RNA Binding Small Molecules

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