- Use of ferrocene scaffolds as pendant groups in hairpin-type pyrrole-imidazole polyamide molecules showing sequence-selective binding to DNA duplexes
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The synthesis and properties of new conjugate molecules, Fc-PIA, composed of ferrocene (Fc) and pyrrole-imidazole polyamides (PIA) are reported. As a PIA sequence, we chose Im-Py-Im/Py-Im-Py considering its future application to the SNPs detection of gene
- Seio, Kohji,Mizuta, Masahiro,Terada, Takeshi,Sekine, Mitsuo
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- Sequence specific and high affinity recognition of 5′-ACGCGT-3′ by rationally designed pyrrole-imidazole H-pin polyamides: Thermodynamic and structural studies
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Imidazole (Im) and Pyrrole (Py)-containing polyamides that can form stacked dimers can be programmed to target specific sequences in the minor groove of DNA and control gene expression. Even though various designs of polyamides have been thoroughly investigated for DNA sequence recognition, the use of H-pin polyamides (covalently cross-linked polyamides) has not received as much attention. Therefore, experiments were designed to systematically investigate the DNA recognition properties of two symmetrical H-pin polyamides composed of PyImPyIm (5) or f-ImPyIm (3e, f = formamido) tethered with an ethylene glycol linker. These compounds were created to recognize the cognate 5′-ACGCGT-3′ through an overlapped and staggered binding motif, respectively. Results from DNaseI footprinting, thermal denaturation, circular dichroism, surface plasmon resonance and isothermal titration microcalorimetry studies demonstrated that both H-pin polyamides bound with higher affinity than their respective monomers. The binding affinity of formamido-containing H-pin 3e was more than a hundred times greater than that for the tetraamide H-pin 5, demonstrating the importance of having a formamido group and the staggered motif in enhancing affinity. However, compared to H-pin 3e, tetraamide H-pin 5 demonstrated superior binding preference for the cognate sequence over its non-cognates, ACCGGT and AAATTT. Data from SPR experiments yielded binding constants of 1.6 × 108 M-1 and 2.0 × 1010 M-1 for PyImPyIm H-pin 5 and f-ImPyIm H-pin 3e, respectively. Both H-pins bound with significantly higher affinity (ca. 100-fold) than their corresponding unlinked PyImPyIm 4 and f-ImPyIm 2 counterparts. ITC analyses revealed modest enthalpies of reactions at 298 K (ΔH of -3.3 and -1.0 kcal mol-1 for 5 and 3e, respectively), indicating these were entropic-driven interactions. The heat capacities (ΔCp) were determined to be -116 and -499 cal mol-1 K-1, respectively. These results are in general agreement with ΔCp values determined from changes in the solvent accessible surface areas using complexes of the H-pins bound to (5′-CCACGCGTGG)2. According to the models, the H-pins fit snugly in the minor groove and the linker comfortably holds both polyamide portions in place, with the oxygen atoms pointing into the solvent. In summary, the H-pin polyamide provides an important molecular design motif for the discovery of future generations of programmable small molecules capable of binding to target DNA sequences with high affinity and selectivity.
- Mackay, Hilary,Brown, Toni,Uthe, Peter B.,Westrate, Laura,Sielaff, Alan,Jones, Justin,Lajiness, James P.,Kluza, Jerome,O'Hare, Caroline,Nguyen, Binh,Davis, Zach,Bruce, Chrystal,David Wilson,Hartley, John A.,Lee, Moses
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- A Convenient Method for the Synthesis of DNA-Recognizing Polyamides in Solution
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A convenient method for the synthesis of polyamides containing N-methylpyrrole (Py) and N-methylimidazole (Im) in solution has been developed. Most of the building blocks have been prepared by a haloform reaction in a simple way that column chromatography can be avoided. By use of the DCC/HOBT coupling reaction, the building blocks prepared have been effectively connected to construct a variety of subchains and polyamides without employing amino protection and deprotection. By use of the present method, an eight-ring polyamide, PyPyPyPyγPyImImPyβDp (γ is γ-aminobutyric acid, β is β-alanine, Dp is N,N-dimethylpropyldiamine), has been synthesized by the coupling of two four-ring subchains in one step.
- Xiao, Junhua,Yuan, Gu,Huang, Weiqiang,Chan, Albert S. C.,Lee, K.-L. Daniel
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- METHODS AND COMPOUNDS FOR THE TREATMENT OF GENETIC DISEASE
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The present disclosure relates to compounds and methods for modulating the expression of dmpk, and treating diseases and conditions in which dmpk plays an active role. The compound can be a transcription modulator molecule having a first terminus, a second terminus, and oligomeric backbone, wherein: a) the first terminus comprises a DNA-binding moiety capable of noncovalently binding to a nucleotide repeat sequence CAG or CTG; b) the second terminus comprises a protein-binding moiety binding to a regulatory molecule that modulates an expression of a gene comprising the nucleotide repeat sequence CAG or CTG; and c) the oligomeric backbone comprising a linker between the first terminus and the second terminus.
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Paragraph 00423; 00425; 00426; 00427
(2021/08/13)
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- SULFONIC ACID SALTS OF HETEROCYCLYLAMIDE-SUBSTITUTED IMIDAZOLES
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The invention relates to sulfonic acid salts of heterocyclylamide-substituted imidazoles, and to solvates and hydrates thereof, to the use thereof for treating and/or preventing diseases, and to use thereof for producing drugs for treating and/or preventi
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Paragraph 0124
(2014/10/29)
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- Novel diamino imidazole and pyrrole-containing polyamides: Synthesis and DNA binding studies of mono- and diamino-phenyl-ImPyIm polyamides designed to target 5′-ACGCGT-3′
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Pyrrole- and imidazole-containing polyamides are widely investigated as DNA sequence selective binding agents that have potential use as gene control agents. The key challenges that must be overcome to realize this goal is the development of polyamides wi
- Satam, Vijay,Babu, Balaji,Chavda, Sameer,Savagian, Mia,Sjoholm, Robert,Tzou, Samuel,Liu, Yang,Kiakos, Konstantinos,Lin, Shicai,David Wilson,Hartley, John A.,Lee, Moses
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experimental part
p. 693 - 701
(2012/03/11)
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- N-formamido-containing mono- and diheterocyclic pyrrole-and imidazole-2-carboxylic acids as building blocks for polyamide synthesis
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Four N-formamido-containing mono-and diheterocyclic pyrrole- and imidazole-2-containing acids 1-4 were synthesized as intermediates for the preparation of polyamide molecules. The N-formamido-moiety forces the compounds to bind strongly as a stacked dimer, and in a staggered fashion, at specific sequences in the minor-groove of DNA. The acid moiety at the C-terminus of compounds enables these molecules to be coupled to amine-containing intermediates to form the amide linkages of the target polyamide. This convergent approach increases the synthetic diversity in polyamide chemistry by enabling one acid to be used with a variety of different C-terminus- functionalized intermediates. Copyright Taylor & Francis Group, LLC.
- Mulder, Keith,Sexton, Jim,Taherbhai, Zarmeen,Jones, Justin,Uthe, Peter,Brown, Toni,Lee, Moses
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- HETEROCYCLYLAMIDE-SUBSTITUTED IMIDAZOLES
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The invention relates to heterocyclylamide-substituted imidazoles and methods for the production of the same, to the use thereof for the treatment and/or prophylaxis of diseases, to the use thereof for the production of medicaments for the treatment and/or prophylaxis of diseases, and especially to the use thereof as antiviral agents, especially against cytomegaloviruses.
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(2008/06/13)
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- SEQUENCE SELECTIVE PYRROLE AND IMIDAZOLE POLYAMIDE METALLOCOMPLEXES
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The present invention relates to sequence selective compounds for targeting therapeutic or diagnostic groups to polynucleotides. More particularly, the present invention relates to sequence selective targeting of metallocomplexes, such as metallodrugs and metallodiagnostics, to polynucleotides.
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Page/Page column 54
(2010/02/11)
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- Orthogonality and compatibility between Tsc and Fmoc amino-protecting groups
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New deprotection conditions that provide a complete orthogonality between Tsc and Fmoc amino-protecting groups are described. The potential of these orthogonal deprotection conditions was then demonstrated by the efficient solid-phase synthesis of branched peptides 20 and 21 using doubly protected amino acids such as Tsc-Lys(Fmoc)-OH 4c and Fmoc-Lys(Tsc)-OH 4d.
- Choi, Jin Seok,Kang, Hunhui,Jeong, Nakcheol,Han, Hogyu
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p. 2493 - 2503
(2007/10/03)
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- The 2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc) amino-protecting group: Use in the solid-phase synthesis of pyrrole-imidazole polyamides
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The development of the 2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc) function, a novel base-sensitive amino-protecting group, and its application to the preparation of DNA-binding polyamides are described. Pyrrole-imidazole polyamides were synthesized by an efficient solid-phase method under conditions compatible with Fmoc chemistry using two Tsc-protected amino acids, Tsc-Py-OH 1a and Tsc-Im-OH 1b.
- Choi, Jin Seok,Lee, Younjoo,Kim, Eunmyoung,Jeong, Nakcheol,Yu, Hosung,Han, Hogyu
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p. 1607 - 1610
(2007/10/03)
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- Nsc-mediated solid-phase synthesis of polyamides containing pyrrole amino acid
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The synthesis of the Nsc-protected amino acid, Nsc-Py-OH 1a, and its oligomerization are described.
- Choi, Jin Seok,Lee, Hwa-Sun,Lee, Younjoo,Jeong, Nakcheol,Kim, Hack-Joo,Kim, Young-Deug,Han, Hogyu
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p. 4295 - 4300
(2007/10/03)
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- DNA sequence-recognizing properties of minor groove alkylating agents / Effects of the replacement of N-methylpyrrole by an N-methylimidazole on tallimustine and its own homologue
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The linkage of an heterocycle, like N-methylimidazole, to minor DNA groove binders containing two or three pyrroles lead to a new class of oligopeptides with reduced antitumor activity both in vitro and in vivo if compared to tallimustine (CAS 115308-98-0) and its tetrapyrrole homologue 9. In the present paper is reported the correlation between the cytoxicity of tallimustine and its derivatives 9-11 with their ability to inhibit polymerase chain reaction (PCR) amplification of oestrogen receptor and Ha- ras gene sequences, containing A+T rich and G+C rich regions, respectively. Tallimustine and its tetrapyrrole homologue 9 were found to have higher sequence selectivity for the human oestrogen receptor (ER) gene with respect to the relative imidazole-containing analogues.
- Baraldi, Pier Giovanni,Romagnoli, Romeo,Spalluto, Giampiero,Cozzi, Paolo,Mongelli, Nicola,Bianchi, Nicoletta,Gambari, Roberto
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p. 309 - 315
(2007/10/03)
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- Synthesis and Metal-Ion Extraction Properties of para-tert-Butylcalixareneglycine Ester Acetamides
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Calixareneglycine ester acetamides 4a-c have been synthesized from calixareneacetyl chlorides 5a-c and glycine ethyl ester (6). Their ion-binding properties have been investigated by liquid-liquid extraction with radiotracer techniques. The experiments re
- Koenig, Burkhard,Fricke, Tom,Gloe, Karsten,Chartroux, Christine
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p. 1557 - 1562
(2007/10/03)
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- An alternative approach to the synthesis of lexitropsins
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An alternative approach to the synthesis of lexitropsins based on the elongation of an oligocarboxamide chain from the N-terminus of a molecule is discussed. This method was applied to the preparation of lexitropsins containing 1-methylpyrrole carboxamide, 1-methylimidazole carboxamide, and 1,3 thiazole carboxamide monomer units.
- Ryabinin,Sinyakov
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p. 531 - 536
(2007/10/03)
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- Solid phase synthesis of polyamides containing imidazole and pyrrole amino acids
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The solid phase synthesis of sequence specific DNA binding polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids is described. Two monomer building blocks, Boc-Py-OBt ester and Boc-Im acid, are prepared on a 50 g scale without column chromatography. Using commercially available Boc-β-alanine-Pam resin, cycling protocols were optimized to afford high stepwise coupling yields (>99%). Deprotection by aminolysis affords up to 100 mg quantities of polyamide. Solid phase methodology increases both the number and complexity of minor groove binding polyamides which can be synthesized and analyzed with regard to DNA binding affinity and sequence specificity. The solid phase synthesis of a representative eight-residue polyamide is reported.
- Baird, Eldon E.,Dervan, Peter B.
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p. 6141 - 6146
(2007/10/03)
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- Design and binding of a distamycin A analog to d(CGCAAGTTGGC)·d(GCCAACTTGCG): Synthesis, NMR studies, and implications for the design of sequence-specific minor groove binding oligopeptides
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An oligopeptide has been synthesized in which an imidazole ring is substituted for the central pyrrole ring of distamycin A. Two-dimensional NMR spectroscopy was used to characterize the complex formed between 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-(formylamino)pyrrole-2-carboxamido] imidazole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride (2-ImD) and d(CGCAAGTTGGC)·d(GCCAACTTGCG). Titration of the AAGTT duplex with 2-ImD yielded a single complex with a ligand:DNA stoichiometry of 2:1. The nuclear Overhauser effect (NOESY) experiment in D2O was used to assign the aromatic and C1'H DNA protons and to identify intermolecular ligand-DNA contacts between nonlabile protons. The NOESY experiment in H2O was used to assign the imino and amino DNA protons and the amide protons of the ligands and to identify ligand-DNA contacts involving these labile protons. These data indicate that two ligand molecules bind simultaneously to the minor groove of the central 5′-AAGTT-3′ sequence in a head-to-tail orientation. Molecular modeling, using 35 ligand-DNA distance constraints derived from a semiquantitative analysis of the NOESY data, shows that the imidazole N3 of one of the ligands forms a hydrogen bond with the C2 amino group of the guanine in the binding site. Additionally, the titration of d(CGCAAATTGGC)·d(GCCAATTTGCG) with 2-ImD was performed. No specific complex was detected by NMR spectroscopy between 2-ImD and the AAATT duplex. This result emphasizes the importance of the imidazole N3 atom of 2-ImD in the recognition of the AAGTT binding site.
- Dwyer, Tammy J.,Geierstanger, Bernhard H.,Bathini, Yadagiri,William Lown,Wemmer, David E.
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p. 5911 - 5919
(2007/10/02)
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- The Preparation and Properties of Partially Protected 4-Amino-1-methylimidazole-2-carboxylic Acids to be Used as Intermediates in the Synthesis of Analogues of Distamycin A
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Partially protected 4-amino-1-methylimidazole-2-carboxylic acid derivatives have been prepared by a convenient route from the corresponding nitro analogue.Such derivatives, blocked on the amino function with tert-butyloxycarbonyl (4) or formyl groups (8)
- Grehn, Leif,Ding, Lu,Ragnarsson, Ulf
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