Design and Synthesis of Cyclic Mismatch‐Binding Ligands (CMBLs) with Variable Linkers by Ring‐Closing Metathesis and their Photophysical and DNA Repeat Binding Properties

Mukherjee, Sanjukta; Dohno, Chikara; Nakatani, Kazuhiko

doi:10.1002/chem.201702064

Cited by 10 publications

(16 citation statements)

References 76 publications

(275 reference statements)

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“…The intense absorption band was observed at λ =319 nm with a shoulder at λ =332 nm in aqueous buffer and the fluorescence was significantly redshifted to λ =432 nm, accompanied by an emission band at λ =360 nm. The emission at λ =432 nm is most likely due to the excimer of two naphthyridine heterocycles because we precisely determined the spectroscopic properties of cyclic MBLs . In methanol, however, absorption spectra, showing two bands at λ =322 and 333 nm, were almost the same as that of 1 ‐OMe.…”

Section: Resultsmentioning

confidence: 97%

“…One approach was to use the cyclized derivatives of NCD, in which two naphthyridine heterocycles were fixed in the stacked position. We recently reported the synthesis of cyclophane derivatives of NCD and their binding ability to various DNA sequences and structures . One of the molecules we synthesized showed only one stacked conformation, and was found to bind to DNA containing the T/GG sequence …”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Naphthyridine Dimers with Conformational Restriction and Binding to DNA and RNA

Nakatani

Natsuhara

Mori

et al. 2017

Chemistry An Asian Journal

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One of the important determinants in the efficiency of a molecular interaction is the necessity for conformational changes in host and/or guest molecules upon binding. In small-molecule interactions with nucleic acids, conformational changes on both molecules are often involved, especially in intercalating binding. Mismatch binding ligands (MBLs) we described here consist of two heterocycles that predominantly exist in one conformation, so it is of interest to determine if such molecules can bind to any DNA and RNA structures. One molecule, 1-NHR, which predominantly exists as the unstacked conformation in aqueous solvent, has been successfully synthesized and characterized. Compound 1-NHR did not efficiently bind to GX/Y DNA and RNA sequences, but the binding pattern is different from that of authentic MBL naphthyridine carbamate dimer. In vitro selection of RNA that specifically binds to 1-NHR was performed from pre-miR-29a loop library RNA, and one RNA, to which 1-NHR bound with high affinity, has been successfully identified. Although it was anticipated that 1-NHR, with a predominantly unstacked conformation, would show entropy-driven binding, isothermal titration calorimetry analysis suggested that the binding of 1-NHR to RNA was enthalpy driven with an apparent K of about 100 nm.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Synthesis of Naphthyridine Dimers with Conformational Restriction and Binding to DNA and RNA

Nakatani

Natsuhara

Mori

et al. 2017

Chemistry An Asian Journal

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“…One type of the aromatic moieties is a 1,8-naphthyridine ring containing two imino groups, which favors guanine as a binding partner (29–31). Recently, we have developed cyclic mismatch-binding ligands (CMBLs) composed of two naphthyridine rings connected by two linkers, which were found to interact with CAG repeats (32,33) (Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

Structural insights into synthetic ligands targeting A–A pairs in disease-related CAG RNA repeats

Mukherjee

Błaszczyk

Rypniewski

et al. 2019

Nucleic Acids Research

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The trinucleotide repeat expansion disorders (TREDs) constitute of a group of >40 hereditary neurodegenerative human diseases associated with abnormal expansion of repeated sequences, such as CAG repeats. The pathogenic factor is a transcribed RNA or protein whose function in the cell is compromised. The disorders are progressive and incurable. Consequently, many ongoing studies are oriented at developing therapies. We have analyzed crystal structures of RNA containing CAG repeats in complex with synthetic cyclic mismatch-binding ligands (CMBLs). The models show well-defined interactions between the molecules in which the CMBLs mimic nucleobases as they form pseudo-canonical base pairs with adenosine residues and engage in extensive stacking interactions with neighboring nucleotides. The binding of ligands is associated with major structural changes of the CAG repeats, which is consistent with results of biochemical studies. The results constitute an early characterization of the first lead compounds in the search for therapy against TREDs. The crystallographic data indicate how the compounds could be further refined in future biomedical studies.

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“…Our group has been focusing on a rational design approach to develop mismatch-binding ligands (MBLs) that target specific noncanonical structure of nucleic acids through complementary hydrogen bonding ( 39–42 ). Compounds used in this study were designed to recognize an array of Gs in the 5′-CGG-3′/5′-CGG-3′ unit by complementary hydrogen bonding to the Watson-Crick surface ( 41–43 ). The different modes of binding alter the structure of RNA CGG repeat and its thermodynamic/kinetic stability, which could have significant effects on interactions with RNA binding proteins and the resulting biological events.…”

Section: Introductionmentioning

confidence: 99%

“…A series of small molecules designed to recognize an array of Gs have been synthesized, including naphthyridine carbamate dimer (NCD; ( 39 )), a naphthyridine tetramer containing two NCD molecules (Z-NCTS; ( 40 , 44 )), and cyclic mismatch binding ligands (CMBLs) that consist of cyclophane containing bis(2-amino-1,8-naphthyridine) moieties connected by variable linkers ( 41 , 42 ). Importantly, Z-NCTS was shown to bind to 5′-CGG-3′/5′-CGG-3′ DNA sequence in vitro with 1:1 binding stoichiometry and a dissociation constant ( K d ) of ca.…”

Section: Introductionmentioning

confidence: 99%

Cyclic mismatch binding ligands interact with disease-associated CGG trinucleotide repeats in RNA and suppress their translation

Konieczny

Mukherjee

Stepniak-Konieczna

et al. 2021

Nucleic Acids Research

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a limited expansion of CGG repeats in the FMR1 gene. Degeneration of neurons in FXTAS cell models can be triggered by accumulation of polyglycine protein (FMRpolyG), a by-product of translation initiated upstream to the repeats. Specific aims of our work included testing if naphthyridine-based molecules could (i) block FMRpolyG synthesis by binding to CGG repeats in RNA, (ii) reverse pathological alterations in affected cells and (iii) preserve the content of FMRP, translated from the same FMR1 mRNA. We demonstrate that cyclic mismatch binding ligand CMBL4c binds to RNA structure formed by CGG repeats and attenuates translation of FMRpolyG and formation of nuclear inclusions in cells transfected with vectors expressing RNA with expanded CGG repeats. Moreover, our results indicate that CMBL4c delivery can reduce FMRpolyG-mediated cytotoxicity and apoptosis. Importantly, its therapeutic potential is also observed once the inclusions are already formed. We also show that CMBL4c-driven FMRpolyG loss is accompanied by partial FMRP reduction. As complete loss of FMRP induces FXS in children, future experiments should aim at evaluation of CMBL4c therapeutic intervention in differentiated tissues, in which FMRpolyG translation inhibition might outweigh adverse effects related to FMRP depletion.

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Design and Synthesis of Cyclic Mismatch‐Binding Ligands (CMBLs) with Variable Linkers by Ring‐Closing Metathesis and their Photophysical and DNA Repeat Binding Properties

Cited by 10 publications

References 76 publications

Synthesis of Naphthyridine Dimers with Conformational Restriction and Binding to DNA and RNA

Synthesis of Naphthyridine Dimers with Conformational Restriction and Binding to DNA and RNA

Structural insights into synthetic ligands targeting A–A pairs in disease-related CAG RNA repeats

Cyclic mismatch binding ligands interact with disease-associated CGG trinucleotide repeats in RNA and suppress their translation

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