Dual recognition of the human telomeric G-quadruplex by a neomycin–anthraquinone conjugate

Ranjan, Nihar; Davis, Erik; Xue, Liang; Arya, Dev P.

doi:10.1039/c3cc42721h

Cited by 59 publications

(49 citation statements)

References 27 publications

(37 reference statements)

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“…18 We approached such multi-recognition using a tridentate ligand. The tridentate ligand, compound 5 , constitutes two neomycin units and a benzimidazole ligand attached via a linker.…”

Section: Significantly Enhances the Thermal Stabilization Of Hiv Tamentioning

confidence: 99%

Multivalency in the recognition and antagonism of a HIV TAR RNA–TAT assembly using an aminoglycoside benzimidazole scaffold

et al. 2016

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Recognition of RNA by high-affinity binding small molecules is crucial for expanding existing approaches in RNA recognition, and for the development of novel RNA binding drugs. A novel neomycin dimer benzimidazole conjugate 5 (DPA 83) was synthesized by conjugating a neomycin-dimer with benzimidazole alkyne using click chemistry to target multiple binding sites on HIV TAR RNA. Ligand 5 significantly enhances the thermal stability of HIV TAR RNA and interacts stoichiometrically with HIV TAR RNA with a low nanomolar affinity. 5 displayed enhanced binding than its individual building blocks including neomycin dimer azide and benzimidazole alkyne. In essence, a high affinity multivalent ligand was designed and synthesized to target HIV TAR RNA.

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“…18 We approached such multi-recognition using a tridentate ligand. The tridentate ligand, compound 5 , constitutes two neomycin units and a benzimidazole ligand attached via a linker.…”

Section: Significantly Enhances the Thermal Stabilization Of Hiv Tamentioning

confidence: 99%

Multivalency in the recognition and antagonism of a HIV TAR RNA–TAT assembly using an aminoglycoside benzimidazole scaffold

et al. 2016

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“…The success of this strategy is dependent upon the choice of ligands for covalent attachment so that their nucleic acid binding sites do not overlap. The conjugation strategy has led to significant increase in the binding affinity of ligands towards the recognition of DNA triplexes, 28 quadruplexes, 29,30,31 and DNA:RNA hybrid structures. 32 Using this strategy, in certain cases, even a weak binder can be used to enhance the nucleic acid stability using a novel mechanism.…”

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confidence: 99%

Linker dependent intercalation of bisbenzimidazole-aminosugars in an RNA duplex; selectivity in RNA vs . DNA binding

Ranjan

Arya

2016

Bioorganic & Medicinal Chemistry Letters

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Neomycin and Hoechst 33258 are two well-known nucleic acid binders that interact with RNA and DNA duplexes with high affinities respectively. In this manuscript, we report that covalent attachment of bisbenzimidazole unit derived from Hoechst 33258 to neomycin leads to intercalative binding of the bisbenzimidazole unit (oriented at 64–74° with respected to the RNA helical axis) in a linker length dependent manner. The dual binding and intercalation of conjugates were supported by thermal denaturation, CD, LD and UV-Vis absorption experiments. These studies highlight the importance of linker length in dual recognition by conjugates, for effective RNA recognition, which can lead to novel ways of recognizing RNA structures. Additionally, the ligand library screens also identify DNA and RNA selective compounds, with compound 9, containing a long linker, showing a 20.0 °C change in RNA duplex Tm with only a 9.0 °C change in Tm for the corresponding DNA duplex. Significantly, the shorter linker in compound 3 shows almost the reverse trend, a 23.8 °C change in DNA Tm, with only a 9.1 °C change in Tm for the corresponding RNA duplex.

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“…20-26 Several aminoglycoside conjugates have been synthesized 27-30 and shown to have enhanced binding to variety of DNA, 31-34 RNA, 35 and DNA:RNA hybrid 36 structures. We have recently reported recognition of TAR-RNA using a series of dimeric neomycin conjugates.…”

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confidence: 99%

Recognition of HIV-TAR RNA using neomycin–benzimidazole conjugates

Ranjan

Kumar

Watkins

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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Synthesis of a novel class of compounds and their biophysical studies with TAR-RNA are presented. The synthesis of these compounds was achieved by conjugating neomycin, an aminoglycoside, with benzimidazoles modeled from a B-DNA minor groove binder, Hoechst 33258. The neomycin-benzimidazole conjugates have varying linkers that connect the benzimidazole and neomycin units. The linkers of varying length (5-23 atoms) in these conjugates contain one to three triazole units. The UV thermal denaturation experiments showed that the conjugates resulted in greater stabilization of the TAR-RNA than either neomycin or benzimidazole used in the synthesis of conjugates. These results were corroborated by the FID displacement and tat-TAR inhibition assays. The binding of ligands to the TARRNA is affected by the length and composition of the linker. Our results show that increasing the number of triazole groups and the linker length in these compounds have diminishing effect on the binding to TAR-RNA. Compounds that have shorter linker length and fewer triazole units in the linker displayed increased affinity towards the TAR RNA.

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Dual recognition of the human telomeric G-quadruplex by a neomycin–anthraquinone conjugate

Cited by 59 publications

References 27 publications

Multivalency in the recognition and antagonism of a HIV TAR RNA–TAT assembly using an aminoglycoside benzimidazole scaffold

Multivalency in the recognition and antagonism of a HIV TAR RNA–TAT assembly using an aminoglycoside benzimidazole scaffold

Linker dependent intercalation of bisbenzimidazole-aminosugars in an RNA duplex; selectivity in RNA vs . DNA binding

Recognition of HIV-TAR RNA using neomycin–benzimidazole conjugates

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