title: Linker dependent intercalation of bisbenzimidazole-aminosugars in an RNA duplex; selectivity in RNA vs. DNA binding.
abstract: 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 20.3°C change in RNA duplex Tmwith only a 13.0°C change in Tmfor 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 Tmfor the corresponding RNA duplex.
authors.affiliation: Laboratory of Bioorganic and Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, SC 29634, United States.
authors.forename: Nihar
authors.initials: N
authors.lastname: Ranjan
authors.affiliation: Laboratory of Bioorganic and Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, SC 29634, United States. Electronic address: dparya@clemson.edu.
authors.forename: Dev P
authors.initials: DP
authors.lastname: Arya
mesh_terms: D000606:Amino Sugars / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D006690:Bisbenzimidazole / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D015394:Molecular Structure; D012313:RNA / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D000606:Amino Sugars; D008024:Ligands; D012313:RNA; D004247:DNA; D006690:Bisbenzimidazole
keywords: Hoechst 33258; Intercalation; Linear dichroism; Neomycin; RNA duplex