title: Development of bright fluorescent quadracyclic adenine analogues: TDDFT-calculation supported rational design.
abstract: Fluorescent base analogues (FBAs) comprise a family of increasingly important molecules for the investigation of nucleic acid structure and dynamics. We recently reported the quantum chemical calculation supported development of four microenvironment sensitive analogues of the quadracyclic adenine (qA) scaffold, the qANs, with highly promising absorptive and fluorescence properties that were very well predicted by TDDFT calculations. Herein, we report on the efficient synthesis, experimental and theoretical characterization of nine novel quadracyclic adenine derivatives. The brightest derivative, 2-CNqA, displays a 13-fold increased brightness (εΦF = 4500) compared with the parent compound qA and has the additional benefit of being a virtually microenvironment-insensitive fluorophore, making it a suitable candidate for nucleic acid incorporation and use in quantitative FRET and anisotropy experiments. TDDFT calculations, conducted on the nine novel qAs a posteriori, successfully describe the relative fluorescence quantum yield and brightness of all qA derivatives. This observation suggests that the TDDFT-based rational design strategy may be employed for the development of bright fluorophores built up from a common scaffold to reduce the otherwise costly and time-consuming screening process usually required to obtain useful and bright FBAs.
authors.affiliation: Department of Chemistry and Chemical Engineering/Chemistry and Biochemistry, Chalmers University of Technology, S-41296 Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Foller Larsen
authors.affiliation: Department of Chemistry and Chemical Engineering/Chemistry and Biochemistry, Chalmers University of Technology, S-41296 Gothenburg, Sweden.
authors.forename: Blaise
authors.initials: B
authors.lastname: Dumat
authors.affiliation: Department of Chemistry and Chemical Engineering/Chemistry and Biochemistry, Chalmers University of Technology, S-41296 Gothenburg, Sweden.
authors.forename: Moa S
authors.initials: MS
authors.lastname: Wranne
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, S-41296 Gothenburg, Sweden.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Lawson
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, DK-8000, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Preus
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, S-41296 Gothenburg, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Bood
authors.affiliation: AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Gradén
authors.affiliation: Department of Chemistry and Chemical Engineering/Chemistry and Biochemistry, Chalmers University of Technology, S-41296 Gothenburg, Sweden.
authors.forename: L Marcus
authors.initials: LM
authors.lastname: Wilhelmsson
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, S-41296 Gothenburg, Sweden.
authors.forename: Morten
authors.initials: M
authors.lastname: Grøtli
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000737:chemistry*
chemical_list: D005456:Fluorescent Dyes; D000225:Adenine