Development of bright fluorescent quadracyclic adenine analogues: TDDFT-calculation supported rational design

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 (epsilon Phi(F) = 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.

Dumat, Blaise,1984Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)blaise (författare)
Sandberg Wranne, Moa,1986Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)moasan (författare)
Lawson, Christopher,1968Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,University of Gothenburg(Swepub:cth)lawson (författare)
Preus, S.Århus Universitet,Aarhus University (författare)
Bood, MattiasGothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,University of Gothenburg(Swepub:gu)xbooma (författare)
Gradén, Henrik,1968AstraZeneca AB(Swepub:cth)grade (författare)
Wilhelmsson, Marcus,1974Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)mawi (författare)
Grøtli, Morten,1966Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,University of Gothenburg(Swepub:cth)grotli (författare)
Füchtbauer, Anders Foller,1984Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)foller (författare)
Chalmers tekniska högskolaInstitutionen för kemi och molekylärbiologi (creator_code:org_t)

Av författaren/redakt...: Larsen, Anders F ...; Dumat, Blaise, 1 ...; Sandberg Wranne, ...; Lawson, Christop ...; Preus, S.; Bood, Mattias; visa fler...; Gradén, Henrik, ...; Wilhelmsson, Mar ...; Grøtli, Morten, ...; Füchtbauer, Ande ...; visa färre...

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