Synthesis of New DNA G‐Quadruplex Constructs with Anthraquinone Insertions and Their Anticoagulant Activity |
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Authors: | Alaa S Gouda Mahasen S Amine Erik B Pedersen |
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Institution: | 1. Department of Physics, Chemistry and Pharmacy, Nucleic Acid Center, University of Southern Denmark, Campusvej 55, DK‐5230 Odense M (phone: +45?65502555);2. Department of Chemistry, Faculty of Science, Benha University, Benha, Egypt 13518 |
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Abstract: | 1,4‐Dihydroxyanthraquinone and 1,8‐dihydroxyanthraquinone were alkylated with 3‐bromopropan‐1‐ol and subsequently transformed into the corresponding DMT protected phosphoramidite building blocks for insertion into loops of the G‐quadruplex of the thrombin binding aptamer (TBA). The 1,4‐disubstituted anthraquinone linker led to a significant stabilization of the G‐quadruplex structure upon replacing a T in each of two neighboring lateral TT loops and a 26.2° increase in thermal melting temperature was found. CD Spectra of the modified quadruplexes confirmed anti‐parallel conformations in all cases under potassium buffer conditions as previously observed for TBA. Although the majority of the anthraquinone modified TBA analogues showed a decrease in clotting times in a fibrinogen clotting assay when compared to TBA, modified aptamers containing a 1,8‐disubstituted anthraquinone linker replacing G8 or T9 in the TGT loop showed improved anticoagulant activities. Molecular modeling studies explained the increased thermal melting temperatures of anthraquinone‐modified G‐quadruplexes. |
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Keywords: | DNA Anthraquinone monomer G‐Quadruplex aptamer Thermal stability Molecular modeling Anti‐thrombin activity |
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