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Synthesis of New DNA G‐Quadruplex Constructs with Anthraquinone Insertions and Their Anticoagulant Activity
Author(s) -
Gouda Alaa S.,
Amine Mahasen S.,
Pedersen Erik B.
Publication year - 2016
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.201500207
Subject(s) - chemistry , anthraquinone , linker , g quadruplex , stereochemistry , dna , aptamer , combinatorial chemistry , organic chemistry , biochemistry , microbiology and biotechnology , computer science , biology , operating system
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 G 8 or T 9 in the TGT loop showed improved anticoagulant activities. Molecular modeling studies explained the increased thermal melting temperatures of anthraquinone‐modified G‐quadruplexes.