title: Disordering of human telomeric G-quadruplex with novel antiproliferative anthrathiophenedione.
abstract: Linear heteroareneanthracenediones have been shown to interfere with DNA functions, thereby causing death of human tumor cells and their drug resistant counterparts. Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethyl)amino]anthra[2,3-b]thiophene-5,10-dione with telomeric DNA structures studied by isothermal titration calorimetry, circular dichroism and UV absorption spectroscopy. New compound demonstrated a high affinity (K(ass)∼10⁶ M⁻¹) for human telomeric antiparallel quadruplex d(TTAGGG)₄ and duplex d(TTAGGG)₄∶d(CCCTAA)₄. Importantly, a ∼100-fold higher affinity was determined for the ligand binding to an unordered oligonucleotide d(TTAGGG TTAGAG TTAGGG TTAGGG unable to form quadruplex structures. Moreover, in the presence of Na+ the compound caused dramatic conformational perturbation of the telomeric G-quadruplex, namely, almost complete disordering of G-quartets. Disorganization of a portion of G-quartets in the presence of K+ was also detected. Molecular dynamics simulations were performed to illustrate how the binding of one molecule of the ligand might disrupt the G-quartet adjacent to the diagonal loop of telomeric G-quadruplex. Our results provide evidence for a non-trivial mode of alteration of G-quadruplex structure by tentative antiproliferative drugs.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation. uzhny@mail.ru
authors.forename: Dmitry
authors.initials: D
authors.lastname: Kaluzhny
authors.forename: Nikolay
authors.initials: N
authors.lastname: Ilyinsky
authors.forename: Andrei
authors.initials: A
authors.lastname: Shchekotikhin
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sinkevich
authors.forename: Philipp O
authors.initials: PO
authors.lastname: Tsvetkov
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tsvetkov
authors.forename: Alexander
authors.initials: A
authors.lastname: Veselovsky
authors.forename: Mikhail
authors.initials: M
authors.lastname: Livshits
authors.forename: Olga
authors.initials: O
authors.lastname: Borisova
authors.forename: Alexander
authors.initials: A
authors.lastname: Shtil
authors.forename: Anna
authors.initials: A
authors.lastname: Shchyolkina
mesh_terms: D000880:Anthraquinones / Q000138:chemical synthesis / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002942:Circular Dichroism; D003110:Colonic Neoplasms / Q000188:drug therapy; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D009841:Oligonucleotides / Q000235:genetics / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C571868:4,11-bis((2-((acetimido)amino)ethyl)amino)anthra(2,3-b)thiophene-5,10-dione; D000880:Anthraquinones; D009841:Oligonucleotides; D013876:Thiophenes; D012964:Sodium; D011188:Potassium
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