title: Site specific replacements of a single loop nucleoside with a dibenzyl linker may switch the activity of TBA from anticoagulant to antiproliferative.
abstract: Many antiproliferative G-quadruplexes (G4s) arise from the folding of GT-rich strands. Among these, the Thrombin Binding Aptamer (TBA), as a rare example, adopts a monomolecular well-defined G4 structure. Nevertheless, the potential anticancer properties of TBA are severely hampered by its anticoagulant action and, consequently, no related studies have appeared so far in the literature. We wish to report here that suitable chemical modifications in the TBA sequence can preserve its antiproliferative over anticoagulant activity. Particularly, we replaced one residue of the TT or TGT loops with a dibenzyl linker to develop seven new quadruplex-forming TBA based sequences (TBA-bs), which were studied for their structural (CD, CD melting, 1D NMR) and biological (fibrinogen, PT and MTT assays) properties. The three-dimensional structures of the TBA-bs modified at T13 (TBA-bs13) or T12 (TBA-bs12), the former endowed with selective antiproliferative activity, and the latter acting as potently as TBA in both coagulation and MTT assays, were further studied by 2D NMR restrained molecular mechanics. The comparative structural analyses indicated that neither the stability, nor the topology of the G4s, but the different localization of the two benzene rings of the linker was responsible for the loss of the antithrombin activity for TBA-bs13.
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Scuotto
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Rivieccio
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Varone
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Corda
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vellecco
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Virgilio
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Esposito
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Galeone
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy nicola.borbone@unina.it.
authors.forename: Nicola
authors.initials: N
authors.lastname: Borbone
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy varra@unina.it.
authors.forename: Michela
authors.initials: M
authors.lastname: Varra
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Mayol
mesh_terms: D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D052157:Aptamers, Nucleotide / Q000737:chemistry* / Q000494:pharmacology; D001593:Benzyl Compounds / Q000737:chemistry; D001780:Blood Coagulation Tests; D049109:Cell Proliferation / Q000187:drug effects; D005340:Fibrinogen; D054856:G-Quadruplexes; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D009691:Nucleic Acid Denaturation; D009841:Oligonucleotides / Q000138:chemical synthesis; D011517:Prothrombin Time
chemical_list: D000925:Anticoagulants; D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D001593:Benzyl Compounds; D009841:Oligonucleotides; C081676:thrombin aptamer; D005340:Fibrinogen