title: Remarkable interference with telomeric function by a G-quadruplex selective bisantrene regioisomer.
abstract: The use of small molecules able to induce and stabilize selected G-quadruplex arrangements can cause telomerase inhibition and telomere dysfunction in cancer cells, thus providing very selective therapeutic approaches. Effective stabilizers usually comprise a planar aromatic portion to grant effective stacking onto the G-quartet and positively charged side chains to exploit the highly negative charge density on the quadruplex grooves. Since the relative position of these two pharmacophoric moieties is expected to play an important role in DNA folding stabilization, we evaluated a series of anthracene derivatives substituted with one or two 4,5-dihydro-1H-imidazol-2-yl-hydrazonic groups (the bisantrene side chain) at different positions of the aromatic system. Indeed, the various regioisomers showed distinct binding affinities for telomeric G-quadruplex, and the most effective was the 1,5 and 1,7 bis-substituted analogues. On turn, the 1,8 regioisomer was poorly effective. Interestingly, G-quadruplex binding is clearly related to telomerase inhibition in this class of compounds, thus confirming their ability to shift the nucleic acid conformational equilibrium upon binding and consequently produce interference with the telomere processing enzyme. Additionally, the 1,5 regioisomer was shown to inhibit telomerase activity at lower concentrations than those required to reduce tumor cell proliferation. Comparative analysis of drug effects in telomerase-positive and telomerase-negative cancer cells showed consistent cell growth impairment, as a consequence of activation of the senescence pathway, which was mainly attributable to anthracene-mediated telomere dysfunction.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy. marco.folini@istitutotumori.mi.it
authors.forename: Marco
authors.initials: M
authors.lastname: Folini
authors.forename: Claudia
authors.initials: C
authors.lastname: Pivetta
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zagotto
authors.forename: Cinzia
authors.initials: C
authors.lastname: De Marco
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: Claudia
authors.initials: C
authors.lastname: Sissi
mesh_terms: D000873:Anthracenes / Q000737:chemistry / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D054856:G-Quadruplexes; D006801:Humans; D020128:Inhibitory Concentration 50; D007536:Isomerism; D008545:Melanoma / Q000188:drug therapy; D015394:Molecular Structure; D009691:Nucleic Acid Denaturation; D012516:Osteosarcoma / Q000188:drug therapy; D013329:Structure-Activity Relationship; D019914:Taq Polymerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016615:Telomere / Q000187:drug effects*
chemical_list: D000873:Anthracenes; D000903:Antibiotics, Antineoplastic; C031404:bisantrene; D019914:Taq Polymerase; D019098:Telomerase