Tri-armed ligands of G-quadruplex on heteroarene-fused anthraquinone scaffolds: Design, synthesis and pre-screening of biological properties

  • Eur J Med Chem. 2018 Nov 5:159:59-73. doi: 10.1016/j.ejmech.2018.09.054.
Alexander S Tikhomirov  1 ,  Vladimir B Tsvetkov  2 ,  Dmitry N Kaluzhny  3 ,  Yulia L Volodina  4 ,  George V Zatonsky  5 ,  Dominique Schols  6 ,  Andrey E Shchekotikhin  7
Affiliations
  • 1. Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow, 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow, 125190, Russia.
  • 2. Research Institute of Influenza, 15/17 Professor Popov Street, St. Petersburg, 197376, Russia; Research and Clinical Center for Physical Chemical Medicine, 1A M. Pirogovskaya Street, Moscow, 119435, Russia; Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 29 Leninsky Prospect, Moscow, 119991, Russia.
  • 3. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow, 119991, Russia.
  • 4. Blokhin National Medical Research Center of Oncology, 24 Kashirskoye Shosse, Moscow, 115478, Russia.
  • 5. Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow, 119021, Russia.
  • 6. Rega Institute for Medical Research, K.U. Leuven, 3000, Leuven, Belgium.
  • 7. Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow, 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow, 125190, Russia. Electronic address: [email protected].
PMID: 30268824 DOI: 10.1016/j.ejmech.2018.09.054
Abstract

Here, a combined molecular modelling methodology was used to identify the binding mode of 4,11-bis((2-guanidinoethyl)amino)anthra[2,3-b]thiophene-5,10-dione (1), a previously reported G4 ligand. After calculating the optimal interaction parameters 1 with the target, two series of tri-armed ligands based on furan- or thiophene-fused anthraquinone scaffolds were designed and synthesized. The new compounds bearing an additional side chain at the 2-position of the heterocycle and the 4,11-side chains with different spacer lengths and structures of terminal groups demonstrated much stronger affinity for telomeric G4 (4-15 times) versus the parental ligand. Moreover, the specificity to the quadruplex over duplex DNA was significantly improved (up to 75 times) when the 3-guanidinopropyl side chain was introduced at the 2-position of the heterocycle ring. All tri-armed ligands demonstrated modest antiproliferative potency, which is likely due to low intracellular penetration. Nevertheless, this work shows how computer-aided rational design of new potent compounds can be used for targeted Anticancer therapy.

Keywords
Anthraquinone; Anticancer agents; G-quadruplex; Ligands; Molecular modelling; Telomerase; anthra[2,3-b]furan-5,10-dione; anthra[2,3-b]thiophene-5,10-dione.