2. Academic Validation
  3. Amides of pyrrole- and thiophene-fused anthraquinone derivatives: A role of the heterocyclic core in antitumor properties

Amides of pyrrole- and thiophene-fused anthraquinone derivatives: A role of the heterocyclic core in antitumor properties

  • Eur J Med Chem. 2020 Aug 1;199:112294. doi: 10.1016/j.ejmech.2020.112294.
Alexander S Tikhomirov 1,  Valeria A Litvinova 2,  Daria V Andreeva 2,  Vladimir B Tsvetkov 3,  Lyubov G Dezhenkova 2,  Yulia L Volodina 4,  Dmitry N Kaluzhny 5,  Ivan D Treshalin 2,  Dominique Schols 6,  Alla A Ramonova 7,  Mikhail M Moisenovich 7,  Alexander A Shtil 4,  Andrey E Shchekotikhin 8
Affiliations

Affiliations

  • 1 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow, 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow, 125047, Russian Federation.
  • 2 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow, 119021, Russia.
  • 3 Computational Oncology Group, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya, 119991, Moscow, Russia; Research and Clinical Center for Physical Chemical Medicine, 1A M. Pirogovskaya Street, Moscow, 119435, Russia.
  • 4 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow, 119021, Russia; Blokhin National Medical Center of Oncology, 24 Kashirskoye Shosse, Moscow, 115478, Russia.
  • 5 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow, 119991, Russia.
  • 6 Rega Institute for Medical Research, K.U. Leuven, 3000, Leuven, Belgium.
  • 7 Department of Biology, Moscow State University, 1 Leninskie Gory, Moscow, 119234, Russia.
  • 8 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow, 119021, Russia. Electronic address: shchekotikhin@gause-inst.ru.
PMID: 32428792 DOI: 10.1016/j.ejmech.2020.112294
Abstract

Heteroarene-fused anthraquinone derivatives represent a class of perspective Anticancer drug candidates capable of targeting multiple vital processes including drug resistance. Taking advantage of previously demonstrated potential of amide derivatives of heteroarene-fused Anthraquinones, we herein dissected the role of the heterocyclic core in antitumor properties. A new series of naphtho[2,3-f]indole-3- and anthra[2,3-b]thiophene-3-carboxamides was synthesized via coupling the respective acids with cyclic diamines. New compounds demonstrated a submicromolar antiproliferative potency close to doxorubicin (Dox) against five tumor cell lines of various tissue origin. In contrast to Dox, the new compounds were similarly cytotoxic for HCT116 colon carcinoma cells (wild type p53) and their isogenic p53 knockout counterparts. Modification of the heterocyclic core changed the targeting properties: the best-in-series naphtho[2,3-f]indole-3-carboxamide 8 formed more affine complexes with DNA duplex than furan and thiophene analogs, a property that can be translated into a stronger inhibition of Topoisomerase 1 mediated DNA unwinding. At tolerable doses the water soluble derivative 8 significantly inhibited tumor growth (up to 79%) and increased the lifespan (153%) of mice bearing P388 lymphoma transplants. Together with better solubility for parenteral administration and well tolerance by Animals of the indole derivative 8 indicates prospects for further search of new antitumor drug candidates among the heteroarene-fused Anthraquinones.

Keywords

Anthraquinone; Antitumor activity; Apoptosis; DNA binding; Indole; Multidrug resistance; Reactive oxygen species; Structure-activity relationship; Thiophene; Topoisomerase 1.

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