Synthesis and evaluation of new antitumor 3-aminomethyl-4,11-dihydroxynaphtho[2,3-f]indole-5,10-diones

  • Eur J Med Chem. 2014 Oct 30:86:797-805. doi: 10.1016/j.ejmech.2014.09.021.
Andrey E Shchekotikhin  1 ,  Valeria A Glazunova  2 ,  Lyubov G Dezhenkova  3 ,  Yuri N Luzikov  3 ,  Vladimir N Buyanov  4 ,  Helena M Treshalina  5 ,  Nina A Lesnaya  5 ,  Vladimir I Romanenko  5 ,  Dmitry N Kaluzhny  6 ,  Jan Balzarini  7 ,  Keli Agama  8 ,  Yves Pommier  8 ,  Alexander A Shtil  2 ,  Maria N Preobrazhenskaya  3
Affiliations
  • 1. Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia. Electronic address: [email protected].
  • 2. Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia; Moscow Engineering and Physics Institute, 31 Kashirskoye Shosse, Moscow 115409, Russia.
  • 3. Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
  • 4. Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia.
  • 5. Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia.
  • 6. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
  • 7. Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
  • 8. Developmental Therapeutics Branch, National Cancer Institute, NIH, 37 Convent Drive, 37-5068, Bethesda, MD 20892, USA.
PMID: 25244612 DOI: 10.1016/j.ejmech.2014.09.021
Abstract

A series of new 3-aminomethyl-4,11-dihydroxynaphtho[2,3-f]indole-5,10-diones 6-13 bearing the cyclic diamine in the position 3 of the indole ring was synthesized. The majority of new compounds demonstrated a superior cytotoxicity than doxorubicin against a panel of mammalian tumor cells with determinants of altered drug response, that is, Pgp expression or p53 inactivation. For naphtho[2,3-f]indole-5,10-diones 6-9 bearing 3-aminopyrrolidine in the side chains, the ability to bind double-stranded DNA and inhibit topoisomerases 1 and 2 mediated relaxation of supercoiled DNA were demonstrated. Only one isomer, (R)-4,11-dihydroxy-3-((pyrrolidin-3-ylamino)methyl)-1H-naphtho[2,3-f]indole-5,10-dione (7) induced the formation of specific DNA cleavage products similar to the known Topoisomerase 1 inhibitors camptothecin and indenoisoquinoline MJ-III-65, suggesting a role of the structure of the side chain of 3-aminomethylnaphtho[2,3-f]indole-5,10-diones in interaction with the target. Compound 7 demonstrated an antitumor activity in mice with P388 leukemia transplants whereas its enantiomer 6 was inactive. Thus, 3-aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione emerge as a new prospective chemotype for the search of antitumor agents.

Keywords
Antitumor activity; Circumvention of multidrug resistance; DNA ligands; Naphtho[2,3-f]indole-5,10-diones; Topoisomerase 1/2 inhibitors.