Synthesis and biological evaluation of novel non-racemic indole-containing allocolchicinoids

  • Eur J Med Chem. 2017 Dec 1:141:51-60. doi: 10.1016/j.ejmech.2017.09.055.
Ekaterina S Shchegravina  1 ,  Alexander A Maleev  1 ,  Stanislav K Ignatov  1 ,  Iuliia A Gracheva  1 ,  Andreas Stein  2 ,  Hans-Günther Schmalz  2 ,  Andrey E Gavryushin  3 ,  Anastasiya A Zubareva  4 ,  Elena V Svirshchevskaya  5 ,  Alexey Yu Fedorov  6
Affiliations
  • 1. Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, 603950 Nizhny Novgorod, Russian Federation.
  • 2. Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne, Germany.
  • 3. Ludwig-Maximilians-Universität, Butenandtstrasse 5-13, 81377 Munich, Germany.
  • 4. Institute of Bioengineering, Research Center of Biotechnology RAS, Leninsky Prospect 33, 119071 Moscow, Russian Federation.
  • 5. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya Street 16/10, 117997 Moscow, Russian Federation. Electronic address: [email protected].
  • 6. Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, 603950 Nizhny Novgorod, Russian Federation. Electronic address: [email protected].
PMID: 29028531 DOI: 10.1016/j.ejmech.2017.09.055
Abstract

Two novel indole-containing allocolchicinoids were prepared from naturally occurring colchicine exploiting the Curtius rearrangement and tandem Sonogashira coupling/Pd-catalyzed cyclization as the key transformations. Their cytotoxic properties, apoptosis-inducing activity, tubulin assembly inhibition and short-time cytotoxic effects were investigated. Compound 7 demonstrated the most pronounced anti-cancer activity: IC50 < 1 nM, cell cycle arrest in the G2/M phase, 25% Apoptosis induction, as well as lower destructive short-time effects on HT-29 cell line in comparison with colchicine. Docking studies for prepared indole-derived allocolchicine analogues were carried out.

Keywords
Antimitotics; Apoptosis; Colchicine; Colchicine site of tubulin; Cytotoxicity; Heterocyclic allocolchicinoids; Short-time effects; Tubulin.