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: esvir@yandex.ru.
6 Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, 603950 Nizhny Novgorod, Russian Federation. Electronic address: afnn@rambler.ru.

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.

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