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

• DOI: 10.1016/j.ejmech.2017.09.055
• Publication Date: 2017-09-28T06:00:22Z
• Authors: Ekaterina S. Shch...; Alexander A. Maleev; Stanislav K. Ignatov; Iuliia A. Gracheva; Andreas Stein; Hans-Günther Schmalz; Andrey E. Gavryushin; Anastasiya A. Zub...; Elena V. Svirshch...; Alexey Yu. Fedorov
• Keywords: 0301 basic medicine; Indoles; Dose-Response Relationship, Drug; Molecular Structure; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; 01 natural sciences; 0104 chemical sciences; 3. Good health; Molecular Docking Simulation; Structure-Activity Relationship; 03 medical and health sciences; Tumor Cells, Cultured; Humans; Drug Screening Assays, Antitumor; Colchicine; Cell Proliferation

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.