Synthesis and biological evaluation of 1-(4′-Indolyl and 6′-Quinolinyl) indoles as a new class of potent anticancer agents

A novel series of the biheterocycles-based compounds with core structure distinguished from combretastatin A-4 (1) and colchicine (5) have been synthesized and evaluated as potent anti-mitotic agents. Compound 1-(4′-Indolyl and 6′-quinolinyl)-4,5,6-trimethoxyindoles 13 and 19 showed substantial anti-proliferative activity against various human cancer cell lines, regardless to the tissue origin and the expression of multiple-drug resistance MDR1, with a mean IC50 value of 38 and 24 nM respectively. Compound 13 (IC50 = 1.7 μM) also exhibited similar anti-tubulin activities to 1 (IC50 = 1.8 μM) and displayed strong binding property to the colchicine binding site on the microtubules. Computational modeling analysis revealed that the binding mechanism of compound 13 is similar to that of CA4.

A novel series of biheterocycles-based compounds, 1-(heteroaryl)-4,5,6-trimethoxyindoles, exhibits substantial microtubule destabilizing activity through interference with the colchicine binding site of the microtubule.Figure optionsDownload as PowerPoint slideHighlights
► 1-(4′-Indolyl and 6′-quinolinyl)indoles as potent anti-mitotic agents.
► Rational design from natural product (cis-stilbene) to afford the biheterocycles.
► Application of copper-mediated 1-arylation of indole.