Inhibition of Microtubule Dynamics in Cancer Cells by Indole-Modified Latonduine Derivatives and Their Metal Complexes

Abstract

Indolo[2,3-<i>d</i>]benzazepines (indololatonduines) are rarely discussed in the literature. In this project, we prepared a series of novel indololatonduine derivatives and their Ru^II and Os^II complexes and investigated their microtubule-targeting properties in comparison with paclitaxel and colchicine. Compounds were fully characterized by spectroscopic techniques (¹H NMR and UV-vis), ESI mass-spectrometry, and X-ray crystallography, and their purity was confirmed by elemental analysis. The stabilities of the compounds in DMSO and water were confirmed by ¹H and ¹³C NMR and UV-vis spectroscopy. Novel indololatonduines demonstrated anticancer activity <i>in vitro</i> in a low micromolar concentration range, while their coordination to metal centers resulted in a decrease of cytotoxicity. The preliminary <i>in vivo</i> activity of the Ru^II complex was investigated. Fluorescence staining and <i>in vitro</i> tubulin polymerization assays revealed the prepared compounds to have excellent microtubule-destabilizing activities, even more potent than the well-known microtubule-destabilizing agent colchicine.