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

作者：Wittmann, Christopher; Sivchenko, Anastasiia S.; Bacher, Felix; Tong, Kelvin K. H.; Guru, Navjot; Wilson, Thomas; Gonzales, Junior; Rauch, Hartmut; Kossatz, Susanne; Reiner, Thomas^*; Babak, Maria, V^*; Arion, Vladimir B.^*

来源：Inorganic Chemistry, 2022, 61(3): 1456-1470.

DOI：10.1021/acs.inorgchem.1c03154

• TUBULIN INHIBITORS
• KINASE INHIBITORS
• RESISTANCE
• COLCHICINE
• MORPHOLINE
• ANALOGS
• SOLUBILITY
• RUTHENIUM
• PAULLONES
• THERAPY

Indolo[2,3-d]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 (H-1 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 H-1 and C-13 NMR and UV-vis spectroscopy. Novel indololatonduines demonstrated anticancer activity in vitro in a low micromolar concentration range, while their coordination to metal centers resulted in a decrease of cytotoxicity. The preliminary in vivo activity of the RuII complex was investigated. Fluorescence staining and in vitro tubulin polymerization assays revealed the prepared compounds to have excellent microtubule-destabilizing activities, even more potent than the well-known microtubule-destabilizing agent colchicine.