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

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

doi:10.1021/acs.inorgchem.1c03154

Abstract

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 RuII and OsII 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 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.

Highlights

Microtubules, microfilaments, and intermediate filaments represent three major types of building blocks that make up the cell cytoskeleton.[1]
J was hydrolyzed using lithium hydroxide followed by acidic work up and recrystallization from ethanol to give K in 92% yield (Scheme 4)
We developed novel tubulintargeting compounds using the scarcely discussed indolo[2,3d]benzazepine scaffold

Summary

Introduction

Microtubules, microfilaments, and intermediate filaments represent three major types of building blocks that make up the cell cytoskeleton.[1] These proteins differ in their structural organization and function. In contrast to intermediate filaments, whose function is strictly structural,[2] microfilaments and microtubules are highly dynamic structures. Microfilaments are flexible helical structures which are responsible for the cell movement and are predominantly composed of the most abundant protein actin.[3] Microtubules are rigid hollow structures composed of α- and β-subunits of tubulin, responsible for maintaining cell shape, motility, and division. At any point of time, a subset of microtubules is rapidly growing by the addition of tubulin to their plus ends, while another subset is shrinking by depolymerization or pausing, thereby allowing rapid reorganization of cell cytoskeleton.[4,5]

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Conclusion