Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib – impact of the organometallic group on the antimitotic activity

Michał Łomzik; Andrzej Błauż; Marta Głodek; Anna Makal; Daniel Tchoń; Daniel Moscoh Ayine-Tora; Christian Hartinger; Błażej Rychlik; Damian Plażuk

doi:10.1039/D3DT01217D

Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib – impact of the organometallic group on the antimitotic activity†

Michał Łomzik,

^a Andrzej Błauż,

^b Marta Głodek,

^a Anna Makal,^c Daniel Tchoń,

^cf Daniel Moscoh Ayine-Tora,^d Christian Hartinger,

^e Błażej Rychlik

^b and Damian Plażuk

*^a

Author affiliations

* Corresponding authors

^a Department of Organic Chemistry, Faculty of Chemistry, University of Lodz, ul. Tamka 12, 91-403 Łódź, Poland
E-mail: damian.plazuk@chemia.uni.lodz.pl

^b Cytometry Lab, Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, ul. Pomorska 141/143, 90-236 Łódź, Poland

^c Laboratory for Structural and Biochemical Research (LBSBio), Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, ul. Zwirki i Wigury 101, 02-089 Warszawa, Poland

^d Department of Chemistry, University of Ghana, LG 56, Legon-Accra, Ghana

^e School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

^f Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

Abstract

Antimitotic agents are among the most important drugs used in anticancer therapy. Kinesin spindle protein (KSP) was proposed as a promising target for new antimitotic drugs. Herein, we report the synthesis of Ru, Os, Rh, and Ir half-sandwich complexes with the KSP inhibitor ispinesib and its (S)-enantiomer. Conjugation of the organometallic moiety with ispinesib and its (S)-enantiomer resulted in a significantly increased cytotoxicity of up to 5.6-fold compared to the parent compounds, with IC₅₀ values in the nanomolar range. The most active derivatives were the ispinesib Ru and Rh conjugates which were able to generate reactive oxygen species (ROS), which may at least partially explain their high cytotoxicity. At the same time, the Os and Ir derivatives acted as KSP inhibitors with no effects on ROS generation.

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DOI: https://doi.org/10.1039/D3DT01217D
Article type: Paper
Submitted: 23 Apr 2023
Accepted: 10 Jul 2023
First published: 11 Jul 2023

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Dalton Trans., 2023,52, 11859-11874

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Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib – impact of the organometallic group on the antimitotic activity

M. Łomzik, A. Błauż, M. Głodek, A. Makal, D. Tchoń, D. M. Ayine-Tora, C. Hartinger, B. Rychlik and D. Plażuk, Dalton Trans., 2023, 52, 11859 DOI: 10.1039/D3DT01217D

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Dalton Transactions

Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib – impact of the organometallic group on the antimitotic activity†

Abstract

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Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib – impact of the organometallic group on the antimitotic activity

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