Expanding on the plecstatin anticancer agent class: exchange of the chlorido ligand for N-heterocyclic ligands

Saawan Kumar; Mie Riisom; Stephen M. F. Jamieson; Tilo Söhnel; Suresh Bhargava; Jing Sun; Christian G. Hartinger

doi:10.1071/CH24080

RESEARCH ARTICLE (Open Access)

Expanding on the plecstatin anticancer agent class: exchange of the chlorido ligand for N-heterocyclic ligands

Saawan Kumar ^A ^B , Mie Riisom ^A ^C , Stephen M. F. Jamieson ^C , Tilo Söhnel ^A , Suresh Bhargava ^D , Jing Sun ^E and Christian G. Hartinger

^A ^*

+ Author Affiliations

- Author Affiliations

^A School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.

^B School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.

^C Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.

^D Centre for Advanced Materials and Industrial Chemistry, School of Science, RMIT University, Melbourne, Vic. 3000, Australia.

^E State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, 130012, PR China.

^* Correspondence to: c.hartinger@auckland.ac.nz

Handling Editor: Curt Wentrup

Australian Journal of Chemistry 77, CH24080 https://doi.org/10.1071/CH24080

Submitted: 6 June 2024 Accepted: 6 August 2024 Published online: 13 September 2024

© 2024 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)

Abstract

Metal piano-stool complexes based on pyridinecarbothioamide (PCA) have shown promising antiproliferative and in vivo anticancer activity, in particular [Ru(cym)(p-F-PCA)Cl]PF₆ (cym is η⁶-p-cymene; plecstatin-1). The impact of modifications of the PCA and π-bound ligands on biological properties has been extensively investigated. Herein, we explored the influence of exchanging the chlorido ligand with the N-heterocycles 1-methylimidazole, 1-methylbenzimidazole and pyridine. In solution, an equilibrium between the protonated and deprotonated forms of the thioamide bond was observed, which was found dictated by the solvent system with both species detected in polar solvents. [Ru(cym)(PCA)Cl]⁺ complexes exhibit unique behaviour in an aqueous environment where they rapidly form dimeric species after substitution of the chlorido ligand for the sulfur donor of the PCA ligand of a second complex molecule. This was also observed for the synthesised complexes with the N-heterocyclic ligands being cleaved from the Ru centre allowing for dimerisation, which may be reversed by acidification of the solution resulting in the formation of equivalent mononuclear compounds. This behaviour explains the similar biological properties of the complexes with respect to that of plecstatin-1.

Keywords: anticancer compounds, antiproliferative activity, bioinorganic chemistry, bioorganometallic chemistry, dimerisation, ligand exchange reactions, piano-stool compounds, plecstatin-1, pyridinecarbothioamide complexes, synthesis.

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