Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Exploring the Mechanisms Behind the Anti-tumoral Effects of Model C-scorpionate Complexes

Version 1 : Received: 1 June 2023 / Approved: 2 June 2023 / Online: 2 June 2023 (12:38:19 CEST)

A peer-reviewed article of this Preprint also exists.

Silva, P.M.G.; Pinheiro, P.F.; Camões, S.P.; Ribeiro, A.P.C.; Martins, L.M.D.R.S.; Miranda, J.P.G.; Justino, G.C. Exploring the Mechanisms behind the Anti-Tumoral Effects of Model C-Scorpionate Complexes. Molecules 2023, 28, 5451. Silva, P.M.G.; Pinheiro, P.F.; Camões, S.P.; Ribeiro, A.P.C.; Martins, L.M.D.R.S.; Miranda, J.P.G.; Justino, G.C. Exploring the Mechanisms behind the Anti-Tumoral Effects of Model C-Scorpionate Complexes. Molecules 2023, 28, 5451.

Abstract

The growing worldwide cancer incidence, coupled to the increasing occurrence of multidrug cancer resistance, requires a continuous effort towards the identification of new leads for cancer management. In this work, two C-scorpionate complexes, [FeCl2(κ3-Tpm)] (1) and [Co(κ3-TpmOH)2] (2), (Tpm = hydrotris(pyrazol-1-yl)methane and TpmOH = 2,2,2-tris(pyrazol-1-yl)ethanol), are studied as potential scaffolds for future anti-cancer drug development. Their cytotoxicity and cell migration inhibitory activity are analyzed, and an untargeted metabolomics approach is em-ployed to elucidate the biological processes significantly affected by these two complexes, using two tumoral cell lines (B16 and HCT116) and a non-tumoral cell line (HaCaT). While [FeCl2(κ3-Tpm)] did not display a significant cytotoxicity, [Co(κ3-TpmOH)2] was particularly cy-totoxic against the B16 cell line. While [Co(κ3-TpmOH)2] significantly inhibited cell migration in all tested cell lines, [FeCl2(κ3-Tpm)] displayed a mixed activity. From a metabolomics perspective, exposure to [FeCl2(κ3-Tpm)] is associated with changes in various metabolic pathways involving tyrosine, where iron-dependent enzymes are particularly relevant. On the other hand, [Co(κ3-TpmOH)2] is associated with dysregulation of cell adhesion and membrane structural pathways, suggesting its antiproliferative and anti-migration properties can be due to changes in the overall cellular adhesion mechanisms.

Keywords

C-scorpionate; anti-cancer drug; anti-proliferation; anti-migration; metabolomics

Subject

Chemistry and Materials Science, Medicinal Chemistry

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