Physical properties and cytotoxicity of Cu(ii) and Zn(ii) complexes with a TMS-substituted indolo[2,3-c]quinoline-derived Schiff base

Abstract

The incorporation of non-native chemical elements, such as silicon, into drug molecules has gained significant attention as a strategy to broaden the chemical space in medicinal chemistry and develop novel drug candidates. Traditionally, research has focused on the isosteric replacement of a carbon atom with silicon (“silicon switch”) in known drug structures or the attachment of a trimethylsilyl (TMS) group to biologically active scaffolds. In this study, a TMS-substituted indoloquinoline-based Schiff base (HL^TMS) and its corresponding metal complexes, Cu(HL^TMS)Cl₂ (1) and Zn(HL^TMS)Cl₂ (2), were synthesized and comprehensively characterized using elemental analysis, spectroscopic techniques (IR, UV-vis, ¹H and ¹³C NMR for HL^TMS and 2), ESI mass spectrometry and single-crystal X-ray diffraction (SC-XRD) for 1 and electron diffraction (ED) for 2. The attachment of the TMS group enhanced the lipophilicity of HL^TMS, while complex formation with Cu(II) substantially improved the antiproliferative activity. Exploitation of their intrinsic fluorescence to investigate cellular uptake and intracellular localization in cancer cells was impeded by limited solubility. Both HL^TMS and 2 were found to generate reactive oxygen species under cell-free conditions in accord with their redox activity established by cyclic voltammetry. The photochemical activity of the indolo[2,3-c]quinoline-based proligand HL^TMS and its complexes 1 and 2 has been disclosed. The compounds exhibited significant toxicity on various human cancer cells and disrupted the mitochondrial membrane potential, suggesting the contribution of mitochondrial dysfunction, triggered by HL^TMS and its metal complexes, to their toxic effects. These findings highlight the potential of TMS-substituted Schiff bases as promising anticancer drug candidates.