A novel benzothiazole-1,2,3-triazole-based arene osmium(ii) complex as an effective rhabdomyosarcoma cancer stem cell agent†

Abstract

We designed a series of pseudo-octahedral arene Os(II) complexes (Os1–Os5) with the general formula [(η⁶-p-cym)Os(BTAT)Cl]⁺, where BTAT represents chelating N^N′ ligands based on the 1-aryl-4-benzothiazolyl-1,2,3-triazole scaffold. The structures of Os3 and Os5 were confirmed by X-ray diffraction, and Os5 exhibits a bathochromic shift in its absorption band compared to the other complexes, likely due to the electron-donating properties of the substituent NMe₂. Os5 also hydrolyzed without losing its BTAT ligand and exhibited the highest cellular accumulation in Rhabdomyosarcoma (RD) cancer cells. The investigated Os(II) complexes demonstrated moderate antiproliferative activity across six cancer cell lines, with Os5 being the most potent, showing activity comparable to or better than conventional cisplatin. Cellular accumulation was a key factor influencing their antiproliferative effect, though binding to human serum albumin did not play a significant role. Further studies with Os5 in RD cells, the most responsive cell line, revealed that its mechanism of action includes mitochondrial dysfunction, apoptosis via a caspase-dependent pathway, and cell cycle arrest at the G1 phase. Os5 also increased the production/generation of reactive oxygen species (ROS) in RD cells, implicating ROS production as a contributor to its activity. Importantly, Os5 was effective against cancer stem cells (CSCs) in 3D spheroid models, marking the first report of an osmium-based compound targeting CSC-enriched RD cells. This highlights the potential of Os5 as a CSC-targeted therapy, addressing the need for treatments that prevent relapse and metastasis. The study underscores the promising role of metal-based complexes in cancer stem cell chemotherapy.