A Novel Substituted\nBenzo[<i>g</i>]quinoxaline-Based\nCyclometalated Ru(II) Complex as a Biocompatible Membrane-Targeted\nPDT Colon Cancer Stem Cell Agent

Herein, we describe and investigate biological activity\nof three\noctahedral ruthenium(II) complexes of the type [Ru(C<sup>∧</sup>N)(phen)<sub>2</sub>]<sup>+</sup>, <b>RuL1</b>–<b>RuL3</b>, containing a π-expansive cyclometalating substituted\nbenzo[<i>g</i>]quinoxaline ligand (C<sup>∧</sup>N\nligand) (phen = 1,10-phenanthroline). Compounds <b>RuL1</b>–<b>RuL3</b> in cervical, melanoma, and colon human cancer cells exhibit\nhigh phototoxicity after irradiation with light (particularly blue),\nwith the phototoxicity index\nreaching 100 for the complex <b>RuL2</b> in most sensitive HCT116\ncells. <b>RuL2</b> accumulates in the cellular membranes. If\nirradiated, it induces lipid peroxidation, likely connected with photoinduced\nROS generation. Oxidative damage to the fatty acids leads to the attenuation\nof the membranes, the activation of caspase 3, and the triggering\nof the apoptotic pathway, thus implementing membrane-localized photodynamic\ntherapy. <b>RuL2</b> is the first photoactive ruthenium-based\ncomplex capable of killing the hardly treatable colon cancer stem\ncells, a highly resilient subpopulation within a heterogeneous tumor\nmass, responsible for tumor recurrence and the metastatic progression\nof cancer.