A Novel Substituted Benzo[ g ]quinoxaline-Based Cyclometalated Ru(II) Complex as a Biocompatible Membrane-Targeted PDT Colon Cancer Stem Cell Agent.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE

Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-

Colonic Neoplasms*/drug therapy ; Colonic Neoplasms*/pathology ; Photochemotherapy* ; Quinoxalines*/chemistry ; Quinoxalines*/pharmacology ; Quinoxalines*/chemical synthesis ; Photosensitizing Agents*/pharmacology ; Photosensitizing Agents*/chemistry ; Photosensitizing Agents*/chemical synthesis ; Photosensitizing Agents*/therapeutic use ; Ruthenium*/chemistry ; Ruthenium*/pharmacology ; Neoplastic Stem Cells*/drug effects ; Neoplastic Stem Cells*/pathology ; Coordination Complexes*/pharmacology ; Coordination Complexes*/chemistry ; Coordination Complexes*/chemical synthesis ; Coordination Complexes*/therapeutic use ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemistry ; Antineoplastic Agents*/chemical synthesis ; Antineoplastic Agents*/therapeutic use; Humans ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Apoptosis/drug effects ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism

Herein, we describe and investigate biological activity of three octahedral ruthenium(II) complexes of the type [Ru(C ^∧ N)(phen) 2 ] ⁺ , RuL1 - RuL3 , containing a π-expansive cyclometalating substituted benzo[ g ]quinoxaline ligand (C ^∧ N ligand) (phen = 1,10-phenanthroline). Compounds RuL1 - RuL3 in cervical, melanoma, and colon human cancer cells exhibit high phototoxicity after irradiation with light (particularly blue), with the phototoxicity index reaching 100 for the complex RuL2 in most sensitive HCT116 cells. RuL2 accumulates in the cellular membranes. If irradiated, it induces lipid peroxidation, likely connected with photoinduced ROS generation. Oxidative damage to the fatty acids leads to the attenuation of the membranes, the activation of caspase 3, and the triggering of the apoptotic pathway, thus implementing membrane-localized photodynamic therapy. RuL2 is the first photoactive ruthenium-based complex capable of killing the hardly treatable colon cancer stem cells, a highly resilient subpopulation within a heterogeneous tumor mass, responsible for tumor recurrence and the metastatic progression of cancer.

0 (Quinoxalines)
0 (Photosensitizing Agents)
7UI0TKC3U5 (Ruthenium)
0 (Coordination Complexes)
0 (Antineoplastic Agents)
0 (Reactive Oxygen Species)

Date Created: 20241202 Date Completed: 20241212 Latest Revision: 20241216

20241216

10.1021/acs.jmedchem.4c02357

39620973