Singlet Oxygen Formation vs Photodissociation for Light-Responsive Protic Ruthenium Anticancer Compounds: The Oxygenated Substituent Determines Which Pathway Dominates

• Published in: Inorganic chemistry 2021-02, Vol.60 (4), p.2138-2148
• Main Authors: Qu, Fengrui, Lamb, Robert W, Cameron, Colin G, Park, Seungjo, Oladipupo, Olaitan, Gray, Jessica L, Xu, Yifei, Cole, Houston D, Bonizzoni, Marco, Kim, Yonghyun, McFarland, Sherri A, Webster, Charles Edwin, Papish, Elizabeth T
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Cell Hypoxia; Cell Line, Tumor; Coordination Complexes - chemistry; Humans; Ligands; Light; Models, Molecular; Molecular Structure; Neoplasms - drug therapy; Neoplasms - metabolism; Photochemical Processes; Protons; Ruthenium Compounds - chemistry; Singlet Oxygen - chemistry; Singlet Oxygen - metabolism; Spectrophotometry, Ultraviolet
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/acs.inorgchem.0c02027

Ruthenium complexes bearing protic diimine ligands are cytotoxic to certain cancer cells upon irradiation with blue light. Previously reported complexes of the type [(N,N)2Ru­(6,6′-dhbp)]­Cl2 with 6,6′-dhbp = 6,6′-dihydroxybipyridine and N,N = 2,2′-bipyridine (bipy) (1 A ), 1,10-phenanthroline (phen) (2 A ), and 2,3-dihydro-[1,4]­dioxino­[2,3-f]­[1,10]­phenanthroline (dop) (3 A ) show EC50 values as low as 4 μM (for 3 A ) vs breast cancer cells upon blue light irradiation ( Inorg. Chem. 2017, 56, 7519 ). Herein, subscript A denotes the acidic form of the complex bearing OH groups, and B denotes the basic form bearing O– groups. This photocytotoxicity was originally attributed to photodissociation, but recent results suggest that singlet oxygen formation is a more plausible cause of photocytotoxicity. In particular, bulky methoxy substituents enhance photodissociation but these complexes are nontoxic ( Dalton Trans 2018, 47, 15685 ). Cellular studies are presented herein that show the formation of reactive oxygen species (ROS) and apoptosis indicators upon treatment of cells with complex 3 A and blue light. Singlet oxygen sensor green (SOSG) shows the formation of 1O2 in cell culture for cells treated with 3 A and blue light. At physiological pH, complexes 1 A -3 A are deprotonated to form 1 B -3 B in situ. Quantum yields for 1O2 (ϕΔ) are 0.87 and 0.48 for 2 B and 3 B , respectively, and these are an order of magnitude higher than the quantum yields for 2 A and 3 A . The values for ϕΔ show an increase with 6,6′-dhbp derived substituents as follows: OMe < OH < O–. TD-DFT studies show that the presence of a low lying triplet metal-centered (3MC) state favors photodissociation and disfavors 1O2 formation for 2 A and 3 A (OH groups). However, upon deprotonation (O– groups), the 3MLCT state is accessible and can readily lead to 1O2 formation, but the dissociative 3MC state is energetically inaccessible. The changes to the energy of the 3MLCT state upon deprotonation have been confirmed by steady state luminescence experiments on 1 A -3 A and their basic analogs, 1 B -3 B . This energy landscape favors 1O2 formation for 2 B and 3 B and leads to enhanced toxicity for these complexes under physiological conditions. The ability to convert readily from OH to O– groups allowed us to investigate an electronic change that is not accompanied by steric changes in this fundamental study.