Fine‐Feature Modifications to Strained Ruthenium Complexes Radically Alter Their Hypoxic Anticancer Activity^†

Abstract

In an earlier study of π‐expansive ruthenium complexes for photodynamic and photochemo‐therapies, it was shown that a pair of structural isomers differing only in the connection point of a naphthalene residue exhibited vastly different biological activity. These isomers are further explored in this paper through the activity of their functionalized derivatives. In normoxia, the inactive 2‐NIP isomer (5) can be made as photocytotoxic as the active 1‐NIP isomer (1) by functionalizing with methyl or methoxy groups, while methoxy variants of the 1‐NIP isomer became inactive. In all cases, the singlet oxygen sensitization quantum yield was below 1%. Hypoxic photocytotoxicity was attenuated, with only three of the series showing any activity, notwithstanding the photodissociative ligands. The results here are consistent with the earlier findings in that seemingly minor structural modifications on the non‐strained ligand can dramatically modulate the normoxic and hypoxic activity of these strained compounds and that these changes appear to exert a greater influence on photocytotoxicity than singlet oxygen sensitization or rates of photosubstitution in cell‐free conditions would suggest.

Unlocking the Potential of Ru(II) Dual‐action Compounds with the Power of the Heavy‐atom Effect†

“…Therefore, both 2 and 4 exhibit excellent PI values, >730 and >140, respectively. The pyridine-containing complex [Ru(tpy)(Me 2 bpy)(py)](OTf) 2 (5) was used to understand the role of the fragment [Ru(tpy) (Me 2 bpy)] 2+ released from 4, since both 4 and 5 generate the same aqua complex, [Ru(tpy)(Me 2 bpy)(H 2 O)] 2+ , upon irradiation. Complex 5 was not toxic under light or dark conditions in MDA-MB-231 cells (EC 50 > 50 μM), indicating that most of the biological activity of 4 is due to released 2 and 1 O 2 generated.…”

“…Ruthenium complexes display rich biological and photochemical properties that make them highly attractive as chemical tools and potential therapeutics (1)(2)(3)(4)(5)(6). These properties include high cell permeability (7,8), low inherent toxicity (2,9), photochemical release of bioactive ligands (10)(11)(12)(13)(14)(15), and high light-to-dark toxicity ratios (16)(17)(18)(19).…”

DNA Interaction, DNA Photocleavage, Photocytotoxicity In Vitro, and Molecular Docking of Naphthyl-Appended Ruthenium Complexes

“…Photofrin ® is the first PDT clinical drug based on porphyrin compound, which showed excellent photocytotoxicity against solid tumors [10]. Ruthenium-based compounds usually exhibit high singlet oxygen quantum yields [11][12][13][14][15][16][17]. Most of them have been reported as efficient photodynamic therapy (PDT) and photochemotherapy (PCT) agents and display remarkable antitumor activities, which provokes interests of more and more scientists [11][12][13][14][15][16][17].…”

“…Naphthyl moiety has shown its importance in developing chemosensors and drugs with chemotherapeutic activities [12,13]. Naphthyl unit is a typical fluorophore, which improves the emission properties of organic molecules and their biological activities, such as DNA topoisomerase inhibition, antitumor agents, and antibacterial activities [10][11][12][13][14][15][16][17][18][19]. Naphthyl moiety is also introduced into the ligand on metal complexes, which exhibits excellent biological properties [14][15][16][17].…”

“…Naphthyl unit is a typical fluorophore, which improves the emission properties of organic molecules and their biological activities, such as DNA topoisomerase inhibition, antitumor agents, and antibacterial activities [10][11][12][13][14][15][16][17][18][19]. Naphthyl moiety is also introduced into the ligand on metal complexes, which exhibits excellent biological properties [14][15][16][17]. Recently, several ruthenium complexes containing naphthyl moiety were synthesized and their biological activities were tested [11,[15][16][17][18][19].…”