Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Jun:68:102143.
doi: 10.1016/j.cbpa.2022.102143. Epub 2022 Apr 25.

Factors that influence singlet oxygen formation vs. ligand substitution for light-activated ruthenium anticancer compounds

Elizabeth T Papish  1 , Olaitan E Oladipupo  2
Affiliations
Review

Factors that influence singlet oxygen formation vs. ligand substitution for light-activated ruthenium anticancer compounds

Elizabeth T Papish et al. Curr Opin Chem Biol. 2022 Jun.

Abstract

This review focuses on light-activated ruthenium anticancer compounds and the factors that influence which pathway is favored. Photodynamic therapy (PDT) is favored by π expansion and the presence of low-lying triplet excited states (e.g. 3MLCT, 3IL). Photoactivated chemotherapy (PACT) refers to light-driven ligand dissociation to give a toxic metal complex or a toxic ligand upon photo substitution. This process is driven by steric bulk near the metal center and weak metal-ligand bonds to create a low-energy 3MC state with antibonding character. With protic dihydroxybipyridine ligands, ligand charge can play a key role in these processes, with a more electron-rich deprotonated ligand favoring PDT and an electron-poor protonated ligand favoring PACT in several cases.

Keywords: Anticancer; Diimine ligands; Photoactivated chemotherapy; Photochemistry; Photodissociation; Photodynamic therapy; Photosubstitution; Protic ligands; Ruthenium; pH responsive.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
Selected Ruthenium PACT Agents that Undergo Light Triggered Photodissociation. All of the Ru compounds above are chiral and have typically been used as a racemic mixture.
Figure 2.
Figure 2.
Selected Ruthenium PDT Agents that Generate Singlet Oxygen. Some of the Ru compounds above are chiral and have typically been used as a racemic mixture.
Figure 3.
Figure 3.
Dual Ruthenium PACT and PDT Agents. Several of the above compounds are protic and the influence of protonation/deprotonation on the dominant pathway (PDT vs. PACT) has been extensively studied for several OH bearing compounds. For 21–28, “A” designates the OH bearing acidic form and “B” designates the O− bearing basic form. The lack of an “A” or “B” indicates a mixture of both protonation states in solution. Most of the Ru compounds above (except 18) are chiral and have typically been used as a racemic mixture.
Scheme 1.
Scheme 1.
Ru complexes herein can utilize both PACT and PDT pathways. This review focuses on the factors that influence which pathway is taken. (a) Schematic showing the excited states typically involved in PACT and PDT. 1MLCT and 3MLCT are shown as the main excited states for the sake of simplicity, but singlet oxygen formation often occurs via 3ILCT and other excited states (e.g. 3LLCT), especially with highly conjugated organic ligands. (b) A specific example showing PACT and PDT for a Ru(II) complex, thus the complex is a dual PDT/PACT agent.
See this image and copyright information in PMC

References

    1. Gaiddon C, Pfeffer M, The Fate of Cycloruthenated Compounds: From C-H Activation to Innovative Anticancer Therapy, Eur. J. Inorg. Chem, 2017 (2017) 1–17.
    1. Flocke LS, Trondl R, Jakupec MA, Keppler BK, Molecular mode of action of NKP-1339 – a clinically investigated ruthenium-based drug – involves ER- and ROS-related effects in colon carcinoma cell lines, Invest. New Drugs, 34 (2016) 261–268. - PMC - PubMed
    1. Hartinger CG, Zorbas-Seifried S, Jakupec MA, Kynast B, Zorbas H, Keppler BK, From bench to bedside – preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A), J. Inorg. Biochem, 100 (2006) 891–904. - PubMed
    1. Trondl R, Heffeter P, Kowol CR, Jakupec MA, Berger W, Keppler BK, NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application, Chem. Sci, 5 (2014) 2925–2932.
    1. Bergamo A, Sava G, Ruthenium anticancer compounds: myths and realities of the emerging metal-based drugs, Dalton Trans., 40 (2011) 7817. - PubMed

Publication types