Increased Lipophilicity of Halogenated Ruthenium(II) Polypyridyl Complexes Leads to Decreased Phototoxicity in vitro when Used as Photosensitizers for Photodynamic Therapy

Abstract

In the fight against cancer, photodynamic therapy is generating great interest thanks to its ability to selectively kill cancer cells without harming healthy tissues. In this field, ruthenium(II) polypyridyl complexes, and more specifically, complexes with dipyrido[3,2-a:2',3'-c]phenazine (dppz) as a ligand are of particular interest due to their DNA-binding and photocleaving properties. However, ruthenium(II) polypyridyl complexes can sometimes suffer from low lipophilicity, which hampers cellular internalisation through passive diffusion. In this study, four new [Ru(dppz-X 2) 3 ] 2 + complexes (X=H, F, Cl, Br, I) were synthesized and their lipophilicity (logP), cytotoxicity and phototoxicity on cancerous and noncancerous cell lines were assessed. This study shows that, counterintuitively, the phototoxicity of these complexes decreases as their lipophilicity increases; this could be due solely to the atomic radius of the halogen substituents.

Synthesis, Characterisation and In Vitro Anticancer Activity of Catalytically Active Indole-Based Half-Sandwich Complexes

“…On the other hand, the addition of sodium chloride led to a different set of signals (Figure 2) and the concentrations of the species present in solution in the 1 H-NMR samples were greatly reduced owing to major precipitation of the neutral chloride complexes. The pKa values for the complexes were measured by dissolving the compounds in 6% acetonitrile/water v/v (aqua adduct formed) and by recording the UV-Vis spectra of the samples at increasing pH (pH [7][8][9][10][11][12]. pKa values of the complexes were calculated using Origin 2018 by plotting the absorbance at the corresponding wavelength against the pH and fitting it to the Boltzmann equation to obtain the inflection point.…”

“…There is a need for the development and screening of anticancer therapeutics with non-conventional mechanisms of action (MoAs) [ 2 , 3 , 4 ]. Metallodrugs can provide rich chemistry and unique MoAs owing to their versatile structures, geometries and reactivities: examples include polypyridyl octahedral complexes of precious metals, some of which have been shown to target mitochondria and generate high levels of reactive oxygen species (ROS), while others can act as photosensitisers for use in photodynamic therapy [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ], and half-sandwich complexes of metals from groups eight and nine (Fe, Ru, Os; Co, Rh, Ir) [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. In this context, the binding of bioactive ligand(s) to metal fragments is of interest since this strategy may lead to the release of at least two biologically active species, therefore potentially offering enhanced activity against resistant cancer cells [ 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

Novel Papaverine Metal Complexes with Potential Anticancer Activities

“…To investigate such a concept for a drug, one approach would be to examine the in vitro activity of the metal complexes including the drug as a ligand. The best examples include the conjugate of ferrocene with quinoline, which has completed the phase II clinical trials [ 30 , 33 ]; the octahedral polypyridyl meatal-complexes, which enhanced the levels of reactive oxygen species by targeting the mitochondria, and are used photodynamic therapy as photosensitizers [ 34 , 35 , 36 , 37 , 38 , 39 , 40 ]; and the nonsteroidal anti-inflammatory drugs coordinated with metals [ 28 ]. Among different metal complexes, ruthenium, gold and vanadium complexes have attracted particular attention.…”

Recent Approaches towards the Development of Ru(II) Polypyridyl Complexes for Anticancer Photodynamic Therapy

“…11) due to the interesting results obtained with other dppz-based complexes for the production of 1 O 2 , internalization and phototoxicity values. [19,30] More specifically, we explored the derivatization of the dppz ligand with halogen groups (F, Cl, Br, and I) to increase the lipophilicity of the complexes, therefore increasing membrane permeability. We studied different parameters of the new series of compounds, such as generation of singlet oxygen, UV-Vis absorption, LogP and photocytotoxicity.…”