Increasing the Cytotoxicity of Ru(II) Polypyridyl Complexes by Tuning the Electronic Structure of Dioxo Ligands

Abstract

Due to the great potential expressed by an anticancer drug candidate previously reported by our group, namely, Ru-sq ([Ru(DIP)2(sq)](PF6) (DIP: 4,7-diphenyl-1,10phenanthroline, sq: semiquinonate ligand), we describe in this work a structure-activity relationship (SAR) that involves a broader range of derivatives resulting from the coordination of different catecholate-type dioxo ligands to the same Ru(DIP)2 core. More in detail, we chose catechols carrying either electron-donating or electronwithdrawing groups EDG or EWG and investigated the physico-chemical and biological properties of their complexes. Several pieces of experimental evidences demonstrated that the coordination of catechols bearing EDGs led to deep red positively charged complexes 1-4 in which the preferred oxidation state of the dioxo ligand is the uninegatively charged semiquinonate. Complexes 5 and 6, on the other hand, are blue/violet neutral complexes, which carry an EWG substituted dinegatively charged catecholate ligand. The biological investigation of complexes 1-6 led to the conclusion that the difference in their physico-chemical properties has a strong impact on their biological activity. Thus, complexes 1-4 expressed much higher cytotoxicities than complexes 5 and 6. Complex 1 constitutes the most promising compound of the series and was selected for a more in-depth biological investigation. Apart from its remarkably high cytotoxicity (IC50 = 0.07-0.7 µM in different cancerous cell lines) complex 1 was taken up by HeLa cells very efficiently by a passive transportation mechanism. Moreover, its moderate accumulation in several cellular compartments (i.e. nucleus, lysosomes, mitochondria and cytoplasm) is extremely advantageous in the search of a potential drug with multiple modes of action. Further DNA metalation and metabolic studies pointed to the direct interaction of complex 1 with DNA and to the severe impairment of the mitochondrial function. Multiple targets, together with its 4 outstanding cytotoxicity, make complex 1 a valuable candidate in the field of chemotherapy research. Noteworthy, a preliminary biodistribution study on healthy mice demonstrated the suitability of complex 1 for further in vivo studies.

NIR‐Absorbing RuII Complexes Containing α‐Oligothiophenes for Applications in Photodynamic Therapy

“…Some of these and related systems have been altered further by introducing a central metal ion into the tetrapyrrolic scaffold to enhance the chemical, photophysical, and biological characteristics of the parent PSs. [29,30] Design of the next generation of PSs has been focused on extending the absorption window to include NIR wavelengths (700-900 nm) [31][32][33][34] and to alter the excited state properties of the molecules to exploit oxygen-independent mechanistic pathways to achieve phototoxic effects in hypoxia. [35][36][37][38][39][40] Ru II polypyridyl complexes are particularly attractive scaffolds for PS design because the photophysics of these complexes is wellestablished [41][42][43][44][45][46][47] and polypyridyl ligand combinations can be chosen to systematically manipulate the excited state dynamics in a rational and consistent manner.…”

“…Various Ru II -based NIR scaffolds are known, but their phototoxic effects on cells were not reported. [31][32][33][34]50] Generally, the 1 O 2 quantum yields are low (and PDT effects thus poor) for metal complexes with lowenergy triplet metal-to-ligand charge transfer ( 3 MLCT) excited states due to efficient intersystem crossing (ISC) that competes effectively with 1 O 2 sensitization. [46] To circumvent this issue, we aimed to design Ru II -based NIR complexes with 3 ILCT states that are lower in energy than the 3 MLCT states and much longer lived, due to their organic 3 ππ* character.…”

“…We hypothesized that combining the PDT‐active ligand in TLD1433 with a Ru II NIR‐absorbing scaffold would generate NIR PDT effects with high potency that might extend to hypoxia. Various Ru II ‐based NIR scaffolds are known, but their phototoxic effects on cells were not reported [31–34,50] . Generally, the 1 O 2 quantum yields are low (and PDT effects thus poor) for metal complexes with low‐energy triplet metal‐to‐ligand charge transfer ( 3 MLCT) excited states due to efficient intersystem crossing (ISC) that competes effectively with 1 O 2 sensitization [46] .…”

An 111In-labelled bis-ruthenium(ii) dipyridophenazine theranostic complex: mismatch DNA binding and selective radiotoxicity towards MMR-deficient cancer cells

“…63 That an evidently different clearance pathway is used by [ 111 In][In-2] 4+ is particularly interesting considering the interest in RPCs as alternative therapeutics to platinum drugs and also the fact that clinical use of cisplatin is limited by nephrotoxicity. 64 We also note with interest that high liver uptake was reported for a hydrophobic mononuclear RPC by the Gasser group, 65 indicating this may be a general outcome for RPCs. Chemical rerouting of an elimination pathway towards hepatic clearance will aid further design of RPCs as nonplatinum chemo/radiotherapeutics, and indicates that hepatotoxicity may be a concern for this class of chemical.…”

“…The with hydrophobic ancillary ligands such as DIP (DIP ¼ 4,7diphenyl-1,10-phenanthroline) could increase cellular uptake, related research has shown this approach leads to a decrease in nuclear DNA targeting 30,66 and results in potentbut non-speciccytotoxicity. 65 Instead, a delivery mechanism may be a more appropriate method to achieve sufficient tumour uptake in vivo for the therapeutic potential of this molecule to be assessed in more detail. One attractive option is bioconjugation employing a cleavable linker to a peptide or antibody that targets surface receptors overexpressed by cancers.…”