A Deadly Organometallic Luminescent Probe: Anticancer Activity of a Re^I Bisquinoline Complex

Abstract

The photophysical properties of [Re(CO)3 (L-N3)]Br (L-N3 =2-azido-N,N-bis[(quinolin-2-yl)methyl]ethanamine), which could not be localized in cancer cells by fluorescence microscopy, have been revisited in order to evaluate its use as a luminescent probe in a biological environment. The Re(I) complex displays concentration-dependent residual fluorescence besides the expected phosphorescence, and the nature of the emitting excited states have been evaluated by DFT and time-dependent (TD) DFT methods. The results show that fluorescence occurs from a (1) LC/MLCT state, whereas phosphorescence mainly stems from a (3) LC state, in contrast to previous assignments. We found that our luminescent probe, [Re(CO)3 (L-N3)]Br, exhibits an interesting cytotoxic activity in the low micromolar range in various cancer cell lines. Several biochemical assays were performed to unveil the cytotoxic mechanism of the organometallic Re(I) bisquinoline complex. [Re(CO)3 (L-N3)]Br was found to be stable in human plasma indicating that [Re(CO)3 (L-N3)]Br itself and not a decomposition product is responsible for the observed cytotoxicity. Addition of [Re(CO)3 (L-N3)]Br to MCF-7 breast cancer cells grown on a biosensor chip micro-bioreactor immediately led to reduced cellular respiration and increased glycolysis, indicating a large shift in cellular metabolism and inhibition of mitochondrial activity. Further analysis of respiration of isolated mitochondria clearly showed that mitochondrial respiratory activity was a direct target of [Re(CO)3 (L-N3)]Br and involved two modes of action, namely increased respiration at lower concentrations, potentially through increased proton transport through the inner mitochondrial membrane, and efficient blocking of respiration at higher concentrations. Thus, we believe that the direct targeting of mitochondria in cells by [Re(CO)3 (L-N3)]Br is responsible for the anticancer activity.

Necroptosis-Inducing Rhenium(V) Oxo Complexes

“…A number of photolabile rhenium(I) derivatives that trigger cell death upon irradiation have also been devised. 15–17 These complexes offer temporal and spatial control over activation and therefore could be useful in overcoming systemic toxicity. Recently, octahedral Re(IV) complexes bearing polypyridyl ligands were discovered to exhibit potent in vitro antiproliferative activity against breast, ovarian, and prostate cancer cells.…”

Pt(IV)/Re(I) Chitosan Conjugates as a Flexible Platform for the Transport of Therapeutic and/or Diagnostic Anticancer Agents

“…When compared with other conventional anticancer treatments, PDT has many advantages, namely spatial and temporal control and the possibility of repeated doses [19,26]. In particular, Re(I) tricarbonyl complexes with ligands derived from bis(quinolin-2-ylmethyl)amine can act as efficient photosensitizers and are endowed with luminescence properties that might also allow for the visualization of their intracellular trafficking by fluorescence microscopy [24,25].…”

“…When compared with other conventional anticancer treatments, PDT has many advantages, namely spatial and temporal control and the possibility of repeated doses [19,26]. In particular, Re(I) tricarbonyl complexes with ligands derived from bis(quinolin-2-ylmethyl)amine can act as efficient photosensitizers and are endowed with luminescence properties that might also allow for the visualization of their intracellular trafficking by fluorescence microscopy [24,25]. In this work, it is reported the preparation and preliminary evaluation of the biological properties of low viscosity chitosan from shrimp shell, modified with (3-carboxypropyl) trimethylammonium chloride (1), coupled with (OC-6-44)-diammine(4-carboxypropanoato) dichloridoethanolatoplatinum(IV) (2) and loaded with the chelating ligand 3, as derived from bis(quinolin-2-ylmethyl)amine for possible coordination of the Re(I) tricarbonyl moiety (Scheme 2).…”

“…Towards this goal, isostructural M(I) (M = 99m Tc or Re) tricarbonyl complexes have useful and unique features: (i) chemical robustness of the fac-[M(CO) 3 ] + core; (ii) well-studied coordination chemistry with a variety of chelating ligands including targeting molecules [21,22]; and, (iii) possible application in the design of metal-based cancer theranostic agents where Re complexes can be incorporated into a cytotoxic entity that will exert a therapeutic effect, while the 99m Tc congeners are part of the corresponding imaging tool for in vivo assessment of tumor accumulation. Furthermore, the Re(I) tricarbonyl complexes have also been recently explored as photosensitizers for photodynamic therapy (PDT) [23][24][25]. PDT is a clinically approved technique used , for instance, for the treatment of certain tumors, which involves light-induced generation of cytotoxic singlet oxygen ( 1 O 2 ) from endogenous 3 O 2 and/or other reactive oxygen species (ROS), mediated by a photosensitizer.…”

“…exert a therapeutic effect, while the 99m Tc congeners are part of the corresponding imaging tool for in vivo assessment of tumor accumulation. Furthermore, the Re(I) tricarbonyl complexes have also been recently explored as photosensitizers for photodynamic therapy (PDT) [23][24][25]. PDT is a clinically approved technique used , for instance,for the treatment of certain tumors, which involves light-induced generation of cytotoxic singlet oxygen ( 1 O2) from endogenous 3 O2 and/or other reactive oxygen species (ROS), mediated by a photosensitizer.…”