Although cyclometalated Ir^IIIcomplexes have emerged as promising photosensitizers for photodynamic therapy, some key drawbacks still hamper clinical translation, such as operability in the phototherapeutic window and reactive oxygen species (ROS) production efficiency and selectivity. In this work, a cyclometalated Ir^IIIcomplex conjugated to a far‐red‐emitting coumarin, Ir^III–COUPY, is reported with highly favourable properties for cancer phototherapy. Ir^III–COUPY was efficiently taken up by HeLa cells and showed no dark cytotoxicity and impressive photocytotoxicity indexes after irradiation with green and blue light, even under hypoxia. Importantly, a clear correlation between cell death and intracellular generation of superoxide anion radicals after visible light irradiation was demonstrated. This strategy opens the door to novel fluorescent photodynamic therapy agents with promising applications in theragnosis.

A photoactivated ruthenium(II) arene complex has been conjugated to two receptor-binding peptides, a dicarba analogue of octreotide and the Arg-Gly-Asp (RGD) tripeptide. These peptides can act as “tumor-targeting devices” since their receptors are overexpressed on the membranes of tumor cells. Both ruthenium–peptide conjugates are stable in aqueous solution in the dark, but upon irradiation with visible light, the pyridyl-derivatized peptides were selectively photodissociated from the ruthenium complex, as inferred by UV–vis and NMR spectroscopy. Importantly, the reactive aqua species generated from the conjugates, [(η⁶-p-cym)Ru(bpm)(H₂O)]²⁺, reacted with the model DNA nucleobase 9-ethylguanine as well as with guanines of two DNA sequences, ^5′dCATGGCT and ^5′dAGCCATG. Interestingly, when irradiation was performed in the presence of the oligonucleotides, a new ruthenium adduct involving both guanines was formed as a consequence of the photodriven loss of p-cymene from the two monofunctional adducts. The release of the arene ligand and the formation of a ruthenated product with a multidentate binding mode might have important implications for the biological activity of such photoactivated ruthenium(II) arene complexes. Finally, photoreactions with the peptide–oligonucleotide hybrid, Phac-His-Gly-Met-linker-p^5′dCATGGCT, also led to arene release and to guanine adducts, including a GG chelate. The lack of interaction with the peptide fragment confirms the preference of such organometallic ruthenium(II) complexes for guanine over other potential biological ligands, such as histidine or methionine amino acids.

Among the palette of fluorescent organic molecules described up to now, coumarins are ideal candidates for developing cellular and molecular imaging tools due to their high cell permeability and minimal perturbation to the living system. However, blue to cyan fluorescence emission usually difficult in vivo applications due to the inherent toxicity and poor tissue penetration of short visible light wavelengths. Here we introduce a new family of coumarin-based fluorophores, nicknamed COUPY, with promising photophysical properties, including emission in the far-red/NIR region, large Stokes’ shifts, high photostability, and excellent brightness. COUPY fluorophores were efficiently synthesized in only three linear synthetic steps from commercially available precursors, the N-alkylation of a pyridine moiety being the key step at the end of the synthetic route since it allows to tune the photophysical properties of the resulting dye. Owing to their low molecular weight, COUPY dyes show excellent cell permeability and accumulate selectively in nucleoli and/or mitochondria of HeLa cells, being their far-red/NIR fluorescence emission easily detected at a concentration as low as 0.5 μM after incubation for only 20 min. We anticipate that these coumarin scaffolds will open the way to the development of novel coumarin-based far-red to NIR-emitting fluorophores with potential applications for organelle imaging and biomolecule labelling.

A new anticancer agent based on the conjugation of a photoactivatable Pt(IV) pro-drug to a cyclic RGD-containing peptide is described. Upon visible light irradiation, phototoxicity was induced preferentially in SK-MEL-28 melanoma cancer cells overexpressing α_Vβ₃ integrin compared to control DU-145 human prostate carcinoma cells.

Photodynamic therapy (PDT) represents a promising approach for cancer treatment. However, the oxygen dependency of PDT to generate reactive oxygen species (ROS) hampers its therapeutic efficacy, especially against hypoxic solid tumors. In addition, some photosensitizers (PSs) have dark toxicity and are only activatable with short wavelengths such as blue or UV-light, which suffer from poor tissue penetration. Herein, we developed a novel hypoxia-active PS with operability in the near-infrared (NIR) region based on the conjugation of a cyclometalated Ru(II) polypyridyl complex of the type [Ru(C^N)(N^N)₂] to a NIR-emitting COUPY dye. The novel Ru(II)-coumarin conjugate exhibits water-solubility, dark stability in biological media and high photostability along with advantageous luminescent properties that facilitate both bioimaging and phototherapy. Spectroscopic and photobiological studies revealed that this conjugate efficiently generates singlet oxygen and superoxide radical anions, thereby achieving high photoactivity toward cancer cells upon highly-penetrating 740 nm light irradiation even under hypoxic environments (2% O₂). The induction of ROS-mediated cancer cell death upon low-energy wavelength irradiation along with the low dark toxicity exerted by this Ru(II)-coumarin conjugate could circumvent tissue penetration issues while alleviating the hypoxia limitation of PDT. As such, this strategy could pave the way to the development of novel NIR- and hypoxia-active Ru(II)-based theragnostic PSs fuelled by the conjugation of tunable, low molecular-weight COUPY fluorophores.

Photodynamic therapy (PDT) for cancer treatment has drawn increased attention over the last decades. Herein, we introduce a novel family of low-molecular-weight coumarins as potential PDT anticancer tools. Through a systematic study with a library of 15 compounds, we have established a detailed structure–activity relationship rationale, which allowed the selection of three lead compounds exhibiting effective in vitro anticancer activities upon visible-light irradiation in both normoxia and hypoxia (phototherapeutic indexes up to 71) and minimal toxicity toward normal cells. Acting as excellent theranostic agents targeting mitochondria, the mechanism of action of the photosensitizers has been investigated in detail in HeLa cells. The generation of cytotoxic reactive oxygen species, which has been found to be a major contributor of the coumarins’ phototoxicity, and the induction of apoptosis and/or autophagy have been identified as the cell death modes triggered after irradiation with low doses of visible light.