Carlos Gonzalo-Navarro

Herein, we report the synthesis of a pyrrole-based symmetric squaraine (SQL) and its supramolecular organization into nanoparticles (SQLNPs) in aqueous media. The aggregation process, driven by non-covalent interactions, gives rise to J- and H-type assemblies and produces pronounced changes in the optical properties of the squaraine. The resulting nanoparticles display selective colorimetric responses toward Zn²⁺, Hg²⁺ and Pd²⁺ and toward low-molecular-weight thiol-containing compounds, with particularly pronounced sensitivity toward glutathione. The photochemical properties of SQL and SQLNPs were also investigated using complementary reactive-oxygen-species assays. Under the experimental conditions employed, blue-light irradiation produced a detectable radical-type ROS response for the aggregated nanoparticles, whereas no measurable response was observed under orange or red-light irradiation. The absence of detectable singlet-oxygen generation together with the response to radical-sensitive assays is consistent with a predominantly Type I radical-mediated photochemical pathway. Computational analysis further indicates that supramolecular aggregation modifies the electronic structure of SQL, particularly for the H-type aggregate. Finally, SQLNPs display blue-light-dependent phototoxicity toward A549 cells. These results demonstrate how supramolecular organization of a multifunctional squaraine can modulate its optical, sensing and photochemical properties and provide a platform for further development of squaraine-based functional nanomaterials.

Platinum-based chemotherapeutic agents remain among the most widely used anticancer drugs; however, they show two main limitations: intrinsic or acquired resistance and severe side effects. To address these limitations, the design of alternative metal-based complexes with tunable properties is of growing interest. In this work, we report the rational design and synthesis of five novel half-sandwich Ir(III) complexes incorporating benzo[h]imidazoquinoline ligands with an aryl ring. Two strategic structural modifications were introduced into the ligand: (i) alkylation of the imidazole nitrogen (H or 4-ethylmorpholine) and (ii) variation of the aryl substituent (OMe or CN), which not only induced the formation of a dinuclear complex but also modulated key physicochemical properties, including lipophilicity, cytotoxicity, or stability. The new complexes exhibited cytotoxicity toward different cancer cell lines, with IC50 values in the low micromolar range, which are within the same order of magnitude as cisplatin, though operating through a distinct mechanism. Notably, the complexes induced mitochondrial dysfunction, even when morpholine-containing ligands, typically associated with lysosomal targeting, were employed. Additional studies revealed interactions of the complexes with cellular molecules such as NADH and glutathione (GSH), disrupting redox homeostasis and increasing ROS (reactive oxygen species) levels. Furthermore, the complexes exhibited moderate binding affinity for bovine serum albumin (BSA), with molecular docking analyses suggesting a specific interaction near tryptophan residue 134. These Ir(III) complexes are promising candidates for further development as anticancer agents with distinct mechanisms of action capable of overcoming drug resistance.

Photocatalysis has emerged as a powerful strategy in synthetic organic chemistry to avoid harsh conditions and toxic oxidants. Herein, we report the photocatalytic activity of half-sandwich Ir(III) complexes in different transformations. For the first time, Cp*Ir(III) complexes were applied in photooxidative coupling reactions of amines, without any additives, achieving quantitative imine formation, and in thioether photooxidation reactions, reaching high chemoselectivity for sulfoxide formation. Furthermore, exceptional activity was observed in photodehydrogenation of N-heterocyclic substrates. Reactions proceeded under mild conditions, including room temperature and an ambient air or oxygen atmosphere, with considerably low catalyst loadings (0.005-0.25 mol %). Complex 1, bearing the π-extended C^∧N pbpn ligand, was also active even in aqueous media (MeCN/H₂O 1:1) and under sunlight, reaching full conversion within hours. Mechanistic studies indicated the involvement of reactive oxygen species, such as singlet oxygen (¹O₂) and superoxide anion radical (O₂^•-), operating via both energy and electron transfer pathways. These findings establish this Cp*Ir(III) complex as an efficient, versatile, and sustainable photocatalyst, constituting one of the first examples of half-sandwich Ir complexes employed in diverse photooxidative organic reactions.

Half-sandwich iridium complexes exhibit poor photophysical properties. We reported the first case of half-sandwich cyclometalated iridium complexes with anticancer photodynamic activity, using two π-expansive ligands differing by one extra ring in [Cp*Ir(C^N)L]BF₄ complexes. Considering the ability of the ligands to aggregate through π-π interactions, which may reduce the emission energy, and the interest in NIR emitters, we envisaged to study the concentration-dependent solution and solid state photophysical properties. Besides emission, aggregation was verified by ¹H NMR, PFGSE-DOSY NMR experiments, X-ray diffraction, and DLS. It was found by X-ray diffraction the formation, with pair of enantiomers, of head-to-tail dimers that were further aggregated in some cases. The complexes with L = N-benzylimidazole became NIR emitters in solid state with a red-shift for the more π-expansive complex. The less π-expansive complex exhibited aggregation-enhanced emission. A significant effect on the emission of the additional ring was observed, that is explained by the stronger distortion of the excited state of the more π-expansive complex that favors disaggregation in solution. These are the first reported half-sandwich derivatives of any metal to exhibit NIR emission. DFT and TD-DFT studies support the experimentally observed features through the study of dinuclear model systems displaying π-π stacking interactions.

π-Extended bis-cyclometalated Ir( iii ) and Rh( iii ) complexes enable efficient visible-light-driven organic transformations.

Novel bis-cyclometalated Ir( iii ) complexes with π-extended ligands encapsulated in nanoparticles as highly active type I and II PDT agents with theragnostic potential.

There is a growing interest in deuterated derivatives in various fields, including the pharmaceutical industry. In this industry, partially hydrogenated heterocycles are also a target. Combining these two concepts, it was studied the reduction of heterocycles with simultaneous deuterium incorporation by transfer deuteration, a process of introducing two deuterium atoms into an organic molecule using non‐D₂ sources, avoiding the use of a gas or harmful reagents. Formic acid/sodium formate and D₂O as the sole deuterium source were used under mild conditions. The precatalyst was [RuCl(p‐cym)(dmbpy)]BF₄, (p‐cym=p‐cymene, dmbpy=4,4’‐dimethyl‐2,2’‐bipyridine), which is able to generate the “Ru−D” fragment from D⁺ by a polarity inversion process (“umpolung”). A wide range of heterocycles were tested. Selective reduction in the nitrogen‐containing ring with deuterium incorporation into the same ring was achieved. The experiments were carried out in a biphasic D₂O/toluene medium, which allowed excellent catalyst recycling with a simple work‐up. Through detailed studies for 3‐methylquinoline using DCOOD/DCOONa, the reaction mechanism that involves D⁺ incorporation at the nitrogen atom and an initial 1,2‐type addition was elucidated. In single‐phase D₂O experiments, a distinct selectivity with deuterium incorporation in the non‐hydrogenated ring was observed thus enabling to modulate it by the choice of the medium.

One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We have used the strategy of coordinating π-expansive ligands to increase the excited state lifetimes of Ir(III) half-sandwich complexes in order to facilitate the generation of ¹O₂. We have obtained derivatives of formulas [Cp*Ir(C^∧N)Cl] and [Cp*Ir(C^∧N)L]BF₄ with different degrees of π-expansion in the C^∧N ligands. Complexes with the more π-expansive ligand are very effective photosensitizers with phototoxic indexes PI > 2000. Furthermore, PI values of 63 were achieved with red light. Time-dependent density functional theory (TD-DFT) calculations nicely explain the effect of the π-expansion. The complexes produce reactive oxygen species (ROS) at the cellular level, causing mitochondrial membrane depolarization, cleavage of DNA, nicotinamide adenine dinucleotide (NADH) oxidation, as well as lysosomal damage. Consequently, cell death by apoptosis and secondary necrosis is activated. Thus, we describe the first class of half-sandwich iridium cyclometalated complexes active in PDT.