Metal–coumarin photosensitizers enhance ROS generation and phototoxicity, offering promising solutions for cancer phototherapy.

Ferroptosis, a recently described form of regulated, nonapoptotic cell death mechanism, presents significant potential for cancer treatment, particularly when combined with photodynamic therapy (PDT). In this study, we report the synthesis and biological evaluation of a series of Ir-COUBPY complexes as novel photosensitizers (PSs) for effective cancer phototherapy. These complexes exhibit high stability under both dark and light conditions and are capable of photogenerating Type I and Type II reactive oxygen species (ROS), as well as photo-oxidizing NADH. Electron paramagnetic resonance (EPR) spectroscopy provided direct evidence of light-induced superoxide and singlet oxygen generation, confirming dual ROS pathways. Moreover, the Ir-COUBPY complexes preferentially accumulated in the mitochondria of cancer cells, leading to the photogeneration of hydroxyl radicals and hydrogen peroxide. Photocytotoxicity studies on HeLa and A375 cancer cells underscored the role of the COUBPY ligand in enhancing PDT efficiency upon irradiation with both green and red light. Among the Ir-COUBPY complexes, the most effective PS, Ir4a, was encapsulated in polyurethane-polyurea hybrid nanocapsules (NC-Ir4a), resulting in a significant increase in phototoxic index values (e.g., from 64 to 179.6 in A375 cells). Mechanistic studies confirmed ferroptosis as the primary cell death pathway induced by Ir4a, supported by light-dependent lipid peroxidation, glutathione oxidation and depletion, intracellular ATP photodepletion, and the viability-restoring effect of Fer-1. These effects were more pronounced upon nanoencapsulation. Photobiological studies with 3D tumor spheroids of A375 cells further confirmed higher cellular uptake of NC-Ir4a, contributing to improved phototoxic efficiency. Overall, these findings highlight the potential of coumarin-based COUBPY ligands in the design of new Ir(III)-based PSs that can be activated with light within the phototherapeutic window, operating through nonconventional cell death mechanisms such as ferroptosis.

We designed a series of pseudo-octahedral arene Os(ii) complexes (Os1-Os5) with the general formula [(eta 6-p-cym)Os(BTAT)Cl]+, where BTAT represents chelating N<^>N ' ligands based on the 1-aryl-4-benzothiazolyl-1,2,3-triazole scaffold. The structures of Os3 and Os5 were confirmed by X-ray diffraction, and Os5 exhibits a bathochromic shift in its absorption band compared to the other complexes, likely due to the electron-donating properties of the substituent NMe2. Os5 also hydrolyzed without losing its BTAT ligand and exhibited the highest cellular accumulation in Rhabdomyosarcoma (RD) cancer cells. The investigated Os(ii) complexes demonstrated moderate antiproliferative activity across six cancer cell lines, with Os5 being the most potent, showing activity comparable to or better than conventional cisplatin. Cellular accumulation was a key factor influencing their antiproliferative effect, though binding to human serum albumin did not play a significant role. Further studies with Os5 in RD cells, the most responsive cell line, revealed that its mechanism of action includes mitochondrial dysfunction, apoptosis via a caspase-dependent pathway, and cell cycle arrest at the G1 phase. Os5 also increased the production/generation of reactive oxygen species (ROS) in RD cells, implicating ROS production as a contributor to its activity. Importantly, Os5 was effective against cancer stem cells (CSCs) in 3D spheroid models, marking the first report of an osmium-based compound targeting CSC-enriched RD cells. This highlights the potential of Os5 as a CSC-targeted therapy, addressing the need for treatments that prevent relapse and metastasis. The study underscores the promising role of metal-based complexes in cancer stem cell chemotherapy.

Ruthenium(II) complexes containing diimine ligands have contributed to the development of agents for photoactivated chemotherapy. Several approaches have been used to obtain photolabile Ru(II) complexes. The two most explored have been the use of monodentate ligands and the incorporation of steric effects between the bidentate ligands and the Ru(II). However, the introduction of electronic effects in the ligands has been less explored. Herein, we report a systematic experimental, theoretical, and photocytotoxicity study of a novel series of Ru(II) complexes Ru1-Ru5 of general formula [Ru(phen)2(N∧N')]2+, where N∧N' are different minimal strained ligands based on the 1-aryl-4-benzothiazolyl-1,2,3-triazole (BTAT) scaffold, being CH3 (Ru1), F (Ru2), CF3 (Ru3), NO2 (Ru4), and N(CH3)2 (Ru5) substituents in the R4 of the phenyl ring. The complexes are stable in solution in the dark, but upon irradiation in water with blue light (λex = 465 nm, 4 mW/cm2) photoejection of the ligand BTAT was observed by HPLC-MS spectrometry and UV-vis spectroscopy, with t1/2 ranging from 4.5 to 14.15 min depending of the electronic properties of the corresponding BTAT, being Ru4 the less photolabile (the one containing the more electron withdrawing substituent, NO2). The properties of the ground state singlet and excited state triplet of Ru1-Ru5 have been explored using density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. A mechanism for the photoejection of the BTAT ligand from the Ru complexes, in H2O, is proposed. Phototoxicity studies in A375 and HeLa human cancer cell lines showed that the new Ru BTAT complexes were strongly phototoxic. An enhancement of the emission intensity of HeLa cells treated with Ru5 was observed in response to increasing doses of light due to the photoejection of the BTAT ligand. These studies suggest that BTAT could serve as a photocleavable protecting group for the cytotoxic bis-aqua ruthenium warhead [Ru(phen)2(OH2)2]2+.

A new generation of benzimidazole-based cyclometalated ruthenium( ii ) complexes with bpy or dpq as ancillary ligands are effective against hypoxic cancers via green light activation and can directly disrupt phospholipid membranes and trigger oncosis.

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.

A family of 6 new 1-aryl-4-benzothiazolyl-1,2,3-triazoles with CH3, F, CF3, NO2, OCH3 and N(CH3)2 substituents in the R4 of the phenyl ring has been prepared from the respective aldehyde treated with ortho-aminothiophenol. The compounds are characterized in solution using multinuclear NMR spectroscopy and in the solid state by X-ray diffraction. The emission spectra of the compounds with stronger electron-donating groups, OCH3 and N (CH3)2, exhibit a red-shifted band (391 and 515 nm, respectively), the latest showing the largest Stokes shift and the highest quantum yield, which increases with the decrease polarity of the solvent. The excited-state lifetimes of all compounds showed a bi-exponential decay with a short (5-12 ns), according to an admixture of intra-molecular charge transfer (ICT) and pi-pi*, and a long (45-100 ns) component. The calculated structures of their first singlet excited state by TD-DFT in acetonitrile (ACN) solution allows to estimate the change in the dipole moments, which explains the ICT character of their first singlet excited state for the NO2 and N(CH3)2 de-rivatives. Important to note that compound with the electron-donating N(CH3)2 substituent showed strong sol-vatofluorochromism (correlated well with the ICT and the dipole moments). Interestingly, some of the compounds are active in human A2780, HeLa and A549 cancer cell lines, exhibiting IC50 values in the low micromolar range, whereas showing low cytotoxicity in healthy CHO cells. Important to note that the N(CH3)2 derivative showed cytoplasmic staining as determined by confocal fluorescent microscopy.

We present the synthesis and characterization of six new heteroleptic osmium(II) complexes of the type [Os(C^N)(N^N)2]OTf (N^N = 2,2'-bipyridine and dipyrido[3,2-d:2',3'-f]quinoxaline; C^N = deprotonated methyl 1-butyl-2aryl-benzimidazolecarboxylate) with varying substituents in the R3 position of the phenyl ring of the cyclometalating C^N ligand. The new compounds are highly kinetically inert and absorb a full-wavelength range of visible light. An investigation of the antiproliferative activity of the new compounds has been performed using a panel of human cancer and noncancerous 2D cell monolayer cultures under dark conditions and green light irradiation. The results demonstrate that the new Os(II) complexes are markedly more potent than conventional cisplatin. The promising antiproliferative activity of selected Os(II) complexes was also confirmed using 3D multicellular tumor spheroids, which have the characteristics of solid tumors and can mimic the tumor tissue microenvironment. The mechanism of antiproliferative action of complexes has also been investigated and revealed that the investigated Os(II) complexes activate the endoplasmic reticulum stress pathway in cancer cells and disrupt calcium homeostasis.

A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C<^>N)(2)(dppz)](+), Ir1-Ir4, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was p-CF3C6H4 or p-Me2NC6H4. These new Ir(III) complexes were assessed as photosensitizers to explore the structure-activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, the complexes exhibited high selective potency across several cancer cell lines predisposed to photodynamic therapy; the benzothiazole derivatives (Ir1 and Ir2) were the best performers, Ir2 being also activatable with green or red light. Notably, when irradiated, the complexes induced leakage of lysosomal content into the cytoplasm of HeLa cancer cells and induced oncosis-like cell death. The capability of the new Ir complexes to photoinduce cell death in 3D HeLa spheroids has also been demonstrated. The investigated Ir complexes can also catalytically photo-oxidate NADH and photogenerate O-1(2) and/or (OH)-O-center dot in cell-free media.

We present the synthesis and characterization of six new heteroleptic osmium(II) complexes of the type [Os(C^N)(N^N) 2 ]OTf (N^N = 2,2′-bipyridine, dipyrido[3,2-d:2',3'-f]quinoxaline; C^N = deprotonated methyl 1-butyl-2aryl-benzimidazolecarboxylate) with varying substituents in the R3 position of the phenyl ring of the cyclometalating C^N ligand. The new compounds are highly kinetically inert and absorb a full-wavelength range of visible light. An investigation of the antiproliferative activity of the new compounds has been performed using a panel of human cancer and noncancerous 2D cell monolayer cultures under dark conditions and green light irradiation. The results demonstrate that the new Os(II) complexes are markedly more potent than conventional cisplatin and that their activity is promoted by irradiation by green light. Promising antiproliferative activity of selected Os(II) complexes was also confirmed using 3D multicellular tumor spheroids, which have the characteristics of solid tumors and can mimic the tumor tissue microenvironment. The mechanism of antiproliferative action of complexes has also been investigated and revealed that under dark conditions, the investigated Os(II) complexes activate the endoplasmic reticulum stress pathway in cancer cells and disrupt calcium homeostasis.

Novel Os(ii) arene complexes with a deprotonated ppy or ppy-CHO C^N ligand have been synthesized to selectively act on cancer cells as proteosynthesis inhibitorsin vitroand exert antitumor activityin vivoinC. elegansmodels.

In the process of synthesis of a new drug, as important as the drug itself is the formulation used, because the same compound can present a very different efficacy depending on how it is administered. In this work, we demonstrate how the antitumor capacity of a new octahedral organo-ruthenium complex, [Ru(ppy-CHO)(phen)(2)][PF6] is affected by its encapsulation in different types of mesoporous silica nanoparticles. The interactions between the Ru complex and the silica matrix and how these interactions are affected at two different pHs (7.4 and 5.4, mimicking physiological and endolysosomal acidic conditions, respectively) have been studied. The encapsulation has also been shown to affect the induction of apoptosis and necrosis and progression of the cell cycle compared to the free drug. The encapsulation of the Ru complex in nanoparticles functionalized with amino groups produced very high anticancer activity in cancer cells in vitro, especially against U87 glioblastoma cells, favoring cellular internalization and significantly increasing the anticancer capacity of the initial non-encapsulated Ru complex.

A family of five heteroleptic complexes [Ru(C<<^>>N)(N<<^>>N)(2)][PF6] (HC<<^>>N = methyl 1-butyl-2-arylbenzimidazolecarboxylate; N<<^>>N = polypyridine) has been synthesized to act as biologically-compatible green light photosensitizers (PSs) with phototherapeutic indexes (PIs) up to higher than 700 under hypoxia (2% O-2) in HeLa cancer cells under short time of irradiation.

Half-sandwich ruthenium(ii) complexes [(η6-p-cymene)Ru(C^N)-(X)]0/+ (X = Cl, py or 4-NMe2-py) containing a cyclometalated 2-ppy or 1-ppz with a non-coordinated CHO group as a handle for further functionalization have been synthesized to achieve selective cytotoxicity to cancer cells, the more potent compounds acting as proteosynthesis inhibitors; this is a new mode of action for half-sandwich metal complexes.

Octahedral Ir(III) complexes bearing cyclometalated ligands exhibit a great stability in biological media and are excellent therapeutical and phototherapeutical candidates for some major human ailments. Interesting examples of the use of luminescent iridium compounds in the area of cancer diagnosis and treatment have been recently reported, including modulators in protein-protein interactions, membrane-disruptors or mitochondria-targeted agents. Likewise, the scope of their conjugation to targeting vehicles as well as to smart nanoplatforms has been studied as a mean for an adequate delivery to cancer cells. Furthermore, several Ir(III) compounds have recently been found to be promising photo dynamic therapy (PDT) agents both for cancer and Alzheimer's disease. Additionally, their use as photoactive species in photoactivated chemotherapy (PACT) has also been explored in spite of their high photostability. Finally, new developments of Ir(III)-based drugs in infectious and inflammatory diseases, and neurological disorders, will be also discussed, including a direct inhibitor of Staphylococcus aureus, containing one amino group in the N boolean AND N ligand, a TACE inhibitor (an enzyme involved in the formation of the biologically active form of TNF-alpha) and a photosensitizer inducing oxidation of amyloidogenic peptides and controlling their aggregation pathways under mild conditions. The mechanism of action of Ir(III) agents together with the relationship between their structures and biomedicinal activities will be discussed. (C) 2018 Elsevier B.V. All rights reserved.

Our study demonstrates that four novel kinetically inert C,N-cyclometalated RuII complexes of the type [Ru(C^N)(N^N)2 ][PF6 ] containing a handle for functionalization on the C^N ligand are very potent cytotoxic agents against several different human cancer cell lines and are up to 400-fold more potent than clinically used cisplatin. In addition, the investigated ruthenium complexes are less cytotoxic in noncancerous cells, and exhibit higher selectivity for cancer cells than conventional platinum anticancer drugs. The high potency of the investigated ruthenium compounds can be attributed to several factors, including enhanced internalization and their capability to change mitochondrial transmembrane potential in cells. The new ruthenium complexes also interfere with protein synthesis with a markedly higher potency than conventional inhibitors of DNA translation. Notably, the latter mechanism has not been hitherto described for other cytotoxic Ru compounds and cisplatin.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Benzazolate complexes of Ni(II), [Ni(pbz)(tren)]ClO4 (pbz = 2-(2'-hydroxyphenyl)-benzimidazole (pbm), 1, 2-(2'-hydroxyphenyl)-benzoxazole (pbx), 2, 2-(2'-hydroxyphenyl)-benzothiazole (pbt), 3; tren = tris(2-aminoethyl)amine), are prepared by self-assembly reaction and structurally characterized. Theoretical DFT simulations are carried out to reproduce the features of their crystal structures and their spectroscopic and photophysic properties. The three complexes are moderately luminescent at room temperature both in acetonitrile solution and in the solid state. The simulations indicate that the absorption spectrum is dominated by two well-defined transitions, and the electronic density concentrates in three MOs around the benzazole ligands. The Stokes shifts of the emission spectra of complexes 1-3 are determined by optimizing the electronic excited state.

The solution/solid state luminescence properties of selected orthometalated palladium complexes have been investigated in parallel with the relevant structural information provided by their X-ray crystal structures and theoretical calculations. Two cyclometalated backbones with different stacking abilities and a selection of bridging O^O, O^N or N^S ligands comprise the series under study, [{Pd(μ-L) (C^N)}2] (C^N = N-phenylpyrazole (Phpz) ; N-benzylideneaniline (Bza) ; L = acetate (Aco) , succinimidate (succ) , phthalimidate (phthal) , 1-methylimidazoline-2 thionate (Smeimid) ), completed with mononuclear [Pd(C^N)(N-pClPhsal)] (N-pClPhsal = chlorophenylsalycilaldiminate) complexes. New compounds , and were synthesized and the X-ray structures of , , , and have been elucidated in order to examine and compare solid-state Pd(C^N)-Pd(C^N) and ligand-ligand interactions with the rest of the series. The molecular structures of the complexes reveal intramolecular PdPd distances between 2.842 and 2.999 Å and π-π and C-Hπ interactions. All complexes studied show emission in the solid state at room temperature and a relationship is observed between emission energy, the nature of the lowest energy excited state, and metal-metal interactions. DFT calculations are undertaken to gain insight into the relationship between the structure and photophysical properties of the complexes.