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Two luminescent cyclometallated IrIII complexes of the type [Ir(C^N)2(N^N)]x (X = 0 (1), and X = +1 (2)) were prepared using methyl 2-phenylquinoline-4-carboxylate as C^N ligands and either a deprotonated or protonated 3-(2-pyridyl)pyrazole as the N^N chelate. The synthesis followed a well-established and straightforward procedure. Photophysical analysis unveiled their remarkable properties, featuring phosphorescent red and orange emissions attributed to 3MLCT and 3LLCT transitions, with high emissive quantum yields in degassed DMSO solutions. Importantly, these complexes exhibited dual functionality as potent chemotherapeutic agents and photosensitisers, with their effectiveness tailored to specific cancer cell lines. Phototherapeutic treatment was particularly effective against lung cancer A549 cells, while a chemotherapeutic approach yielded superior results against breast cancer 4T1-luc2 cells. Both complexes primarily targeted lysosomes, leading to cell death through apoptotic pathways, with IC50 values in the nanomolar range. Importantly, they demonstrated no cytotoxicity against lymphocytes, mimicking the behaviour observed in healthy cells. Encouragingly, 1 and 2 exhibited minimal in vivo toxicity. The most striking finding was the exceptional chemotherapeutic efficacy of complexes 1 and 2 against 4T1-luc2 cells in BALB/c mice. These complexes surpassed the performance of the clinically employed 5-fluorouracil, especially at early tumor stages, significantly retarding 4T1-luc2 proliferation. Further investigations at vascularised and organised tumor stages revealed that complex 1 could reduce tumor size by half compared to untreated mice, which was also confirmed through tumoral weight analysis. While these findings are preliminary, the outstanding performance of these complexes at early tumor stages against breast cancer 4T1-luc2 in vivo, their selective therapeutic feasibility (chemotherapy vs. PDT) tailored to specific cancerous cell lines, and their stra

Delivering alternative strategies to deal with cancer is a huge milestone in research. Cancer cells can give a senescence response as consequence of cellular stress or external stimuli such as the use of chemotherapies, which could end up eventually in cancer relapse. Controlling cellular senescence will surely open new cancer treatment approaches. Cancer senescence induction can be used as an added timeframe to look for alternative treatments and senolytic drugs to avoid cancer relapse destroying the senescent cells (SnCs). Within cancer senescence research, metal complexes are underdeveloped in comparison with that of organic molecules or nanoparticles. Herein, we highlight the scarce investigation performed with metal complexes in the field of senescence and how a great input on them could be a huge step towards the search of alternative cancer treatments.

1,4-Dihydropyridine is a privileged scaffold present in many bioactive molecules, from coenzymes to commercially available drugs. Among other interesting properties, it has been found good anticancer activity in some of these 1,4-DHPs, therefore many research groups are trying to develop new compounds based on this structural core. For this purpose, in this work, a family of 23 new 1,4-dihydropyridines has been synthesized using hydrazide and malononitrile derivatives as precursors. This straightforward catalytic process has given rise to the desired products with moderate to excellent yields. All the compounds have been tested against four different cancer cell lines [HeLa (human cervical carcinoma), Jurkat (leukemia), A549 (human lung cancer) and MIA PaCa-2 (pancreatic cancer)] to establish a preliminary structure–activity relationship. From this study, and among the best candidates, we chose 4-chlorophenyl and 4-(trifluoromethyl)phenyl derivatives in the malononitrile ring to synthesize a second generation of molecules with enhanced cytotoxicity, modifying the substituent in the N-heterocyclic position (acylhydrazine moieties). With this second generation of compounds, we successfully decreased the IC50 until 7 µM. An in-depth analysis of their biological properties suggests that these promising compounds trigger a non-conventional cell death mechanism known as paraptosis. Moreover, the tested photophysical properties of these products show in some cases an interesting long wavelength emission and excitation, potentially leading to new biosensors or theragnostic agents. Finally, in vivo assays concerning the acute toxicity in mice of two of the most active compounds (with an alkyl chain of seven carbon atoms in the acylhydrazine moiety) demonstrated that even dosed at thousands fold the corresponding IC50 values (2500 and 3300 times more concentrated than the IC50 values for the two compounds studied), there was no sign of harmful effects on the tested subjects

Perylenediimes (PDIs) are very interesting compounds due to their outstanding electrooptical properties, high fluorescence quantum yields, and huge versatility in their synthetic chemistry. Although PDIs are mainly used in optoelectronic applications, the number of biological studies using PDIs has been growing in the last few years. Here, we report on the synthesis and biological studies of two new families of PDIs as phototherapeutic agents. (Figure 1: a) Imidazolium-PDI, b) [AgPy2(PPh3)]-PDI). Thus, we have prepared water-soluble PDIs based on imidazolium salts as photosensitizes to generate singlet oxygen (1O2), which plays a key role in photodynamic therapy. Internalization and cytotoxicity assays were carried out in HeLa and SHSY5Y human neuroblastoma cells lines. On the other hand, taking advantage of the medicinal potential of some metals, we have synthesized new PDIs linked to silver and copper complexes to study their behavior as metallodrugs. Biological assays were also carried out in HeLa cells line.

Photodynamic therapy (PDT) is a cancer treatment still bearing enormous prospects of improvement. Within the toolbox of PDT, developing photosensitizers (PSs) that can specifically reach tumor cells and promote the generation of high concentration of reactive oxygen species (ROS) is a constant research goal. Mitochondria is known as a highly appealing target for PSs, thus being able to assess the biodistribution of the PSs prior to its light activation would be crucial for therapeutic maximization. Bifunctional Ir(III) complexes of the type [Ir(C^N)2(N^N-R)]+, where N^C is either phenylpyridine (ppy) or benzoquinoline (bzq), N^N is 2,2′-dipyridylamine (dpa) and R either anthracene (1 and 3) or acridine (2 and 4), have been developed as novel trackable PSs agents. Activation of the tracking or therapeutic function could be achieved specifically by irradiating the complex with a different light wavelength (405 nm vs. 470 nm respectively). Only complex 4 ([Ir(bzq)2(dpa-acr)]+) clearly showed dual emissive pattern, acridine based emission between 407–450 nm vs. Ir(III) based emission between 521 and 547 nm. The sensitivity of A549 lung cancer cells to 4 evidenced the importance of involving the metal center within the activation process of the PS, reaching values of photosensitivity over 110 times higher than in dark conditions. Moreover, complex 4 promoted apoptotic cell death and possibly the paraptotic pathway, as well as higher ROS generation under irradiation than in dark conditions. Complexes 2–4 accumulated in the mitochondria but species 2 and 4 also localizes in other subcellular organelles.

Heterometallic drugs are emerging as a great alternative to conventional metallodrugs. Careful selection of different metallic fragments makes possible to enhance not only the therapeutic potential by a synergistic effect, but also to incorpore key features like traceability. Drugs that integrate traceability and therapy in one system are known as theranostic agents. In cancer research, theranostic agents are becoming increasingly important. They deliver crucial information regarding their biological interplay that can ultimately be used for optimization. The well‐established therapeutic potential of PtII‐, RuII‐ and AuI‐based drugs combined with the outstanding optical properties of d6 transition metal complexes grant the delivery of traceable metallodrugs. These species can be easily fine‐tuned through modification of their respective ligands to provide a new generation of drugs.

Metal complexes are playing an important role over the last few years in the design of new fluorophores with potential application in cell imaging and cancer therapy. Focusing on DNA as the cellular target, G-quadruplex DNA-forming sequences have attracted great attention because they are involved in several biological processes, from chromosome protection to senescence process. In fact, the higher prevalence of these structures in cancer cells than in normal cells, link G4 structures with cancer. So a growing interest is devoted to drugs with a good affinity for G4-DNA and selectivity towards G-quadruplex over duplex DNA to enhance and/or promote quadruplex-related biological effects., Bearing in mind the above-mentioned, we have synthesized a couple of Ir(III) biscyclometallated phosphorescent complexes, [Ir1]Cl and [Ir2]Cl, which incorporate two different imidazolephenanthroline ligands, L1 and L2, where L1 holds an acidic N-H group, while L2 is decorated with a N-Ph group. As shown in this work, such a trivial functional change influences the acidbase and redox chemistry of [Ir1]Cl and [Ir2]Cl, and what is more interesting, it also affects the subcellular localization of these derivatives, their cytotoxic behaviour and their mechanism of action. Finally, both complexes are able to stabilize a battery of G4 structures with preference for antiparallel two-tetrads G4 (Bom17 and TBA). In addition, [Ir1]Cl exhibits selectivity for G-quadruplex even in the presence of a DNA double helix as competitor revealing the potential of this complex for specifically target G4 structures.

A pyrene tetraalkynyl ligand has been used for the preparation of three different tetraalkynyl Au(I) complexes. Two of these complexes display fluorescent emission in CH2Cl2 solution, with quantum yields exceeding 90%. Although the emission is mainly due to ligand-centered excited states, the presence of the metal center is key to reaching such excellent quantum yield values, providing an extra rigidity to the system and therefore, minimizing the nonradiative deactivation pathways. To the best of our knowledge, these quantum yields lie among the highest reported for metal-based luminophores in solution, a quality that makes them resemble molecular torches. Preliminary studies on healthy cheek cells show that one of the complexes is efficiently and rapidly taken up into the cell.

In this work, the synthesis of interesting urea derivatives 5 based on 1,4-dihydropyridines 3 is described for the first time. Considering that both families exhibit potential as drugs to treat various diseases, their activity as anticancer agents has been evaluated in HeLa (cervix), Jurkat (leukaemia) and A549 (lung) cancer cell lines as well as on healthy mice in vivo. In general, whereas 1,4-dihydropyridines show a moderate cytotoxic activity, their urea analogues cause an extraordinary increase in their antiproliferative activity, specially towards HeLa cells. Because of the chiral nature of these compounds, enantiomerically enriched samples were also tested, showing different cytotoxic activity than the racemic mixture. Although the reason is not clear, it could be caused by a complex amalgam of physical and chemical contributions. The studied compounds also exhibit luminescent properties, which allow performing a biodistribution study in cancer cells. They have emission maxima between 420 and 471 nm, being the urea derivatives in general red shifted. Emission quenching was observed for those compounds containing a nitro group (3e,f and 5e,f). Fluorescence microscopy showed that 1,4-dihydropyridines 3a and 3g localised in the lysosomes, in contrast to the urea derivatives 5h that accumulated in the cell membrane. This different distribution could be key to explain the differences found in the cytotoxic activity and in the mechanism of action. Interestingly, a preliminary in vivo study regarding the acute toxicity of some of these compounds on healthy mice has been conducted, using a concentration up to 7200 times higher than the corresponding IC50 value. No downgrade in the welfare of the tested mice was observed, which could support their use in preclinical tumour models.

A simple approach to synthesize new highly substituted 4H-pyran derivatives is described. Efficient Et3N acts as a readily accessible catalyst of this process performed in pure water and with only a 20 mol% of catalyst loading. The extremely simple operational methodology, short reaction times, clean procedure and excellent product yields render this new approach extremely appealing for the synthesis of 4H-pyrans, as potentially biological scaffolds. Additionally, DNA interaction analysis reveals that 4H-pyran derivatives behave preferably as minor groove binders over major groove or intercalators. Therefore, this is one of the scarce examples where pyrans have resulted to be interesting DNA binders with high binding constants (Kb ranges from 1.53 × 104 M−1 to 2.05 × 106 M−1).

Diverse iridium peptide bioconjugates and the corresponding iridium/gold bimetallic complexes have been synthesized starting from a cyclometallated carboxylic acid substituted IrIII complex [Ir(ppy)2(Phen‐5‐COO)] by solid phase peptide synthesis (SPPS). The selected peptide sequences were an enkephalin derivative Tyr‐Gly‐Gly‐Phe‐Leu together with the propargyl‐substituted species Tyr‐Gly‐Pgl‐Phe‐Leu to allow gold coordination (Pgl: propyrgyl‐glycine, HC≡C‐Gly), and a specific short peptide, Ala‐Cys‐Ala‐Phen, containing a cysteine residue. Introduction of the gold center has been achieved via a click reaction with the alkynyl group leading to an organometallic Au−C(triazole) species, or by direct coordination to the sulfur atom of the cysteine. The photophysical properties of these species revealed predominantly an emission originating from the Ir complex, using mixed metal‐to‐ligand and ligand‐to‐ligand charge transfer excited states of triplet multiplicity. The formation of the peptide bioconjugates caused a systematic redshift of the emission profiles. Lysosomal accumulation was observed for all the complexes, in contrast to the expected mitochondrial accumulation triggered by the gold complexes. Only the cysteine‐containing Ir/Au bioconjugate displayed cytotoxic activity. The absence of activity may be related to the lack of endosomal/lysosomal escape for the cationic peptide conjugates. Interestingly, the different coordination sphere of the gold atom may play a crucial role, as the Au−S(cysteine) bond may be more readily cleaved in a biological environment than the Au−C(triazole) bond, and thus the Au fragment could be released from or trapped in the lysosomes, respectively. This work represents a starting point in the development of bimetallic peptide bioconjugates as theranostics and in the knowledge of factors that contribute to anti‐proliferative activity.

A series of neutral and cationic heterotrimetallic complexes of the type fac-[Re(CO)3(bipy(CC)2-(AuL)2)X]n, where bipy(CC)2 is 4,4′-alkynyl-2,2′-bipyridine; L is either triphenylphosphine (PPh3), [1,3-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene] (IPr), or tert-butyl isocyanide (CNtBu); and X is a chloride (n = 0) or acetonitrile (n = 1), were synthesized and characterized together with their Re(I) precursors, i.e., fac-[Re(CO)3(bipy(CC)2)X]n. X-ray diffraction of complexes 1, 3, and 6 corroborated the expected octahedral and linear distribution of the ligands along the Re(I) and Au(I) centers, respectively. Luminescent studies showed that all the complexes displayed a broad emission band centered between 565 and 680 nm, corresponding to a 3MLCT from the Re(I) to the diimine derivative. The presence of the gold fragment coordinated to the diimine ligand shifted in all cases the emission maxima toward higher energies. Such an emission difference could be potentially used for assessing the precise moment of interaction of the probe with the biological target if the gold fragment is implicated. Antiproliferative studies in cancer cells, A549 (lung cancer) and HeLa (cervix cancer), showed a generalized selectivity toward HeLa cells for those heterotrimetallic species incubated at longer times (72 vs 24 h). ICP-MS spectrometry revealed the greater cell internalization of cationic vs neutral species. Preliminary fluorescence microscopy experiments showed a different behavior of the complexes in HeLa and A549 cell lines. Whereas the complexes in A549 were randomly distributed in the outside of the cell, those incubated with HeLa cells were located close to the cellular membrane, suggesting some type of interaction, and possibly explaining their cellular selectivity when it comes to the antiproliferative activity displayed in the different cell lines.

The direct reaction between CuI and 3,5-dichloropyridine, in acetonitrile at room temperature, gives rise to [Cu(Cl2-py)I]n (Cl2-py = 3,5-dichloropyridine), which consists of a Cu(I)–I double chain based coordination polymer (CP) grafted with 3,5-dichloropyridine. In this simple one-pot process, the modulation of the reaction conditions, i.e. slight variations in the CuI and Cl2-py ratio caused by in situ disproportion, can, however, produce significant changes in the physical properties of the materials. For instance, the reaction carried out in a 1 : 1 ratio under ambient conditions leads to compound 1, while compound 1′ is obtained upon a solvothermal process of stoichiometric reaction mixture, Cl2-py and CuI, which produces partial disproportion (<0.5% in weight) of the initial Cu(I). Interestingly, compounds 1 and 1′ show an identical chemical composition and structure as determined by both single crystal and powder X-ray diffraction. However, they display remarkable differences in the luminescence behavior, featuring broad emission bands centered at 515 and 670 nm and associated to photoluminescence quantum yields of 12 and 5% for 1 and 1′, respectively. Density functional theory (DFT) calculations allowed us to rationalize the nature of this rare behavior. This is attributed to structural defects related to the weaker coordination bond present in these structures that provoke the strong red-shifted emission.