Critical Aspects and Challenges in the Design of Small Molecules for Electrochemiluminescence (ECL) Application.

Electrochemiluminescence (ECL) has gained renewed interest due to the strong parallel development of luminophores in the field of organic light emitting diodes (OLEDs) with which this technique shares several aspects. In this perspective review we discuss the most relevant advances of the past 15 years in the study of organic and organometallic compounds as ECL emitters, by dividing them in three different classes: i) fluorescent emitters, ii) phosphorescent emitters and iii) Thermally Activated Delayed Fluorescence (TADF) emitters; then, water-soluble organic luminophores will be also discussed. We focus on how their design, their photo- and electrochemical properties and, in particular, the nature of the emitter, affect their efficiency in ECL. Regardless of the type of luminophore or the photoluminescence quantum yield (PLQY), the literature converges on the fact that the most determining aspect is the stability of the oxidized/reduced form of the emitter. Even if phosphorescent emitters can show outstanding efficiency, this often requires the absence of oxygen. In the case of TADFs, there is also a strong dependence of photoluminescence both in terms of PLQY and emission energy on the polarity of the media, so compounds, that appear promising in organic solvents, may be very inefficient in aqueous media.

Dinuclear NHC-gold(I)-thiolato and -alkynyl complexes: synthesis, anticancer activity, and catalytic activity in lactonization reactions.

A series of novel dinuclear NHC-gold-thiolato and -alkynyl complexes bearing aromatic linkers were successfully synthesized by an efficient and simple synthetic route. The catalytic activity of these complexes was tested in a lactonization reaction. The reaction proceeds in high efficiency, in short reaction time and under mild conditions, and is complementary to existing methods. Furthermore, the digold(I)-thiolato derivatives exhibit remarkable cytotoxicity towards several cancer cell lines.

Unveiling the promising anticancer activity of palladium(II)-aryl complexes bearing diphosphine ligands: a structure-activity relationship analysis.

In continuation of our previous works on the cytotoxic properties of organopalladium compounds, in this contribution we describe the first systematic study of the anticancer activity of Pd(II)-aryl complexes. To this end, we have prepared and thoroughly characterized a wide range of palladium derivatives bearing different diphosphine, aryl and halide ligands, developing, when necessary, specific synthetic protocols. Most of the synthesized compounds showed remarkable cytotoxicity towards ovarian and breast cancer cell lines, with IC50 values often comparable to or lower than that of cisplatin. The most promising complexes ([PdI(Ph)(dppe)] and [PdI(p-CH3-Ph)(dppe)]), characterized by a diphosphine ligand with a low bite angle, exhibited, in addition to excellent cytotoxicity towards cancer cells, low activity on normal cells (MRC5 human lung fibroblasts). Specific immunofluorescence tests (cytochrome c and H2AX assays), performed to clarify the possible mechanism of action of this class of organopalladium derivatives, seemed to indicate DNA as the primary cellular target, whereas caspase 3/7 assays proved that the complex [PdI(Ph)(dppe)] was able to promote intrinsic apoptotic cell death. A detailed molecular docking analysis confirmed the importance of a diphosphine ligand with a reduced bite angle to ensure a strong DNA-complex interaction. Finally, one of the most promising complexes was tested towards patient-derived organoids, showing promising ex vivo cytotoxicity.

Platinum(0)-η2-1,2-(E)ditosylethene Complexes Bearing Phosphine, Isocyanide and N-Heterocyclic Carbene Ligands: Synthesis and Cytotoxicity towards Ovarian and Breast Cancer Cells.

A wide range of platinum(0)-η2-(E)-1,2-ditosylethene complexes bearing isocyanide, phosphine and N-heterocyclic carbene ancillary ligands have been prepared with high yields and selectivity. All the novel products underwent thorough characterization using spectroscopic techniques, including NMR and FT-IR analyses. Additionally, for some compounds, the solid-state structures were elucidated through X-ray diffractometry. The synthesized complexes were successively evaluated for their potential as anticancer agents against two ovarian cancer cell lines (A2780 and A2780cis) and one breast cancer cell line (MDA-MB-231). The majority of the compounds displayed promising cytotoxicity within the micromolar range against A2780 and MDA-MB-231 cells, with IC50 values comparable to or even surpassing those of cisplatin. However, only a subset of compounds was cytotoxic against cisplatin-resistant cancer cells (A2780cis). Furthermore, the assessment of antiproliferative activity on MRC-5 normal cells revealed certain compounds to exhibit in vitro selectivity. Notably, complexes 3d, 6a and 6b showed low cytotoxicity towards normal cells (IC50 > 100 µM) while concurrently displaying potent cytotoxicity against cancer cells.

Synergistic applications of cyclodextrin-based systems and metal-organic frameworks in transdermal drug delivery for skin cancer therapy.

This review article explores the innovative field of eco-friendly cyclodextrin-based coordination polymers and metal-organic frameworks (MOFs) for transdermal drug delivery in the case of skin cancer therapy. We critically examine the significant advancements in developing these nanocarriers, with a focus on their unique properties such as biocompatibility, targeted drug release, and enhanced skin permeability. These attributes are instrumental in addressing the limitations inherent in traditional skin cancer treatments and represent a paradigm shift towards more effective and patient-friendly therapeutic approaches. Furthermore, we discuss the challenges faced in optimizing the synthesis process for large-scale production while ensuring environmental sustainability. The review also emphasizes the immense potential for clinical applications of these nanocarriers in skin cancer therapy, highlighting their role in facilitating targeted, controlled drug release which minimizes systemic side effects. Future clinical applications could see these nanocarriers being customized to individual patient profiles, potentially revolutionizing personalized medicine in oncology. With further research and clinical trials, these nanocarriers hold the promise of transforming the landscape of skin cancer treatment. With this study, we aim to provide a comprehensive overview of the current state of research in this field and outline future directions for advancing the development and clinical application of these innovative nanocarriers.

Rational Design of Palladium(II) Indenyl and Allyl Complexes Bearing Phosphine and Isocyanide Ancillary Ligands with Promising Antitumor Activity.

A new class of palladium-indenyl complexes characterized by the presence of one bulky alkyl isocyanide and one aryl phosphine serving as ancillary ligands has been prepared, presenting high yields and selectivity. All the new products were completely characterized using spectroscopic and spectrometric techniques (NMR, FT-IR, and HRMS), and, for most of them, it was also possible to define their solid-state structures via X-ray diffractometry, revealing that the indenyl fragment always binds to the metal centre with a hapticity intermediate between ƞ3 and ƞ5. A reactivity study carried out using piperidine as a nucleophilic agent proved that the indenyl moiety is the eligible site of attack rather than the isocyanide ligand or the metal centre. All complexes were tested as potential anticancer agents against three ovarian cancer cell lines (A2780, A2780cis, and OVCAR-5) and one breast cancer cell line (MDA-MB-231), displaying comparable activity with respect to cisplatin, which was used as a positive control. Moreover, the similar cytotoxicity observed towards A2780 and A2780cis cells (cisplatin-sensitive and cisplatin-resistant, respectively) suggests that our palladium derivatives presumably act with a mechanism of action different than that of the clinically approved platinum drugs. For comparison, we also synthesized Pd-ƞ3-allyl derivatives, which generally showed a slightly higher activity towards ovarian cancer cells and lower activity towards breast cancer cells with respect to their Pd-indenyl congeners.

Tailoring thermally activated delayed fluorescence emitters for efficient electrochemiluminescence with tripropylamine as coreactant.

Using a unified metal-free procedure, a selection of Thermally Activated Delayed Fluorescence (TADF) emitters has been synthesized and characterized. Different acceptor and donor moieties have been explored in order to develop red emitting dyes with reduction potentials suitable for the application in ECL using tri-propylamine as coreactant. The most promising compound shows terephthalonitrile as the acceptor and diphenylamines as donors, and it displayed an ECL efficiency that is double the one of the standard [Ru(bpy)3](PF6)2. Based on such findings, a novel water-soluble TADF emitter (Na4[4DPASO3TPN]) has been synthesized and characterized to enable electrochemiluminescence in an aqueous medium.

Highly Efficient Electrochemiluminescence from Imidazole-Based Thermally Activated Delayed Fluorescence Emitters.

A family of novel thermally activated delayed fluorescence (TADF) emitters has been synthesized by a straightforward and metal-free synthesis, and structurally characterized. In this work we kept the acceptor moiety, 4-(1H-imidazol-1-yl)benzonitrile, fixed and systemically tested different donors to correlate their photophysical and electrochemical properties with their performance in electrochemiluminescence using both benzoyl peroxide as co-reactant and co-reactant free (annihilation) conditions. Some compounds exceeded the efficiency of the standard [Ru(bpy)3 ]Cl2 by up to 28 times with benzoyl peroxide and 38 times in annihilation. Interestingly, we found that the efficiency is mainly dictated by the electrochemical reversibility of the redox processes rather than by the photophysical properties in terms of photoluminescence quantum yields or excited-state lifetime. In addition, the annihilation electrochemiluminescence efficiency strongly depends on the pulse sequence. The imidazole moiety can be conveniently alkylated, thus allowing the insertion of functional groups, such a carboxylic acid, and enabling practical applications.

Gold(I)-N-Heterocyclic Carbene Synthons in Organometallic Synthesis.

The prominent role of gold-N-heterocyclic carbene (NHC) complexes in numerous research areas such as homogeneous (photo)catalysis, medicinal chemistry and materials science has prompted organometallic chemists to design gold-based synthons that permit access to target complexes through simple synthetic steps under mild conditions. In this review, the main gold-NHC synthons employed in organometallic synthesis are discussed. Mechanistic aspects involved in their synthesis and reactivity as well as applications of gold-NHC synthons as efficient pre-catalysts, antitumor agents and/or photo-emissive materials are presented.

Combined Treatment of Cancer Cells Using Allyl Palladium Complexes Bearing Purine-Based NHC Ligands and Molecules Targeting MicroRNAs miR-221-3p and miR-222-3p: Synergistic Effects on Apoptosis.

Combined treatments employing lower concentrations of different drugs are used and studied to develop new and more effective anticancer therapeutic approaches. The combination therapy could be of great interest in the controlling of cancer. Regarding this, our research group has recently shown that peptide nucleic acids (PNAs) that target miR-221 are very effective and functional in inducing apoptosis of many tumor cells, including glioblastoma and colon cancer cells. Moreover, in a recent paper, we described a series of new palladium allyl complexes showing a strong antiproliferative activity on different tumor cell lines. The present study was aimed to analyze and validate the biological effects of the most active compounds tested, in combination with antagomiRNA molecules targeting two miRNAs, miR-221-3p and miR-222-3p. The obtained results show that a "combination therapy", produced by combining the antagomiRNAs targeting miR-221-3p, miR-222-3p and the palladium allyl complex 4d, is very effective in inducing apoptosis, supporting the concept that the combination treatment of cancer cells with antagomiRNAs targeting a specific upregulated oncomiRNAs (in this study miR-221-3p and miR-222-3p) and metal-based compounds represents a promising therapeutic strategy to increase the efficacy of the antitumor protocol, reducing side effects at the same time.

Gold-Catalyzed Formal [4+2] Cycloaddition as Access to Antitumor-Active Spirocyclic Oxindoles from Alkynes and Isatin-Derived Ketimines.

Due to its excellent bioactivity profile, which is increasingly utilized in pharmaceutical and synthetic chemistry, spirooxindole is an important core scaffold. We herein describe an efficient method for the construction of highly functionalized new spirooxindolocarbamates via a gold-catalyzed cycloaddition reaction of terminal alkynes or ynamides with isatin-derived ketimines. This protocol has a good functional group compatibility, uses readily available starting materials, mild reaction conditions, low catalyst loadings and no additives. It enables the transformation of various functionalized alkyne groups into cyclic carbamates. Gram-scale synthesis was achieved and DFT calculations verify the feasibility of the mechanistic proposal. Some of the target products exhibit good to excellent antiproliferative activity on human tumor cell lines. In addition, one of the most active compounds displayed a remarkable selectivity towards tumor cells over normal ones.

Synthesis of Adagrasib (MRTX849), a Covalent KRASG12C Inhibitor Drug for the Treatment of Cancer.

A concise, transition-metal and protection-free synthesis of adagrasib (MRTX849), a novel KRASG12C inhibitor drug recently approved by the FDA, is reported. Introduction of two chiral building blocks to the tetrahydropyridopyrimidine core was accomplished via two sequential SNAr reactions. Extensive reaction optimization led to a robust, transition-metal-free oxidation of the sulfide intermediate. A judicious choice of the leaving group with favorable steric and electronic characteristics at the 4-OH position of the tetrahydropyridopyrimidine core enabled a facile SNAr displacement to introduce the chiral piperazine. This new, five-step, chromatography-free synthesis of adagrasib from readily available starting materials obviated the palladium catalysis and protecting group manipulations in the current commercial route and significantly improved the efficiency of the process in 45% overall yield.

Reactions of proteins with a few organopalladium compounds of medicinal interest.

Pd compounds form a promising class of experimental anticancer drug candidates whose mechanism of action is still largely unknown; in particular, a few organopalladium compounds seem very attractive. To gain mechanistic insight into medicinal palladium compounds, we have explored here - through ESI MS analysis - the interactions of four organopalladium agents (1-4) - showing remarkable in vitro antiproliferative properties - with a few representative model proteins, i.e., lysozyme (HEWL), ribonuclease A (RNase), and carbonic anhydrase (hCAI). The tested panel included three Pd allyl compounds with one or two carbene ligands and a palladacyclopentadienyl complex. Notably, the Pd allyl compounds turned out to manifest, on the whole, a modest tendency to react with the above proteins. Only complex 3 produced small amounts of characteristic adducts with hCAI bearing either one or two Pd allyl groups. In contrast, the palladacyclopentadienyl complex 4 manifested a greater and peculiar reactivity with all the above proteins generating invariably protein adducts with a mass increase of +256 Da where a butadienyl group - with no associated Pd - is attached to the proteins. Afterwards, we extended our investigations to the C-terminal dodecapeptide of thioredoxin reductase bearing the -Cys-Sec- reactive motif. In this latter case adducts were formed with all tested Pd compounds; however, complex 4 manifested towards this dodecapeptide a type of reactivity deeply different from that observed with HEWL, RNase A and hCAI. The mechanistic implications of these findings are discussed.

Cationic palladium(II)-indenyl complexes bearing phosphines as ancillary ligands: synthesis, and study of indenyl amination and anticancer activity.

The reactivity of palladium(II) indenyl derivatives and their applications are topics relatively less studied, though in recent times these compounds have been used as pre-catalysts able to promote challenging cross-coupling processes. Herein, we propose the first systematic study concerning the nucleophilic attack on the palladium(II) coordinated indenyl fragment and, for this purpose, we have prepared a library of new Pd-indenyl complexes bearing mono- or bidentate phosphines as spectator ligands, developing specific synthetic strategies. All novel compounds are thoroughly characterized, highlighting that the indenyl ligand presents always a hapticity intermediate between η3 and η5. Secondary amines have been chosen as nucleophiles for the present study and indenyl amination has been monitored by UV-Vis and NMR spectroscopies, deriving a second order rate law, with dependence on both complex and amine concentrations. The rate-determining step of the process is the initial attack of the amine to the coordinated indenyl fragment, and this conclusion has been supported also by DFT calculations. The determination of second order rate constants has allowed us to assess the impact of the phosphine ligands on the kinetics of the process and identify the steric and electronic descriptors most suitable for predicting the reactivity of these systems. Finally, in vitro tests have proven that these organometallic compounds promote antiproliferative activity towards ovarian cancer cells better than cisplatin and possibly by adopting a different mechanism of action.

Synthesis of Carbene-Metal-Amido (CMA) Complexes and Their Use as Precatalysts for the Activator-Free, Gold-Catalyzed Addition of Carboxylic Acids to Alkynes.

A straightforward synthetic protocol leading to carbene-metal-amido (CMA) complexes (metal=Au, Cu) using a mild base and an environmentally desirable solvent (EtOH) has been explored, with a focus on complexes bearing backbone-substituted N-heterocyclic carbene (NHC) ligands, including BIAN-NHCs (BIAN=bis(imino)acenaphthene). The novel CMAs were structurally characterized, and gold-based CMAs bearing diverse NHCs were screened as simple, Brønsted-basic precatalysts. The readily accessible complexes display high catalytic activity in the intermolecular and intramolecular hydrocarboxylation of internal alkynes and alkynoic acids respectively, while the screening reveals the ancillary ligand effect of NHCs in these catalytic systems.

A Nucleophilic Deprotection of Carbamate Mediated by 2-Mercaptoethanol.

Carbamates, typically used for the protection of amines, including Cbz, Alloc, and methyl carbamate, can be readily deprotected by treatment with 2-mercaptoethanol in the presence of potassium phosphate tribasic in N,N-dimethylacetamide at 75 °C. This nucleophilic deprotection protocol is superior to the standard hydrogenolysis or Lewis acid-mediated deprotection conditions for substrates bearing a functionality sensitive to these more traditional methods.

Stereospecific α-(hetero)arylation of sulfoximines and sulfonimidamides.

The occurrence of sulfoximines and sulfonimidoyl groups in biologically active molecules within pharmaceuticals and agrochemicals has notably increased in the past decade. This increase has prompted a wave of discovery of methods to install S(VI) functionality into complex organic molecules. Traditional synthetic methods to form α-substituted sulfonimidoyl motifs rely on S-C bond disconnections and typically require control of the stereogenic S-centre or late-stage modification at sulfur, and comprise multistep routes. Here, we report the development of a stereospecific, modular SNAr approach for the introduction of sulfonimidoyl functional groups into heterocyclic cores. This strategy has been demonstrated across 85 examples, in good to excellent yield, of complex and diverse heterocycles. Sulfoximines, sulfonimidamides and sulfondiimines are all compatible nucleophiles in the SNAr reaction and hence, the methodology was applied to the synthesis of four sulfoximine-containing pharmaceuticals. Of these synthetic applications, most notably ceralasertib, an ATR inhibitor currently in clinical trials, was synthesized in an eight-step procedure on a gram-scale.

A Green Synthesis of Carbene-Metal-Amides (CMAs) and Carboline-Derived CMAs with Potent in†vitro and ex vivo Anticancer Activity.

The modularity and ease of synthesis of carbene-metal-amide (CMA) complexes based on the coinage metals (Au, Ag, Cu) and N-heterocyclic carbenes (NHCs) as ancillary ligands pave the way for the expansion of their applications beyond photochemistry and catalysis. Herein, we further improve the synthesis of such compounds by circumventing the use of toxic organic solvents which were previously required for their purification, and we expand their scope to include complexes incorporating carbolines as the amido fragments. The novel complexes are screened both in vitro and ex vivo, against several cancer cell lines and high-grade serous ovarian cancer (HGSOC) tumoroids, respectively. Excellent cytotoxicity values are obtained for most complexes, while the structural variety of the CMA library screened thus far, provides promising leads for future developments. Variations of all three components (NHC, metal, amido ligand), enable the establishment of trends regarding cytotoxicity and selectivity towards cancerous over normal cells.

A simple synthetic entryway into new families of NHC-gold-amido complexes and their in vitro antitumor activity.

A simple synthetic pathway to Au-NHC amido complexes is described. Syntheses and isolation of [Au(NHC)(NR1R2)] complexes, bearing various NHC ligands and NH-containing heterocycles under mild conditions are reported. The in vitro anticancer activity of these gold-complexes was investigated on three human cancer cell lines. A number of these show comparable or even better antiproliferative activity than cisplatin. Noteworthy is the non-toxicity of most of the complexes on normal cells.

Straightforward synthesis of [Cu(NHC)(alkynyl)] and [Cu(NHC)(thiolato)] complexes (NHC = N-heterocyclic carbene).

Synthetic access to monomeric copper-alkynyl and copper-thiolato complexes of the type [(NHC)Cu(R)] (R = alkynyl or thiolato) using a weak base approach is reported. All reported reactions proceed under mild conditions in air and in environmentally acceptable solvents. The novel complexes are fully characterized and single crystal X-ray analyses unambiguously establish the atom connectivity in these mononuclear complexes. The importance of the supporting NHC ligand's steric properties in stabilizing mononuclear complexes is discussed.