Ferrocene-modified half-sandwich iridium(III) and ruthenium(II) propionylhydrazone complexes and anticancer application.

Ferrocene, ruthenium(II) and iridium(III) organometallic complexes, potential substitutes for platinum-based drugs, have shown good application prospects in the field of cancer therapy. Therefore, in this paper, six ferrocene-modified half-sandwich ruthenium(II) and iridium(III) propionylhydrazone complexes were prepared, and the anticancer potential was evaluated and compared with cisplatin. These complexes showed potential in-vitro anti-proliferative activity against A549 cancer cells, especially for Ir-based complexes, and showing favorable synergistic anticancer effect. Meanwhile, these complexes showed little cytotoxicity and effective anti-migration activity. Ir3, the most active complex (ferrocene-appended iridium(III) complex), could accumulate in the intracellular mitochondria, disturb the cell cycle (S-phase), induce the accumulation of reactive oxygen species, and eventually cause the apoptosis of A549 cells. Then, the design of these complexes provides a good structural basis for the multi-active non­platinum organometallic anticancer complexes.

Design and anticancer behaviour of cationic/neutral half-sandwich iridium(III) imidazole-phenanthroline/phenanthrene complexes.

Considerable attention has been devoted to the exploration of organometallic iridium(III) (IrIII) complexes for their potential as metallic anticancer drugs. In this study, twelve half-sandwich IrIII imidazole-phenanthroline/phenanthrene complexes were prepared and characterized. Complexes exhibited promising in-vitro anti-proliferative activity, and some are obviously superior to cisplatin towards A549 cells. These complexes possessed suitable fluorescence, and a non-energy-dependent uptake pathway was identified, subsequently leading to their accumulation in the lysosome and the lysosomal damage. Additionally, complexes could inhibit the cell cycle (G1-phase) and catalyze intracellular NADH oxidation, thus substantiating the elevation of intracellular reactive oxygen species (ROS) level, which confirming the oxidative mechanism. Western blotting further confirmed that complexes could induce A549 cell apoptosis through the lysosomal-mitochondrial anticancer pathway, which was inconsistent with cisplatin. In summary, these complexes offer fresh concepts for the development of organometallic non­platinum anticancer drugs.

The anticancer application of half-sandwich iridium(III) ferrocene-thiosemicarbazide Schiff base complexes.

Ferrocenyl derivatives and organometallic iridium(III) complexes have been prospective substitutes for platinum-based anticancer drugs. Eight half-sandwich iridium(III) ferrocene-thiosemicarbazide (Fc-TSC) Schiff base anticancer complexes were prepared in this study. These complexes displayed a dimeric structure and exhibited a particular fluorescence due to the "enol" orientation of the TSC pro-ligand. An energy-dependent pathway of the uptake mechanism was ascertained, which ended in the lysosome and led to lysosome damage and apoptosis. Flow cytometry confirmed that the complexes could block the cell cycle (G1 phase) and improve the levels of intracellular reactive oxygen species, indicating an anticancer mechanism of oxidation. Then, a lysosomal-mitochondrial anticancer pathway was verified through western blotting. In vivo toxicity assays confirmed that these complexes showed better anti-migration ability and less toxicity in comparison to cisplatin. Thus, these complexes provide a new strategy for the design of non-platinum organometallic anticancer drugs.

Configurationally regulated half-sandwich iridium(III)-ferrocene heteronuclear metal complexes: Potential anticancer agents.

Half-sandwich iridium(III) (IrIII) complexes and ferrocenyl (Fc) derivatives are becoming the research hotspot in the field of anticancer because of their good bioactivity and unique anticancer mechanism different from platinum-based drugs. Then, a series of half-sandwich IrIII-Fc pyridine complexes have been prepared through the structural regulation in this study. The incorporation of half-sandwich IrIII complex with Fc unit successfully improves their anticancer activity, and the optimal performance (IrFc5) is almost 3-fold higher than that of cisplatin against A549 cells, meanwhile, which also shows better anti-proliferative activity against A549/DDP cells. Complexes can aggregate in the intracellular lysosome of A549 cells and induce lysosomal damage, disrupt the cell cycle, increase the level of intracellular reactive oxygen species, and eventually lead to cell apoptosis. Half-sandwich IrIII-Fc heteronuclear metal complexes possess a different anticancer mechanism from cisplatin, which can serve as a potential alternative to platinum-based drugs and show a good application prospect.

In Vitro and In Vivo Antitumor Assay of Mitochondrially Targeted Fluorescent Half-Sandwich Iridium(III) Pyridine Complexes.

Half-sandwich iridium(III) complexes show potential value in the anticancer field. However, complexes with favorable luminescence performance are rare, which limits further investigation of the anticancer mechanism. In this paper, 10 triphenylamine-modified fluorescent half-sandwich iridium(III) pyridine complexes {[(η5-Cpx)Ir(L)Cl2]} (Ir1-Ir10) were prepared and showed potential antiproliferative activity, effectively inhibiting the migration of A549 cells. Ir6, showing the best activity among these complexes, exhibited excellent fluorescence performance (absolute fluorescence quantum yield of 15.17%) in solution. Laser confocal detection showed that Ir6 followed an energy-dependent cellular uptake mechanism, specifically accumulating in mitochondria (Pearson co-localization coefficient of 0.95). A Western blot assay further confirmed the existence of a mitochondrial apoptotic channel. Additionally, Ir6 could arrest the cell cycle at the G2/M phase, catalyze NADH oxidation, reduce the mitochondrial membrane potential, induce an increase in the level of intracellular reactive oxygen species, and exhibit a mechanism of oxidation. An in vivo antitumor assay confirmed that Ir6 can effectively inhibit tumor growth and is safer than cisplatin.

Insights into α-Alkynylation and α-Allenylation of Aldehydes under the Synergisitic Catalysis of Gold/Amine: A DFT Study.

A mechanistic investigation of α-alkynylation and α-allenylation of aldehydes under the synergistic catalysis of AuCl/amine was performed using density functional theory (DFT) calculations. For such a reaction that delivers two products, this study reveals that the reaction undergoes such a mechanistic mode: reactants → alkynyl product → allenyl product, implying that the allenyl product cannot be obtained directly from reactants. The product ratio obtained experimentally was rationalized based on the computed results that both products can reversibly interconvert with AuCl as the catalyst and with N-containing Lewis bases as additives such as 4,5-diazafluorenone. For the relative stability of alkynyl versus allenyl compounds, unsaturated substituents are found to favor the allenyl compounds.

Anticancer application of ferrocene appended configuration-regulated half-sandwich iridium(III) pyridine complexes.

Ferrocenyl derivatives and half-sandwich iridium(III) complexes have received extensive attention in the field of anticancer. In this paper, series of configuration-controlled ferrocene-modified half-sandwich iridium(III) pyridine complexes were prepared. The combination of half-sandwich iridium(III) complexes and ferrocenyl unit successfully improved the anticancer activity of these complexes, especially for trans-configurational one towards A549 cells, and the best-performing (FeIr5) was almost 3.5 times more potent than that of cisplatin. In addition, these complexes could inhibit the migration of A549 cells. Complexes can accumulate in intracellular lysosomes (PCC: >0.75), induce lysosomal damage, disturb the cell circle, decrease the mitochondrial membrane potential, improve the intracellular reactive oxygen species (ROS) levels, and eventually lead to apoptosis. Meanwhile, complexes could bind to serum protein following a static quenching mechanism and transport through it. Then, ferrocene-modified half-sandwich iridium(III) pyridine complexes hold the promise as potential organometallic anticancer agents for further investigation.

Distinctive Mechanistic Scenarios and Substituent Effects of Gold(I) versus Copper(I) Catalysis for Hydroacylation of Terminal Alkynes with Glyoxal Derivatives.

Density functional theory (DFT) calculations have been conducted to study the mechanisms, substituent effects, and the role of bases in Au- and Cu-catalyzed hydroacylation of terminal alkyne with glyoxal derivatives. The two reactions, despite being catalyzed by the same group of transition metals, follow distinctive reaction mechanisms. Through the detailed DFT calculations, insights into the mechanisms are obtained, and the substituent effects and the role of the bases are understood.

Photoexcited Chiral Copper Complex-Mediated Alkene E → Z Isomerization Enables Kinetic Resolution.

While asymmetric synthesis has been established as a powerful synthetic tool for the construction of versatile enantioenriched molecules in the most efficient and practical manner, the resolution of racemates is still the most universal industrial approach to the synthesis of chiral compounds. However, the direct formation of enantiopure Z-isomers through the catalytic nonenzymatic kinetic resolution of racemic E-alkenes remains challenging. Herein, we disclose an unprecedented enantioselective E → Z isomerization mediated by a photoexcited chiral copper complex. This catalytic system enables kinetic resolution of 2-styrylpyrrolidines. This process is difficult to realize under thermal conditions. Mechanistic experiments and density functional theory (DFT) calculations revealed that different overall sensitization rates of the substrate-catalyst complex of the two enantiomers led to the observed excellent kinetic resolution efficiency. This photochemical transformation expands the potential of kinetic resolution beyond their established ground-state reactivity, furnishing a novel reaction mode for enantioselective catalysis at its excited state.

Noncovalent Interaction- and Steric Effect-Controlled Regiodivergent Selectivity in Dimeric Manganese-Catalyzed Hydroarylation of Internal Alkynes: A Computational Study.

Selective hydroarylation of internal alkynes catalyzed by a dimeric manganese complex provides a powerful strategy for the construction of multisubstituted alkenes. In this work, density functional theory (DFT) calculations and experimental studies were carried out to explore the mechanism and origin of regiodivergent hydroarylation of internal alkynes reported by our group. The results demonstrate that this reaction first proceeds via a bimetallic mechanism to generate the active catalyst that subsequently undergoes a monometallic mechanism to run the three-stage catalytic cycle: alkyne migratory insertion, protonation, and active catalyst regeneration. Alkyne migratory insertion is considered as the regioselectivity-determining step. Energy decomposition analyses on insertion transition states suggest that the interaction between the substrate and catalyst is mainly responsible for the observed exclusive γ-selectivity of 1a, while the deformation of these two sections induced by the sterically hindered phenyl group and aryl group accounts for the complete ß-position arylation of 1e. The decrease of γ-selectivity with the regulation of a tertiary alcohol motif in 1a originates from the reduced noncovalent interaction. The computational results provide important insights into the origin of regiodivergent selectivities and useful information for further designing and adjusting the strategy in Mn-catalyzed alkyne hydroarylation.

Preparation and antitumor application of N-phenylcarbazole/triphenylamine-modified fluorescent half-sandwich iridium(III) Schiff base complexes.

Four N-phenylcarbazole/triphenylamine-appended half-sandwich iridium(III) salicylaldehyde Schiff base complexes ([(η5-Cpx)Ir(O^N)Cl]) were prepared and characterized. The complexes exhibited similar antitumor activity to cisplatin and effectively inhibited the migration of tumor cells. Furthermore, the complexes showed favourable hydrolytic activity, while remaining relatively stable in the plasma environment, which facilitated the binding of serum proteins and transport through them. These complexes could decrease the mitochondrial membrane potential, catalyze the oxidation of nicotinamide adenine dinucleotide, induce an increase in intracellular reactive oxygen species (ROS), and eventually result in apoptosis. Aided by their suitable fluorescence property, laser confocal detection showed that the complexes followed an energy-dependent mechanism for their cellular uptake, effectively accumulating in the lysosome and leading to lysosomal damage. In summary, the half-sandwich iridium(III) salicylaldehyde Schiff base complexes could induce lysosomal damage, increase intracellular ROS, and lead to apoptosis, which contributed to their antitumor mechanism of oxidation.

Diastereoselective and Stereodivergent Synthesis of 2-Cinnamylpyrrolines Enabled by Photoredox-Catalyzed Iminoalkenylation of Alkenes.

A photoredox-catalyzed iminoalkenylation of γ-alkenyl O-acyl oximes has been developed. Readily available alkenylboronic acids serve as alkenylation reagents, leading to densely functionalized pyrrolines. Both (E)- and (Z)-cinnamylpyrrolines are accessible depending on the reaction solvent. In dichloromethane, (E)-cinnamylpyrrolines are produced through a photoredox-mediated single-electron-transfer process. In tetrahydrofuran, (Z)-cinnamylpyrrolines are generated by photocatalytic contra-thermodynamic E-to-Z isomerization of (E)-cinnamylpyrrolines though an energy-transfer pathway. Two stereocenters are established with complete diastereoselectivity and only one diastereomer is isolated.

Manganese-catalysed divergent silylation of alkenes.

Transition-metal-catalysed, redox-neutral dehydrosilylation of alkenes is a long-standing challenge in organic synthesis, with current methods suffering from low selectivity and narrow scope. In this study, we report a general and simple method for the manganese-catalysed dehydrosilylation and hydrosilylation of alkenes, with Mn2(CO)10 as a catalyst precursor, by using a ligand-tuned metalloradical reactivity strategy. This enables versatility and controllable selectivity with a 1:1 ratio of alkenes and silanes, and the synthetic robustness and practicality of this method are demonstrated using complex alkenes and light olefins. The selectivity of the reaction has been studied using density functional theory calculations, showing the use of an iPrPNP ligand to favour dehydrosilylation, while a JackiePhos ligand favours hydrosilylation. The reaction is redox-neutral and atom-economical, exhibits a broad substrate scope and excellent functional group tolerance, and is suitable for various synthetic applications on a gram scale.

Preparation and Bioactivity of Iridium(III) Phenanthroline Complexes with Halide Ions and Pyridine Leaving Groups.

A series of half-sandwich structural iridium(III) phenanthroline (Phen) complexes with halide ions (Cl- , Br- , I- ) and pyridine leaving groups ([(η5 -CpX )Ir(Phen)Z](PF6 )n , Cpx : electron-rich cyclopentadienyl group, Z: leaving group) have been prepared. Target complexes, especially the Cpxbiph (biphenyl-substituted cyclopentadienyl)-based one, showed favourable anticancer activity against human lung cancer (A549) cells; the best one (Ir8) was almost five times that of cisplatin under the same conditions. Compared with complexes involving halide ion leaving groups, the pyridine-based one did not display hydrolysis but effectively caused lysosomal damage, leading to accumulation in the cytosol, inducing an increase in the level of intracellular reactive oxygen species and apoptosis; this indicated an anticancer mechanism of oxidation. Additionally, these complexes could bind to serum albumin through a static quenching mechanism. The data highlight the potential value of half-sandwich iridium(III) phenanthroline complexes as anticancer drugs.

Preparation and the anticancer mechanism of configuration-controlled Fe(II)-Ir(III) heteronuclear metal complexes.

A series of configuration-controlled Fe(ii)-Ir(iii) heteronuclear metal complexes, including ferrocene and half-sandwich like iridium(iii) complex units, have been designed and prepared. These complexes show better anticancer activity than cisplatin under the same conditions, especially cis-configurational ones. Laser confocal microscopy analysis confirms that the complexes follow a non-energy-dependent cellular uptake mechanism, accumulate in lysosomes (pearson co-localization coefficient: ∼0.7), lead to lysosomal damage, and eventually induce apoptosis. These complexes can reduce the mitochondrial membrane potential, disturb the cell circle, catalyze the oxidation of nicotinamide-adenine dinucleotide (NADH) and increase the levels of intracellular reactive oxygen species (ROS), following an anticancer mechanism of oxidation. In addition, the complexes could bind to serum protein, and transport through it. Above all, the Fe(ii)-Ir(iii) heteronuclear metal complexes hold promise as potential anticancer agents for further study.

Triphenylamine/carbazole-modified ruthenium(ii) Schiff base compounds: synthesis, biological activity and organelle targeting.

Four triphenylamine/carbazole-modified half-sandwich ruthenium(ii) compounds [(η6-p-cymene)Ru(N/O^N)Cl]0/+ with Schiff base chelating ligands (N/O^N) are synthesized and characterized. The introduction of Schiff base units effectively increases the antitumor activity of these compounds (IC50: 1.70 ± 0.56-17.75 ± 3.10 µM), which, meanwhile, can inhibit the metastasis of tumor cells effectively. These compounds follow an energy-dependent cellular uptake mechanism, mainly accumulate in lysosomes to destroy their integrity, and then eventually promote apoptosis. In addition, these compounds can induce an increase of intracellular reactive oxygen species (ROS) levels and provide an antitumor mechanism of oxidation, which is confirmed by the decrease of mitochondrial membrane potential (MMP) and the catalytic oxidation of the coenzyme nicotinamide-adenine dinucleotide (NADH). All these indicate that these ruthenium(ii) compounds are expected to be dual-functional antitumor agents: anti-metastasis and lysosomal damage.

A Highly Efficient Dimeric Manganese-Catalyzed Selective Hydroarylation of Internal Alkynes.

We have developed a general and site-predictable manganese-catalyzed hydroarylation of internal alkynes in the presence of water, under an air atmosphere without the involvement of ligand. The unique catalytic feature of this reaction is highlighted by comparison with other widely used transition metal catalysts including palladium, rhodium, nickel, or copper. The simple operation, high efficiency and excellent functional group compatibility make this protocol practical for more than 90 structurally diverse internal alkynes, overcoming the influence of both electronic and steric effect of alkynes. Its exclusive regio- and chemoselectivity originates from the unique reactivity of the manganese-based catalyst towards an inherent double controlled strategy of sterically hindered propargyl alcohols without the installing of external directing groups. Its synthetic robustness and practicality have been illustrated by the concise synthesis of bervastatin, a hypolipidemic drug, and late-stage modification of complex alkynes with precise regioselectivity.

Dimeric Manganese-Catalyzed Hydroarylation and Hydroalkenylation of Unsaturated Amides.

An unprecedented Mn(I)-catalyzed selective hydroarylation and hydroalkenylation of unsaturated amides with commercially available organic boronic acids is reported. Alkenyl boronic acids have been successfully employed for the first time in Mn(I)-catalyzed carbon-carbon bond formation. A wide array of ß-alkenylated amide products can be obtained in moderate to good yields, which offers practical access to five- and six-membered lactams. This protocol has predictable regio- and chemoselectivity, excellent functional group compatibility and ease of operation in air, representing a significant step-forward towards manganese-catalyzed C-C coupling.

Dual functions of iridium(III) 2-phenylpyridine complexes: Metastasis inhibition and lysosomal damage.

Six N-phenylcarbazole/triphenylamine-appended half-sandwich iridium(III) 2-phenylpyridine complexes ([(η5-Cp*)Ir(C^N)Cl]) were prepared and characterized. Compared with cisplatin, these complexes exhibited potential antitumor activity against A549 and HeLa tumor cells, with IC50 values (half-maximum inhibitory concentration) that changed from 2.8 ± 0.8 µM to 39.5 ± 2.7 µM, and could block the migration of tumor cells. These complexes also effectively bound to protein (binding constant: ~104 M-1) and were transported through serum proteins, catalyzed the oxidation of coenzyme nicotinamide-adenine dinucleotide. Additionally, laser confocal microscopy and flow cytometry confirmed that these complexes possessed a non-energy-dependent cellular uptake mechanism, effectively accumulated in lysosomes (Pearson colocalization coefficient: ~0.74), damaged the integrity of acidic lysosomes, led to a change in the mitochondrial membrane potential, disrupted the cell cycle (G0/G1 phase), and eventually induced apoptosis. Above all, these complexes are potential antitumor agents with dual functions: metastasis inhibition and lysosomal damage.

Cyclometalated Iridium(III) Complexes Incorporating Aromatic Phosphonate Ligands: Syntheses, Structures, and Tunable Optical Properties.

The incorporation of phosphonate ligands into the cyclometalated iridium(III) complexes can not only tune their electronic and optical properties but also provide the possibility of anchoring these molecules on the semiconductor surfaces for further applications. Herein, we report the first examples of mononuclear cyclometallated iridium(III) complexes incorporating phosphonate ligands, namely, [Ir(ppy)2(HL1)]·0.5H2O (1), [Ir(ppy)2(HL2)]·0.5H2O (2), [Ir(dfppy)2(HL1)] (3), and [Ir(dfppy)2(HL2)]·3.5H2O (4) (ppy = 2-phenylpyridine, dfppy = 2-(2,4-difluorophenyl)pyridine, H2L1 = 2-pyridylphosphonic acid, H2L2 = 2-quinolinephosphonic acid). Luminescent spectra are studied both in solution and in the solid state, and significantly red-shifted broad emission bands are observed in complexes 2 and 4. The experimental and density functional theory (DFT) time-dependent-DFT calculation results indicate that the expansion of the aromatic conjugation length in the ancillary phosphonate ligands decreases the lowest unoccupied molecular orbital energy levels of the systems, originating from the triplet state associated with the ancillary ligand such as 3MLCT, 3LC, and 3LLCT charge-transfer transitions.