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.

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.

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.

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.

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 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.

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.

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.

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.

New Organometallic Tetraphenylethylene⋠Iridium(III) Complexes with Antineoplastic Activity.

Iridium(III) complexes have attracted more and more attention in the past few years because of their potential antineoplastic activity. In this study, four IrIII complexes of the types [(η5 -Cpx )Ir(N^N)Cl]PF6 (complexes 1 and 2) and [Ir(Phpy)2 (N^N)]PF6 (complexes 3 and 4) have been synthesized and characterized. They exhibit potential antineoplastic activity towards A549 cells, especially in the case of complex 1 [IC50 =(3.56±0.5) µm], which was nearly six times as effective as cisplatin [(21.31±1.7) µm]. Additionally, these complexes show some selectivity towards cancer cells over normal cells. They could be transported by serum albumin (binding constants were changed from 0.37×105 to 81.71×105 m-1 ). IrIII complexes 1 and 2 could catalyze the transformation of nicotinamide adenine dinucleotide reduced form (NADH) into NAD+ (turnover numbers 43.2, 11.9] and induce the accumulation of reactive oxygen species, thus confirming their antineoplastic mechanism of oxidation, whereas the cyclometalated complexes 3 and 4 were able to target the lysosome [Pearson co-localization coefficient (PCC)=0.73], cause lysosomal damage, and induce apoptosis. Understanding the mechanism of action would help further structure-activity optimization on these IrIII complexes as emerging cancer therapeutics.

Deoxygenative Arylation of Carboxylic Acids by Aryl Migration.

An unprecedented deoxygenative arylation of aromatic carboxylic acids has been achieved, allowing the construction of an enhanced library of unsymmetrical diaryl ketones. The synergistic photoredox catalysis and phosphoranyl radical chemistry allows for precise cleavage of a stronger C-O bond and formation of a weaker C-C bond by 1,5-aryl migration under mild reaction conditions. This new protocol is independent of substrate redox-potential, electronic, and substituent effects. It affords a general and promising access to 60 examples of synthetically versatile o-amino and o-hydroxy diaryl ketones under redox-neutral conditions. Furthermore, it also brings one concise route to the total synthesis of quinolone alkaloid, (±)-yaequinolone A2, and a viridicatin derivative in satisfying yields.

Ferrocene-Appended Iridium(III) Complexes: Configuration Regulation, Anticancer Application, and Mechanism Research.

A series of ferrocene-appended half-sandwiched iridium(III) phenylpyridine complexes have been designed and synthesized. These complexes show better anticancer activity than cisplatin widely used in clinic under the same conditions. Meanwhile, complexes could effectively inhibit cell migration and colony formation. Complexes could interact with protein and transport through serum protein, effectively catalyzing the oxidation of nicotinamide-adenine dinucleotid and inducing the accumulation of reactive oxygen species (ROS, 1O2), which confirmed the anticancer mechanism of oxidation. Furthermore, laser scanning confocal detection indicates that these complexes can enter cells followed by a non-energy-dependent cellular uptake mechanism, effectively accumulating in the lysosome (Pearson's colocalization coefficient: ∼0.90), leading to lysosome damage, and reducing the mitochondrial membrane potential (MMP). Taken together, ferrocene-appended iridium(III) complexes possess the prospect of becoming a new multifunctional therapeutic platform, including lysosome-targeted imaging and anticancer drugs.

Deoxygenative Deuteration of Carboxylic Acids with D2 O.

We report a general, practical, and scalable means of preparing deuterated aldehydes from aromatic and aliphatic carboxylic acids with D2 O as an inexpensive deuterium source. The use of Ph3 P as an O-atom transfer reagent can facilitate the deoxygenation of aromatic acids, while Ph2 POEt is a better O-atom transfer reagent for aliphatic acids. The highly precise deoxygenation of complex carboxylic acids makes this protocol promising for late-stage deoxygenative deuteration of natural product derivatives and pharmaceutical compounds.

Synergistic Photoredox Catalysis and Organocatalysis for Inverse Hydroboration of Imines.

The first catalytic inverse hydroboration of imines with N-heterocyclic carbene (NHC) boranes has been realized by means of cooperative organocatalysis and photocatalysis. This catalytic combination provides a promising platform for promoting NHC-boryl radical chemistry under sustainable and radical-initiator-free conditions. The highly important functional-group compatibility and possible application in late-stage hydroborations represent an important step forward to an enhanced α-amino organoboron library.

Selective Hydroarylation of 1,3-Diynes Using a Dimeric Manganese Catalyst: Modular Synthesis of Z-Enynes.

The transition-metal-catalyzed selective hydroarylation of unsymmetrical alkynes represents the state-of-art in organic chemistry, and still mainly relies on the use of precious late-transition-metal catalysts. Reported herein is an unprecedented MnI -catalyzed hydroarylation of unsymmetrical 1,3-diyne alcohols with commercially available arylboronic acids with predictive selectivity. This method addresses the challenges in regio-, stereo-, and chemoselectivity. It offers a general, convenient and practical strategy for the modular synthesis of multisubstituted Z-configurated conjugated enynes. This protocol is distinguished by its operational simplicity, complete selectivity, excellent functional-group compatibility, and gram-scale potential. A dimeric MnI species, Mn2 (CO)8 Br2 , was proven to be a much more efficient catalyst precursor than Mn(CO)5 Br.

Synergistic Catalysis for the Umpolung Trifluoromethylthiolation of Tertiary Ethers.

The first transition-metal-free, site-specific umpolung trifluoromethylthiolation of tertiary alkyl ethers has been developed, achieving the challenging tertiary C(sp3 )-SCF3 coupling under redox-neutral conditions. The synergism of organophotocatalyst 4CzIPN and BINOL-based phosphorothiols can site-selectively cleave tertiary sp3 C(sp3 )-O ether bonds in complex molecules initiated by a polarity-matching hydrogen-atom-transfer (HAT) event. The incorporation of several competing benzylic and methine C(sp3 )-H bonds in alkyl ethers has little influence on the regioselectivity. Selective difluoromethylthiolation of C-O bonds has also been achieved. This represents not only an important step forward in trifluoromethylthiolation but also a promising means for site-selective C-O bond functionalization of unsymmetrical tertiary alkyl ethers.

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.

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.

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.