Synthesis of Polycyclic 3,3'-Biindoles via AgOTf-Catalyzed Nucleophilic Addition and Cycloisomerization.

A method for the rapid synthesis of polycyclic 3,3'-biindole derivatives has been developed through AgOTf-catalyzed nucleophilic addition and cycloisomerization processes. The cascade reaction employs readily accessible indoles and their N-2-formylphenyl derivatives and provides functionalized polycyclic 3,3'-biindoles in moderate to good yields under mild conditions. This reaction is highly efficient and takes only several minutes (∼5 min). Notably, the method is also highlighted by a Selectfluor-mediated oxidation reaction that quickly generates the oxindole derivatives.

Electrochemical Cyclization of Alkynyl Enaminones: Controllable Synthesis of Indeno[1,2-c]pyrroles or Indanones.

We report an electrochemical intramolecular [3 + 2] cyclization of alkynyl enaminones in a user-friendly undivided cell under constant current conditions without an oxidant and catalyst, and indeno[1,2-c]pyrrole derivatives could be obtained in good to excellent yields. Notably, preliminary substituent-controlled selective transformation is also achieved under electrocatalysis alone, and indeno[1,2-c]pyrrole (R4 ≠ H) or indanone derivatives (R4 = H) could be prepared directly under electrocatalysis without adding a base and heating process.

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.

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.

TBAF-Catalyzed O-Nucleophilic Cyclization of Enaminones: A Process for the Synthesis of Dihydroisobenzofuran Derivatives.

A novel methodology for the stereoselective synthesis of dihydroisobenzofuran derivatives is described in this paper. The procedure was realized by the bifunctional TBAF catalyzed selective O-nucleophilic cyclization of enaminone with intramolecular alkyne under mild and non-metal-mediated conditions. The results of control experiments suggested that the cation-π interaction and basicity, offered by TBAF, might be indispensable for the isomerization of enaminone and the formation of carbon-oxygen bond.

Ferrocenyl-Triphenyltin Complexes as Lysosome-Targeted Imaging and Anticancer Agents.

In this paper, two ferrocenyl-triphenyltin complexes were synthesized and characterized. Complex 2 is constructed as new multifunctional therapeutic platform for lysosome-targeted imaging and displayed much higher cytotoxicity than its analogue 1 by the introduction of a methyl group instead of a hydrogen atom in acylhydrazone. The cyclic voltammograms and reaction with GSH (glutathione) further confirmed that complex 1 has a reversible redox peak and can react with GSH, which indicate that complex 1 might lose its anticancer effect by undergoing reaction with GSH once it enters the cancer cell. Complex 2 could effectively catalyze the oxidation of NADH (the reduced form of nicotinamide adenine dinucleotide) to NAD+ and induce the production of reactive oxygen species (ROS), lead to caspase-dependent apoptosis through damaged mitochondria, simultaneously, accounting for the mitochondrial vacuolization and karyorrhexis. The caspase-3 activation and cytoplasmic vacuolation karyorrhexis induced by complex 2 revealed that the A549 cell lines might undergo cell death primarily mediated by apoptosis and oncosis; however, 1 cannot reproduce this effect. Taken together, these results indicated that complex 2 has more potential for evolution as a new bioimaging and anticancer agent.

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.

AgNTf2-catalyzed formal [3 + 2] cycloaddition of ynamides with unprotected isoxazol-5-amines: efficient access to functionalized 5-amino-1H-pyrrole-3-carboxamide derivatives.

A formal [3 + 2] cycloaddition between ynamides and unprotected isoxazol-5-amines has been developed in the presence of catalytic AgNTf2 in an open flask. By the protocol, a variety of functionalized 5-amino-1H-pyrrole-3-carboxamide derivatives can be obtained in up to 99% yield. The reaction mechanism might involve the generation of an unusual α-imino silver carbene intermediate (or a silver-stabilized carbocation) and subsequent cyclization/isomerization to build the significant pyrrole-3-carboxamide motif. The reaction features the use of an inexpensive catalyst, simple reaction conditions, simple work-up without column chromatographic purification for most of products and high yields.

Gold-Catalyzed Reaction of ortho-Alkynylarylaldehydes with Conjugated Dienes: An Efficient Access to Highly Strained Tetracyclic Bridgehead Olefins.

An unprecedented access to strained tetracyclic bridgehead alkenes by reaction of easily accessible ortho-alkynylarylaldehydes with conjugated dienes is described. The process involves a chemo- and stereo-selective, gold-catalyzed, tandem intermolecular [3+2] cycloaddition/Prins-type ring-closing reaction that allows generating structural complexity in a straightforward manner. This approach for the preparation of anti-Bredt compounds is synthetically superior to those previously reported: the procedure is easy to implement, operates under mild experimental conditions, is efficient, and exhibits a good substrate scope.

Metal-Free Reaction of ortho-Carbonylated Alkynyl-Substituted Arylaldehydes with Common Amines: Selective Access to Functionalized Isoindolinone and Indenamine Derivatives.

Herein we describe a reaction of ortho-carbonylated alkynyl-substituted arylaldehydes with common primary amines that can provide functionalized isoindolinone and 3-hydroxylindenamine products in high yields. Depending on the substituent size of primary amines, two distinct reaction pathways were exploited selectively, that are, an initial aza-conjugate addition followed by hydrogen transfer to access isoindolinone framework and a unique oxa-conjugate addition followed by Petasis-Ferrier rearrangement to afford indenamine derivatives. In the presence of Et3 N, the reaction property of small primary amines was changed, proceeding to afford 3-hydroxylindenamine derivatives efficiently. These products contain interesting substructures that exist in many natural products and bioactive molecules. The reaction features contain the use of transition-metal-free catalysts, simple operation, broad substrate scope, and product diversity.

Silver-Catalyzed Domino Reaction of ortho-Carbonylated Alkynyl-Substituted Arylaldehydes with Conjugated Dienes: Stereoselective Access to Indanone-Fused Cyclohexenes.

A silver-catalyzed domino reaction of ortho-carbonylated alkynyl-substituted arylaldehydes with conjugated dienes is described here. Through this reaction, the synthesis of a variety of indanone-fused cyclohexene derivatives can be achieved efficiently. The formation of these tricyclic products could involve a key Diels-Alder reaction of in situ generated indanenone dienophiles with conjugated dienes. Particularly, the products can be accomplished in a high endo/exo selective way.

Catalyst-Free Regioselective C-3 Thiocyanation of Imidazopyridines.

A direct and straightforward approach for highly regioselective thiocyanation of imidazoheterocycles through sp(2) C-H functionalization has been realized at room temperature. Various C-3 thiocyanated imidazopyridines are formed in moderate to good yield. The present method exhibits a mild and selective access to a variety of imidazopyridine derivatives of pharmacological interest.

Silver-catalyzed double-decarboxylative cross-coupling of α-keto acids with cinnamic acids in water: a strategy for the preparation of chalcones.

A silver-catalyzed double-decarboxylative protocol has been proposed for the construction of chalcone derivatives via cascade coupling of substituted α-keto acids with cinnamic acids under the mild aqueous conditions. The developed method for constructing C-C bonds via double-decarboxylative reactions is efficient, practical, and environmentally benign by using the readily available starting materials. It should provide a promising synthesis candidate for the formation of diverse and useful chalcone derivatives in the fields of synthetic and pharmaceutical chemistry.

Catalyst-free direct decarboxylative coupling of α-keto acids with thiols: a facile access to thioesters.

A novel, efficient, and catalyst-free strategy has been initially developed for the construction of thioesters via the direct radical oxidative decarboxylation of α-keto acids with thiols, and the corresponding target products were obtained in moderate to good yields. It offers an alternative approach for the synthesis of useful diverse thioesters.

Csp3-H Imination Using Arylazo Sulfone as a N Source: An Approach to Access Imines.

An unprecedented Csp3-H imination reaction using arylazo sulfones as the readily accessible and stable N source is reported. The synthetic virtues are demonstrated through mild conditions, simple operation, good air compatibility, and functional group tolerance, as well as suitability for gram-scale reaction. The resulting imines can be further converted to α-amino acids. The presented results shed light on an unusual usage of arylazo sulfones and will inspire novel experimental design by using arylazo sulfones as the N source.

Catalyst-Free gem-Difluorination/Spirocyclization of Indole-2-carboxamides: Synthesis of C2-Spiroindoline Derivatives.

A catalyst-free gem-difluorination/spirocyclization reaction has been successfully developed for the synthesis of gem-difluorinated C2-spiroindoline derivatives from indole-2-carboxamides. The resulting gem-difluorinated C2-spiroindolines can be easily converted into 2-spiropseudoindoxyls through hydrolysis. This method offers the benefits of simple operation, convenient access to raw materials, and mild conditions. Dual function of Selectfluor in this reaction is noteworthy as it can serve as both a fluorinating agent and an alkaline accelerator precursor.

PhB(OH)2-Promoted Electrochemical Sulfuration-Formyloxylation of Styrenes and Selectfluor-Mediated Oxidation-Olefination.

We report a PhB(OH)2-promoted electrochemical sulfuration-formyloxylation reaction of styrenes employing commercially available thiophenols/thiols as thiolating agents. Specifically, metal catalysts and external chemical oxidants are not needed in the reaction for the formation of ß-formyloxy sulfides, and these sulfides can be further converted to (E)-vinyl sulfones via the Selectfluor-mediated oxidation-olefination. Notably, on the basis of this electrochemical oxidation strategy, ß-hydroxy sulfide, ß-formyloxy sulfoxide, ß-formyloxy sulfone, and (E)-vinyl sulfoxide can also be easily prepared.

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.

Fluorescent iridium(iii) coumarin-salicylaldehyde Schiff base compounds as lysosome-targeted antitumor agents.

Six fluorescent half-sandwich iridium(iii) coumarin-salicylaldehyde Schiff base (O^N) compounds ([(η5-Cp*)Ir(O^N)Cl]) were prepared and characterized. The introduction of a coumarin unit increased the antitumor activity (IC50: 9.9 ± 0.1 µM-40.7 ± 12.9 µM) of these compounds, the best of which was nearly two times that of clinical cisplatin. The results of laser confocal microscopy demonstrated that these compounds possessed an energy-dependent cellular uptake mechanism, accumulated in the lysosomes (Pearson co-localization coefficient: ∼0.7), damaged the integrity of the lysosomes, and induced apoptosis. The compounds could also decrease the mitochondrial membrane potential, catalyze the oxidation of the coenzyme (nicotinamide-adenine dinucleotide) and improve the levels of the intracellular reactive oxygen species, following an antitumor mechanism of oxidation. Additionally, these compounds could block the metastasis of tumor cells. Above all, these iridium(iii) compounds show potential as antitumor agents with dual functions: lysosomal damage and anti-metastasis.

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.