Indoline Derivatives Research Articles

Design, synthesis and biological evaluation of indoline derivatives as multifunctional agents for the treatment of ischemic stroke

In this work, a series of indoline derivatives as multifunctional neuroprotective agents for battling ischemic stroke were designed, synthesized, and biologically evaluated. In antioxidant assay, all compounds showed significant protective effects against H2O2-induced death of RAW 264.7 cells. In oxygen glucose deprivation/reperfusion (OGD/R)-induced neuronal damage, some compounds significantly elevated the cell survival rate. Among them, 7i, 7j and 7r exerted comparable neuroprotective effects to ifenprodil, and exhibited binding affinity to N-methyl-D-aspartic acid receptors 2B (NMDA-GluN2B). At the concentrations of 0.1, 1 and 10 μM, 7i, 7j and 7r dose-dependently lowered the LPS-induced secretion of inflammatory cytokines, including TNF-α, IL-6 and NO, by BV-2 cells. Importantly, 7i and 7j can dramatically reduce the cerebral infarction rate and improve neurological deficit scores in middle cerebral artery occlusion (MCAO) rat model. As demonstrated by the above results, 7i and 7j are potential neuroprotective agents for the treatment of ischemic stroke. Graphical abstract

Samarium(II)‐Promoted Cyclizations of Nonactivated Indolyl Sulfinyl Imines to Polycyclic Tertiary Carbinamines

AbstractSamarium(II)‐promoted cyclizations of N‐acylated indolyl sulfinyl imines without electron‐withdrawing groups at C‐3 furnished tertiary carbinamines in good yield. Screening of the reaction conditions revealed that application of an excess of samarium diiodide in the presence of water and lithium bromide provided the cleanest reactions and the highest yields. The most striking observation during this investigation was the reductive detachment of the sulfur functional group, which most likely precedes the cyclization step. As consequence no enantioselectivity could be observed if enantiopure sulfinyl imines were employed. The mechanisms of the N−S cleavage and of the cyclization of the intermediate imines as well as the role of the additives are discussed. The presented method generates interesting polycyclic indoline derivatives; a cascade reaction involving an ethoxycarbonyl‐substituted side‐chain provided unique tetracyclic spiro‐γ‐lactams.

Divergent Synthesis of Indolenine and Indoline Ring Systems by Palladium‐Catalyzed Asymmetric Dearomatization of Indoles**

AbstractDearomatized indole derivatives bearing a C3‐ or C2‐stereocenter exist ubiquitously in natural products and biologically active molecules. Despite remarkable advances in their synthesis, stereoselective and regio‐divergent methods are still in a high demand. Herein, a Pd‐catalyzed intermolecular asymmetric spiroannulation of 2,3‐disubstituted indoles with internal alkynes has been developed for the efficient construction of indoline structures with a C2‐quaternary stereocenter. Stereospecific aza‐semipinacol rearrangement of these indoline derivatives under acidic conditions afforded indolenine products bearing a C3‐quaternary stereocenter, where the migrating group could be controlled by the reaction sequence. The asymmetric spiroannulation together with the subsequent aza‐semipinacol rearrangement enabled a divergent access to dearomatized indole derivatives with either a C3‐ or a C2‐quaternary stereocenter.

Divergent Synthesis of Indolenine and Indoline Ring Systems by Palladium‐Catalyzed Asymmetric Dearomatization of Indoles**

Dearomatized indole derivatives bearing a C3- or C2-stereocenter exist ubiquitously in natural products and biologically active molecules. Despite remarkable advances in their synthesis, stereoselective and regio-divergent methods are still in a high demand. Herein, a Pd-catalyzed intermolecular asymmetric spiroannulation of 2,3-disubstituted indoles with internal alkynes has been developed for the efficient construction of indoline structures with a C2-quaternary stereocenter. Stereospecific aza-semipinacol rearrangement of these indoline derivatives under acidic conditions afforded indolenine products bearing a C3-quaternary stereocenter, where the migrating group could be controlled by the reaction sequence. The asymmetric spiroannulation together with the subsequent aza-semipinacol rearrangement enabled a divergent access to dearomatized indole derivatives with either a C3- or a C2-quaternary stereocenter.

Palladium-Catalyzed Thiocarbonylations with Triisopropylsilyl Thioethers

AbstractWe have developed a palladium-catalyzed thiocarbonylation through the reaction of a σ-alkyl palladium intermediate with carbon monoxide and a triisopropylsilyl (TIPS) thioether. The use of CsF, (IPr)Pd(allyl)Cl [IPr =1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene], CO, and a TIPS thioether in THF are key to obtaining alkyl and aryl thioesters in high yields. The yield of the palladium-catalyzed thiocarbonylation depended on the structure of the substrate; indoline-2-one derivatives were formed faster than indoline derivatives. The reactions of benzoyl and hydrocinnamoyl fluorides with TIPSSPh and CsF also gave the corresponding thioesters.

Visible-Light-Driven Palladium-Catalyzed Radical Tandem Dearomatization of Indoles with Unactivated Alkenes.

A mild visible-light-driven palladium-catalyzed radical tandem dearomatization of indoles with unactivated alkenes is described with moderate to good yields and good to excellent diastereoselectivities. Under visible-light irradiation, the photoexcited state of the palladium complex was formed, which could transfer a single electron to N-(2-bromobenzoyl)indoles, leading to a hybrid palladium radical chemistry. This provides efficient and atom-economical access to diverse 2,3-disubstituted indoline derivatives.

Palladium‐Catalyzed Stereoselective Intramolecular Heck Dearomative Silylation of Indoles

AbstractA palladium‐catalyzed stereoselective intramolecular Heck dearomative of indoles with silyl termination has been developed. A type of tetracyclic indoline derivatives containing silicon were prepared, involving N‐(2‐bromobenzoyl)indoles and silylboronates. This protocol not only led to a broad substrate scope in acceptable yields but also could be scaled up to gram quantities as well as further synthetic transformation.magnified image

Hydrogen bond serving as a protecting group to enable the photocatalytic [2+2] cycloaddition of redox-active aliphatic-amine-containing indole derivatives.

Redox-sensitive functionalities such as aliphatic amines with low oxidation potentials and easily oxidized by photocatalysts are generally not compatible with photocatalytic reactions. We describe a hydrogen-bond-assisted visible-light-mediated [2+2] cycloaddition of redox-sensitive aliphatic-amine-containing indole derivatives providing a range of cyclobutane-fused polycyclic indoline derivatives, especially bridged-cyclic indolines. Mechanistic studies indicated that the success of the reaction was based on on the formation of H-bonds between the N-atom and alcohol proton of TFE or HFIP, with this formation preventing or blocking the single-electron transfer from the aliphatic amine functionality to the excited photocatalyst.

Regiodivergent cascade cyclization/alkoxylation of allenamides via N-protecting group driven rearrangement to access indole and indoline derivatives.

A mild, palladium-catalyzed domino Heck-cyclization/alkoxylation sequence of aryl halide tethered allenamides is described, providing regiodivergent indole and indoline derivatives controlled by the N-protecting group. This room temperature reaction provided a functionalizable olefinic moiety with broad substrate scope. Preliminary mechanistic studies support the rearrangement of an indoline-derived intermediate to indoles with the N-acetyl allenamides forming free (NH) indoles.

Highly diastereoselective cascade dearomatization of 3-(2-isocyanoethyl)indoles with nitrile imines: a facile access to unexpected polycyclic indolines

A novel cascade annulation between 2-isocyanoethylindoles and hydrazonyl chlorides has been realized to assemble a variety of unexpected polycyclic indoline derivatives with excellent diastereoselectivities under simple reaction conditions.

Catalytic Atroposelective C7 Functionalisation of Indolines and Indoles.

Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry. In particular, axially chiral indole‐ and indoline‐based frameworks have been recognised as important heterobiaryl classes because they are the core units of bioactive natural alkaloids, chiral ligands and bioactive compounds. Among them, the synthesis of C7‐substituted indole biaryls and the analogous indoline derivatives is particularly challenging, and methods for their efficient synthesis are in high demand. Transition‐metal catalysis is considered one of the most efficient methods to construct atropisomers. Here, we report the enantioselective synthesis of C7‐indolino‐ and C7‐indolo biaryl atropisomers by means of C−H functionalisation catalysed by chiral RhJasCp complexes.

Synthesis and Evaluation of Enantiopure HMPA Analogs in Samarium‐Diiodide‐Promoted Dearomatizations of N‐Acylated Indole Derivatives

AbstractA series of (S)‐proline‐based enantiopure phosphorus triamide derivatives were prepared and evaluated as HMPA alternative in samarium diiodide cyclization reactions of N‐acylated indole derivatives. The expected tricyclic indoline derivatives were generally obtained in good to excellent yields, however, the induced enantioselectivities were at best moderate. In our model reaction, the phosphorus triamide derivative with a (dimethyl)hydroxymethyl group at the stereogenic center provided the cyclization product in almost quantitative yield and with an enantiomeric excess of approximately 24 %. No separate proton source is required by applying this chiral Lewis base which was recovered in 93 % yield. Bulkier substituents at the stereogenic center did not furnish improved results. Although in our preliminary study only low to moderate enantioselectivities could be achieved, the observed fast conversions and the high yields demonstrate the basic suitability of chiral pyrrolidine‐based phosphoramide Lewis bases in samarium(II)‐induced reactions.

Palladium-Catalyzed Asymmetric Intramolecular Dearomative Heck Annulation of Aryl Halides to Furnish Indolines.

An unprecedented Pd-catalyzed asymmetric intramolecular cascade cyclization of aryl halides with readily available arylboronic acids proceeds through a Heck-type dearomative cyclization terminated with arylation in the presence of Pd2(dba)3 (10 mol %), Cu2O (5 mol %), and Cs2CO3 (2.0 equiv) in 1,2-dichloroethane (1.0 mL) at 100 °C for 15 h in air using BINOL-based phosphoramidite as the chiral ligand. This dearomative Heck protocol, which tolerates a broad variety of functional groups, is amenable to the generation of optically active indoline derivatives bearing all-carbon quaternary stereogenic centers in one step in moderate to excellent yields, with excellent diastereoselectivities (>20:1) and enantioselectivities (up to >99% ee). It is worth mentioning that no decrease in the enantiopurity of the indoline derivatives was observed during the synthetic transformations of the products.

Rh(III)-Catalyzed [3 + 2] Annulation of Aniline Derivatives with Vinylsilanes via C–H Activation/Alkene Cyclization: Access to Highly Regioselective Indoline Derivatives

Rh(III)-Catalyzed [3 + 2] Annulation of Aniline Derivatives with Vinylsilanes <i>via</i> C–H Activation/Alkene Cyclization: Access to Highly Regioselective Indoline Derivatives

Molecular interaction of HIC, an agonist of P2Y1 receptor, and its role in prostate cancer apoptosis

Prostate cancer is a heterogeneous, slow growing asymptomatic cancer that predominantly affects man. A purinergic G-protein coupled receptor, P2Y1R, is targeted for its therapeutic value since it plays a crucial role in many key molecular events of cancer progression and invasion. Our previous study demonstrated that indoline derivative, 1 ((1-(2-Hydroxy-5-nitrophenyl) (4-hydroxyphenyl) methyl)indoline-4‑carbonitrile; HIC), stimulates prostate cancer cell (PCa) growth inhibition via P2Y1R. However, the mode of interaction of P2Y1R with HIC involved in this process remains unclear. Here, we have reported the molecular interactions of HIC with P2Y1R. Molecular dynamics simulation was performed that revealed the stable specific binding of the protein-ligand complex. In vitro analysis has shown increased apoptosis of PCa-cells, PC3, and DU145, upon specific interaction of P2Y1R-HIC. This was further validated using siRNA analysis that showed a higher percentage of apoptotic cells in PCa-cells transfected with P2Y-siRNA-MRS2365 than P2Y-siRNA-HIC treatment. Decreased mitochondrial membrane potential (MMP) activity and reduced glutathione (GSH) level show their role in P2Y1R-HIC mediated apoptosis. These in silico and in vitro results confirmed that HIC could induce mitochondrial apoptotic signaling through the P2Y1R activation. Thus, HIC being a potential ligand upon interaction with P2Y1R might have therapeutic value for the treatment of prostate cancer.

Synthesis and Preclinical Validation of Novel Indole Derivatives as a GPR17 Agonist for Glioblastoma Treatment.

The discovery of a potential ligand-targeting G protein-coupled receptor 17 (GPR17) is important for developing chemotherapeutic agents against glioblastoma multiforme (GBM). We used the integration of ligand- and structure-based cheminformatics and experimental approaches for identifying the potential GPR17 ligand for GBM treatment. Here, we identified a novel indoline-derived phenolic Mannich base as an activator of GPR17 using molecular docking of over 6000 indoline derivatives. One of the top 10 hit molecules, CHBC, with a glide score of −8.390 was synthesized through a multicomponent Petasis borono–Mannich reaction. The CHBC–GPR17 interaction leads to a rapid decrease of cAMP and Ca2+. CHBC exhibits the cytotoxicity effect on GBM cells in a dose-dependent manner with an IC50 of 85 μM, whereas the known agonist MDL29,951 showed a negligible effect. Our findings suggest that the phenolic Mannich base could be a better GPR17 agonist than MDL29,951, and further uncovering their pharmacological properties could potentiate an inventive GBM treatment.

WITHDRAWN: Discovery of indoline derivatives as anticancer agents via inhibition of tubulin polymerization

Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d, which exhibited potent antiproliferative activity with IC50 values of 1.84μM (MGC-803 cells), 6.82μM (A549 cells), 1.61μM (Kyse30 cells), 1.49μM (Kyse450 cells), 2.08μM (Kyse510 cells) and 2.24μM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC50 value of 3.4µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of β-tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in time and dose-dependent manners. All the results suggest that the indoline derivatives might be a class of novel tubulin inhibitors with potential anticancer activity and is worthy of further study.

Synthesis of Tetracyclic Indolines through Palladium‐Catalyzed Asymmetric Dearomative reaction of Aryl Iodides

AbstractA palladium‐catalyzed asymmetric intramolecular Heck reaction of aryl iodides with alkynyl carboxylic acids has been developed, delivering various indoline frameworks in moderate to excellent yields (up to 95 %) with excellent enantioselectivities (up to 96 % ee) and diastereoselectivities (&gt;20 : 1) using BINOL‐based phosphoramidite as chiral ligand. This cascade annulation protocol, which tolerates a broad variety of functional groups and is conducted under an argon atmosphere, provides efficient and atom‐economical access to structurally diverse 2,3‐disubstituted indolines bearing vicinal tertiary and quaternary stereocenters. Additionally, the synthetic products could be converted to useful unique indoline derivatives without loss of enantiomeric excess.

Discovery of indoline derivatives as anticancer agents via inhibition of tubulin polymerization

Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d, which exhibited potent antiproliferative activity with IC50 values of 1.84 μM (MGC-803 cells), 6.82 μM (A549 cells), 1.61 μM (Kyse30 cells), 1.49 μM (Kyse450 cells), 2.08 μM (Kyse510 cells) and 2.24 μM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC50 value of 3.4 µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in a time and dose-dependent manner. All the results suggest that the indoline derivatives may be a class of novel tubulin inhibitors with potential anticancer activity, and which is worthy of further study.

Asymmetric Counteranion Directed Catalytic Heck/Tsuji-Trost Annulation of Aryl Iodides and 1,3-Dienes.

A chiral anion-mediated asymmetric Heck/Tsuji-Trost reaction of aryl iodides and 1,3-dienes is presented. Chiral indoline derivatives could be afforded with remarkably higher yields and enantioselectivities than our previous chiral ligand-based method. Silver carbonate is employed as both base and halide scavenger to ensure fast and recyclable exchange of the catalytic amount of chiral anions. Fast salt metathesis, as well as the acceleration effect of the chiral anion, could both benefit the stereocontrol of the reaction.