Access to chiral dihydrophenanthridines via a palladium(0)-catalyzed Suzuki coupling and C-H arylation cascade reaction using new chiral-bridged biphenyl bifunctional ligands.

A class of chiral-bridged biphenyl phosphine-carboxylate bifunctional ligands CB-Phos has been developed and successfully applied to Pd(0)-catalyzed single enantioselective C-H arylation and a one pot cascade reaction involving Suzuki cross-coupling and C-H arylation. The catalytic system provides a new and convenient way for the synthesis of versatile chiral dihydrophenanthridines with rich structures and broad functional group tolerance. Good to excellent yields with high enantioselectivities were generally achieved. The reaction mechanism of the cascade reaction was also preliminarily discussed.

Fluoxetine mitigates depressive-like behaviors in mice via anti-inflammation and enhancing neuroplasticity.

Neuroplasticity and inflammation represent a common final pathway for effective antidepressant treatment. SSRIs are the most commonly prescribed medications for depression and have demonstrated efficacy in reducing depressive symptoms. However, the precise impact of SSRIs on neuroplasticity and inflammation remains unclear. In this study, we aimed to investigate the influence of long-term treatment with SSRIs on hippocampal neuron, inflammation, synaptic function and morphology. Our findings revealed that fluoxetine treatment significantly alleviated behavioral despair, anhedonia, and anxiety in reserpine-treated mice. Moreover, fluoxetine mitigated hippocampal neuron impairment, inhibited inflammatory release, and increased the expression of synaptic proteins markers (SYP and PSD95) in mice. Notably, fluoxetine also suppressed reserpine-induced synapse loss in the hippocampus. Based on these results, fluoxetine has been demonstrated effectively to ameliorate depressive mood and cognitive dysfunction, possibly through the enhancement of synaptic plasticity. Overall, our study contributes to a further understanding of the mechanisms underlying the therapeutic effects of fluoxetine and its potential role in improving depressive symptoms and cognitive impairments.

Solvent-Free Buchwald-Hartwig Amination of Heteroaryl Chlorides by N-Heterocyclic Carbene-Palladium Complex (SIPr)Ph2Pd(cin)Cl at Room Temperature.

Using the robust N-heterocyclic carbene-palladium complex (SIPr)Ph2Pd(cin)Cl, a highly efficient and easy-to-operate method has been developed at room temperature for the solvent-free Buchwald-Hartwig amination of heteroaryl chlorides with various amines. The amount of catalyst can be as low as 0.05 wt %. The system was demonstrated on 47 substrates and successfully applied to the synthesis of commercial pharmaceuticals and candidate drugs with high yields. Furthermore, the protocol can be used to prepare aniline derivatives on a multigram scale without yield loss.

Iridium-Catalyzed Intramolecular Asymmetric Allylic Etherification of Pyrimidinemethanols: Enantioselective Construction of Multifunctionalized Pyrimidine-Fused Oxazepines.

An iridium-catalyzed intramolecular asymmetric allylic etherification of pyrimidinemethanols is described. In the presence of chiral-bridged biphenyl phosphoramidite ligand L3 and triethylborane, this process provided a class of novel pyrimidine-fused oxazepanes in up to 99% yield with 99.5% enantiomeric excess. The work addresses the challenge of insufficient nucleophilicity of aliphatic alcohols for allyl substitution and indicates the vital value of chiral-bridged biphenyl phosphoramidites. Various multifunctionalized transformations of the products further demonstrate the robust synthetic utility of this methodology.

Design, synthesis and pharmacological evaluation of ß-carboline derivatives as potential antitumor agent via targeting autophagy.

A series of novel ß-carboline derivatives was designed, synthesized and evaluated as potential anticancer agents. Among them, compound 6g showed the most potent antiproliferative activity against the 786-0, HT-29 and 22RV1 cell lines with IC50 values of 2.71, 2.02, and 3.86 µM, respectively. The antitumor efficiency of compound 6gin vivo was also evaluated, and the results revealed that compound 6g significantly suppressed tumor development and reduced tumor weight in a mouse colorectal cancer homograft model. Further investigation on mechanisms of action demonstrated that compound 6g inhibited HCT116 cell growth by stimulating the ATG5/ATG7-dependent autophagic pathway. These molecules might be served as candidates for further development of colorectal cancer therapy agent.

Synthesis of novel 4,7-disubstituted quinoline derivatives as autophagy inducing agents via targeting stabilization of ATG5.

A series of new 4,7-disubstituted quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 10c, 10g, 10i, 10j and 10k displayed potent antiproliferative activity with IC50 value of lower than 5.0 µM against human tumor cell lines, and N-(3-nitrophenyl)-7-((3,4,5-trimethoxybenzyl)oxy)quinoline - 4-amine 10k was found to be the most potent antiproliferative agent against HCT-116, HepG2, BCG-823, A549 and A2780 cell lines with IC50 values of 0.35, 1.98, 0.60, 0.39 and 0.67 µM, respectively. The antitumor efficacy of the representative compound 10k in mice was also evaluated, and the results showed that compound 10k effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 10k could inhibit colorectal cancer growth through inducing autophagy via excessively targeting stabilization of ATG5. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.

Copper-Catalyzed Enantioselective C-H Arylation between 2-Arylindoles and Hypervalent Iodine Reagents.

The copper-catalyzed enantioselective C-H arylation between 2-arylindoles and hypervalent iodine reagents has been successfully developed, which provides a convenient and economical route to the highly atroposelective synthesis of axially chiral indole derivatives with a 2-aryl structure (up to 99% ee). Density functional theory calculations and wave function analysis show that the key "sandwich" intermediate leads to high enantioselectivity of the reaction.

Copper-catalyzed (4+1) and (3+2) cyclizations of iodonium ylides with alkynes.

The copper(ii)-catalyzed (4+1) cyclizations and copper(i)-catalyzed (3+2) cycloadditions of iodonium ylides and alkynes were successfully developed by employing efficient and safe iodonium ylides instead of traditional diazo compounds. Highly functionalized dimethyl (E)-3-benzylideneindoline-2,2-dicarboxylates and methyl 5-(2-hydroxyphenyl)-2-methoxy-4-phenylfuran-3-carboxylates were conveniently prepared in moderate to excellent yields. The possible reaction mechanisms were also discussed.

Crystal Facet Induced Single-Atom Pd/Cox Oy on a Tunable Metal-Support Interface for Low Temperature Catalytic Oxidation.

Atomic dispersed metal sites in single-atom catalysts are highly mobile and easily sintered to form large particles, which deteriorates the catalytic performance severely. Moreover, lack of criterion concerning the role of the metal-support interface prevents more efficient and wide application. Here, a general strategy is reported to synthesize stable single atom catalysts by crafting on a variety of cobalt-based nanoarrays with precisely controlled architectures and compositions. The highly uniform, well-aligned, and densely packed nanoarrays provide abundant oxygen vacancies (17.48%) for trapping Pd single atoms and lead to the creation of 3D configured catalysts, which exhibit very competitive activity toward low temperature CO oxidation (100% conversion at 90 °C) and prominent long-term stability (continuous conversion at 60 °C for 118 h). Theoretical calculations show that O vacancies at high-index {112} facet of Cox Oy nanocrystallite are preferential sites for trapping single atoms, which guarantee strong interface adhesion of Pd species to cobalt-based support and play a pivotal role in preventing the decrement of activity, even under moisture-rich conditions (≈2% water vapor). The progress presents a promising opportunity for tailoring catalytic properties consistent with the specific demand on target process, beyond a facile design with a tunable metal-support interface.

Pd-catalyzed asymmetric Suzuki-Miyaura coupling reactions for the synthesis of chiral biaryl compounds with a large steric substituent at the 2-position.

Pd-catalyzed asymmetric Suzuki-Miyaura couplings of 3-methyl-2-bromophenylamides, 3-methyl-2-bromo-1-nitrobenzene and 1-naphthaleneboronic acids have been successfully developed and the corresponding axially chiral biaryl compounds were obtained in very high yields (up to 99%) with good enantioselectivities (up to 88% ee) under mild conditions. The chiral-bridged biphenyl monophosphine ligands developed by our group exhibit significant superiority to the naphthyl counterpart MOP in both reactivity and enantioselectivity control. The large steric hindrance from π-conjugated ortho-substituents of the bromobenzene substrates and the Pd···O interaction between carbonyl and palladium seem essential to achieve high enantioselectivity.

Design, synthesis and biological evaluation of new quinoline derivatives as potential antitumor agents.

A series of new quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 11p, 11s, 11v, 11x and 11y exhibited potent antiproliferative activity with IC50 value of lower than 10 µM against seven human tumor cell lines, and N-(3-methoxyphenyl)-7- (3-phenylpropoxy)quinolin-4-amine 11x was found to be the most potent antiproliferative agent against HCT-116, RKO, A2780 and Hela cell lines with an IC50 value of 2.56, 3.67, 3.46 and 2.71 µM, respectively. The antitumor efficacy of the representative compound 11x in mice was also evaluated, and the results showed that compound 11x effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 11x could inhibit colorectal cancer growth through ATG5-depenent autophagy pathway. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.

Enantioselective synthesis of chiral heterocyclic biaryls via asymmetric Suzuki-Miyaura cross-coupling of 3-bromopyridine derivatives.

A series of chiral heterocyclic biaryls with a pyridyl moiety were prepared in moderate to good yields with up to 92% ee via asymmetric Suzuki-Miyaura coupling. The chiral-bridged biphenyl monophosphine ligand L1 was found to be much more effective in the reaction enantioselection than its counterpart binaphthyl monophosphine ligands.

Enantioselective Syntheses of Tricyclic Benzimidazoles via Intramolecular Allylic Aminations with Chiral-Bridged Biphenyl Phosphoramidite Ligands.

The first iridium-catalyzed enantioselective intramolecular allylic aminations of benzimidazole-tethered allylic carbonates were developed, providing three classes of tricyclic benzimidazoles bearing a tertiary carbon stereogenic center in high yields and excellent enantioselectivities (up to 99% yield, 99% ee). Wide substrate scope, excellent catalytic efficiency and mild conditions rendered this protocol particularly superior and practical. Impressively, the chiral bridge with a tunable structure was shown to provide a very good adjustment space for the chiral environment. The excellent catalytic performance of the ligands manifested their advantages over the bisphenol-based and BINOL-derived counterparts in these transformations. It also highlighted the potential application value of the chiral-bridged ligands.

Design, synthesis, structure-activity relationships and mechanism of action of new quinoline derivatives as potential antitumor agents.

A series of new quinoline derivatives was designed, synthesized and evaluated as potential antitumor agents. The results indicated that most compounds exhibited potent antiproliferative activity, and 7-(4-fluorobenzyloxy)N-(2-(dimethylamino)- ethyl)quinolin-4-amine 10g was found to be the most potent antiproliferative agent against human tumor cell lines with an IC50 value of less than 1.0 µM. Preliminary structure-activity relationships analysis suggested that (1) the large and bulky alkoxy substituent in position-7 might be a beneficial pharmacophoric group for antiproliferative activity; (2) the amino side chain substituents in position-4 facilitated the antiproliferative activity of this class of compounds; and (3) the length of the alkylamino side chain moiety affected the antiproliferative potency, with two CH2 units being the most favorable. Further investigation of the mechanism of action of this class of compounds demonstrated that the representative compound 10g triggered p53/Bax-dependent colorectal cancer cell apoptosis by activating p53 transcriptional activity. Moreover, the results showed that compound 10g effectively inhibited tumor growth in a colorectal cancer xenograft model in nude mice. Thus, these quinoline derivatives might serve as candidates for the development of new antitumor drugs.

Highly efficient synthesis of benzodioxins with a 2-site quaternary carbon structure by secondary amine-catalyzed dual Michael cascade reactions.

Salicylic acids and substituted ynones were employed as substrates to afford a class of valuable 4H-benzo[d][1,3]dioxin-4-ones with a 2-site quaternary carbon structure in up to 92% yield by secondary amine-catalyzed dual Michael cascade reactions under mild reaction conditions. The α,ß-unsaturated ketone as the key intermediate in the cascade process was successfully separated and characterized. As a result, a new reaction route for ynone species is demonstrated, which is totally different from the existing allenamine activation model.

Intolerable side effects during propranolol therapy for infantile hemangioma: frequency, risk factors and management.

Currently, propranolol is the most preferred systemic therapy for problematic infantile hemangiomas (IHs). However, the side effects such as bronchial hyperreactivity may be intolerable. The aim of this study was to evaluate the frequency, risk factors and management of intolerable side effects (ISEs) during propranolol therapy. In total, 1260 children were studied. The incidence of ISEs was 2.1% (26 patients). Severe sleep disturbance was the most common reason for propranolol cessation, accounting for 65.4% of cases. In total, 23 and 3 patients received atenolol and prednisolone as second-line therapy, respectively. Treatment response was observed in 92.3% (24/26) of cases (showing excellent or good response to therapy). No toxicity-related permanent treatment discontinuation occurred during atenolol or prednisolone therapy. In the univariate analysis, younger age, premature birth, and lower body weight were associated with ISEs (P < 0.05). In the multivariate analysis, only age (95% confidence interval [CI]: 1.201-2.793, P = 0.009) and body weight (95% CI: 1.036-1.972, P = 0.014) were associated with ISEs. Our study suggests that ISEs are rare in patients with IHs who are treated with propranolol. Predictive factors for ISEs include younger age and lower body weight. Atenolol and prednisolone are effective and safe alternatives to propranolol in the treatment of refractory IHs.

Synthesis of six-membered spirooxindoles via a chiral Brønsted acid-catalyzed asymmetric intramolecular Friedel-Crafts reaction.

By means of the direct condensation of N-aminoethylpyrroles and isatins, followed by a chiral phosphoric acid-catalyzed asymmetric intramolecular Friedel-Crafts reaction, a new class of valuable chiral 3',4'-dihydro-2'H-spiro[indoline-3,1'-pyrrolo[1,2-a]pyrazin]-2-ones bearing a quaternary carbon stereocenter were successfully synthesized in good to excellent yields and with moderate to good enantioselectivities under mild reaction conditions.

Synthesis of a Class of Chiral-Bridged Phosphoramidite Ligands and Their Applications in the First Iridium-Catalyzed Asymmetric Addition of Arylboronic Acids to Isatins.

A series of novel chiral phosphoramidite ligands based on chiral-bridged biphenyl backbones have been prepared conveniently and characterized. The ligands complexed with [IrCodCl]2 provided the first iridium catalyst system for the asymmetric addition of arylboronic acids to N-protected isatins with high efficiency. When performed in THF/H2O at 80 °C with 2 equiv of the arylboronic acids, the transformations acquired good to excellent results (up to 98% yield and 95% ee).

Design and synthesis of novel xyloketal derivatives and their protective activities against H2O2-induced HUVEC injury.

In this work, we designed and synthesized a series of amide derivatives (1-13), benzoxazine derivatives (16-28) and amino derivatives (29-30) from xyloketal B. All 28 new derivatives and seven known compounds (14, 15, 31-35) were evaluated for their protection against H2O2-induced HUVEC injury. 23 and 24 exhibited more potential protective activities than other derivatives; and the EC50 values of them and the leading compound 31 (xyloketal B) were 5.10, 3.59 and 15.97 µM, respectively. Meanwhile, a comparative molecular similarity indices analysis (CoMSIA) was constructed to explain the structural activity relationship of these xyloketal derivatives. This 3D QSAR model from CoMSIA suggested that the derived model exhibited good predictive ability in the external test-set validation. Derivative 24 fit well with the COMSIA map, therefore it possessed the highest activity of all compounds. Compounds 23, 24 and 31 (xyloketal B) were further to examine in the JC-1 mitochondrial membrane potential (MMP) assay of HUVECs using flow cytometry (FCM). The result indicated that 23 and 24 significantly inhibited H2O2-induced decrease of the cell mitochondrial membrane potential (ΔΨm) at 25 µM. Collectively, the protective effects of xyloketals on H2O2-induced endothelial cells may be generated from oxidation action by restraining ROS and reducing the MMP.

Highly enantioselective synthesis of 2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-ones via catalytic asymmetric intramolecular cascade imidization-nucleophilic addition-lactamization.

Highly enantioselective catalytic asymmetric intramolecular cascade imidization-nucleophilic addition-lactamization of N(1)-alkylethane-1,2-diamine with methyl 2-formylbenzoate catalyzed by a chiral phosphoric acid represents the first efficient method for the preparation of medicinally interesting chiral 2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-ones with high yields and excellent enantioselectivities. This strategy has been shown to be quite general toward various methyl 2-formylbenzoates.