Selective Synthesis of Amides and α-Ketoamides via Electrochemical Decarboxylation and Dehydration.

An electrochemical and selective decarboxylation and dehydration using α-keto acids with amines is accomplished, which leads to the easy accessibility of amides and α-ketoamides, which are not only ubiquitous and valuable structure motifs found in pharmaceuticals, but also versatile building blocks in synthetic chemistry. Notably, for this efficient and green protocol, neither metal catalysts nor external oxidants are required. The process exhibits a broad scope and functional group tolerance to deliver various amides and α-ketoamides. Moreover, these two reactions have also been applied to late-stage derivatization and can be safely conducted on gram scale.

Electrochemical oxidative thioetherification of aldehyde hydrazones with thiophenols.

An electrochemically promoted oxidative dehydrogenation cross-coupling reaction between aldehyde hydrazones and thiophenols is demonstrated for the first time, which resulted in a variety of (Z)-thioetherified products in moderate to excellent yields. This strategy can be carried out under an air atmosphere, featuring scalability and excellent stereoselectivity. In addition, the transformation efficiently produces readily recyclable disulfide as a by-product with high yields, which significantly reduces the environmental pollution caused by thioetherification.

Electrochemical N-Acylation of Sulfoximine with Hydroxamic Acid.

Despite the widespread applications of sulfoximines, green and efficient access to functionalized sulfoximines remains a challenge. By employing an electrochemical strategy, we describe an approach for the construction of N-aroylsulfoximines, which features a broad substrate scope, mild reaction conditions, safety on a gram scale, and no need for an external oxidant and transition metal catalysts.

Electrochemical Oxidative Carbonylation of NH-Sulfoximines.

The electrochemical synthesis of N-aroylsulfoximines features the use of tetra-n-butylammonium iodide (TBAI) as the medium and a broad substrate scope, thus affording a wide range of N-aroylated sulfoximines in moderate to good yields. The advantages of this electrochemical strategy are augmented by mild reaction conditions that are external oxidant-free, ligand-free, and easy to scale up to gram scale. Both the control experiments and the mechanistic studies revealed that the whole electrochemical process proceeded through a palladium (II/IV/II) catalytic cycle.

Selective Electrochemical Halogenation of Functionalized Quinolone.

This work describes an effective C3-H halogenation of quinoline-4(1H)-ones under electrochemical conditions, in which potassium halides serve as both halogenating agents and electrolytes. The protocol provides expedient access to different halogenated quinoline-4(1H)-ones with unique regioselectivity, broad substrate scope, and gram-scale synthesis employing convenient, environmentally friendly electrolysis, in an undivided cell. Mechanism studies have shown that halogen radicals can promote the activation of N-H bonds in quinolones.

A Palladium-Catalyzed Carbonylative Acetylation of N-Phenylpyridin-2-amine Using DMF and CO as the Acetyl Source.

This study reports a carbonylative acetylation for the synthesis of N-phenyl-N-(pyridin-2-yl)acetamides using N,N-dimethylformamide (DMF) as a methyl source and CO as a carbonyl source. Interestingly, dimethyl sulfoxide (DMSO) can be also used as a methyl source when using only DMSO as the solvent. Mechanistic studies using DMSO-d6 revealed that the methyl group was derived from the methyl group of DMF instead of DMSO when using DMF and DMSO as a mixed solvent. These results indicated that DMF was a preferential methyl source.

Transcatheter arterial chemoembolization plus apatinib with or without camrelizumab for unresectable hepatocellular carcinoma: a multicenter retrospective cohort study.

BACKGROUND: The evidence of transcatheter arterial chemoembolization (TACE) plus tyrosine kinase inhibitor and immune checkpoint inhibitor in unresectable hepatocellular carcinoma (HCC) was limited. This study aimed to evaluate the role of TACE plus apatinib (TACE + A) and TACE combined with apatinib plus camrelizumab (TACE + AC) in patients with unresectable HCC. METHODS: This study retrospectively reviewed patients with unresectable HCC who received TACE + A or TACE + AC in 20 centers of China from January 1, 2019 to June 31, 2021. Propensity score matching (PSM) at 1:1 was performed to reduce bias. Treatment-related adverse events (TRAEs), overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were collected. RESULTS: A total of 960 eligible patients with HCC were included in the final analysis. After PSM, there were 449 patients in each group, and the baseline characteristics were balanced between two groups. At data cutoff, the median follow-up time was 16.3 (range: 11.9-21.4) months. After PSM, the TACE + AC group showed longer median OS (24.5 vs 18.0 months, p < 0.001) and PFS (10.8 vs 7.7 months, p < 0.001) than the TACE + A group; the ORR (49.9% vs 42.5%, p = 0.002) and DCR (88.4% vs 84.0%, p = 0.003) of the TACE + AC group were also higher than those in the TACE + A group. Fever, pain, hypertension and hand-foot syndrome were the more common TRAEs in two groups. CONCLUSIONS: Both TACE plus apatinib and TACE combined with apatinib plus camrelizumab were feasible in patients with unresectable HCC, with manageable safety profiles. Moreover, TACE combined with apatinib plus camrelizumab showed additional benefit.

Electrochemically Driven Selective Removal of the S═N Bond-Directing Group Using Cyclohexanone Oxime as the Mediator.

An inexpensive electrochemical induction system was used for the efficient reductive defunctionalization of sulfoximines through a radical pathway. This practical and robust strategy could be used for the removal of the S═N bond-directing group from various sulfoximines. The practicability of this method was demonstrated by its mild conditions, simple operation, one-pot procedure, gram-scale synthesis, and the undivided cell. Furthermore, preliminary mechanistic studies suggested that the reaction might proceed via a homocoupling reaction and a denitrification procedure.

Copper-Catalyzed Sulfonylation Reaction of NH-Sulfoximines with Aryldiazonium Tetrafluoroborates and Sulfur Dioxide: Formation of N-Sulfonyl Sulfoximines.

An efficient and practical SO2 insertion protocol of NH-sulfoximines with aryldiazonium tetrafluoroborates and DABSO toward N-sulfonyl sulfoximines has been developed under mildly basic conditions. This transformation features easy operation, readily available substrates, and mild conditions. A tentative mechanism is proposed, which indicates that the aryldiazonium tetrafluoroborates would be radical donors under standard reaction conditions. The aryl radical produced in situ from diazonium salts would be trapped by SO2 to generate an arylsulfonyl radical and then undergo further transformation to generate the final N-sulfonyl sulfoximines.

Oxidative C-H/N-H Carbonylation of Benzamide by Nickel Catalysis with CO as the Carbonyl Source.

An efficient and direct carbonylation of aminoquinoline benzamides has been developed using abundant and inexpensive Ni(OAc)2·4H2O as the catalyst and carbon monoxide as a cost-efficient C1 building block. This process features good functional-group tolerance and can be conducted on gram scale. The directing group can be easily removed under mild conditions.

Copper-Catalyzed Divergent C-H Functionalization Reaction of Quinoxalin-2(1H)-ones and Alkynes Controlled by N1-Substituents for the Synthesis of (Z)-Enaminones and Furo[2,3-b]quinoxalines.

With control by N1-substituents, the switchable divergent C-H functionalization reaction of quinoxalin-2(1H)-ones is achieved for the synthesis of (Z)-enaminones and furo[2,3-b]quinoxalines using the combination of a copper catalyst and an oxidant. This new protocol features mild reaction conditions, readily available materials, and a broad substrate scope. Gram-scale and mechanistic studies were also investigated. Furthermore, the desired products exhibited excellent antitumor activity against A549, HepG-2, MCF-7, and HeLa cells, which were tested by MTT assay.

Systematic evaluation of the antitumor activity of three ruthenium polypyridyl complexes.

Ruthenium-containing complexes have emerged as good alternative to the currently used platinum-containing drugs for malignant tumor therapy. In this work, cytotoxic effects of recently synthesized ruthenium polypyridyl complexes [Ru(bpy)2(CFPIP)](ClO4)2 (bpy = 2,2'-bipyridine, CFPIP = (E)-2-(4-fluorostyryl)-1H-imidazo[4,5-f][1,10]phenanthroline, Ru(II)-1), [Ru(phen)2(CFPIP)](ClO4)2 (phen = 1,10-phenanthroline, Ru(II)-2) and [Ru(dmb)2(CFPIP)](ClO4)2 (dmb = 4,4'-dimethyl-2,2'-bipyridine, Ru(II)-3) toward different tumor cells were investigated in vitro and compared with cisplatin, the most widely used chemotherapeutic drug against hepatocellular carcinoma (HepG-2). The results demonstrate that target complexes show excellent cytotoxicity against HepG-2 cells with low IC50 value of 21.4 ± 1.5, 18.0 ± 2.1 and 22.3 ± 1.7 µM, respectively. It was important noting that target Ru(II) complexes exhibited better antitumor activity than cisplatin (IC50 = 28.5 ± 2.4 µM) against HepG-2 cells, and has no obvious toxicity to normal cell LO2. DNA binding results suggest that Ru(II)-1, Ru(II)-2 and Ru(II)-3 interact with CT DNA (calf thymus DNA) through intercalative mode. Complexes exerted its antitumor activity through increasing anti-migration and inducing cell cycle arrest at the S phase. In addition, the apoptosis was tested by AO (acridine orange)/EB (ethidium bromide) staining and flow cytometry. Mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and colocalization tests were also evaluated by ImageXpress Micro XLS system. Overall, the results show that the ruthenium polypyridyl complexes induce apoptosis in HepG-2 cells through ROS-mediated mitochondria dysfunction pathway.

Identification of ruthenium (II) complexes with furan-substituted ligands as possible antibacterial agents against Staphylococcus aureus.

The growing burden of antibiotic resistance worldwide calls for developing new classes of antimicrobial strategy. Recently years, the use of adjuvants that rescue antibiotics identified as a promising strategy for overcoming bacterial resistance. In this study, three ruthenium complexes functionalized with furan-substituted ligands([Ru(phen)2 (CAPIP)](ClO4 )2 (Ru(Ⅱ)-1), [Ru(dmp)2 (CAPIP)](ClO4 )2 (Ru(Ⅱ)-2) and [Ru(dmb)2 (CAPIP)](ClO4 )2 (Ru(Ⅱ)-3) (dmb=4,4'-dimethyl-2,2'-bipyridine, phen=1,10-phenanthroline, dmp=2,9-dimethyl-1,10-phenanthroline, CAPIP=(E)-2- (2-(furan-2-yl)vinyl)-1H-imidazo[4,5-f][1,10]phenanthroline)) were designed and synthesized. The antimicrobial activities of all compounds against S. aureus were assessed by growth inhibition assays. The MIC values of three complexes range from 0.015 to 0.050 mg/ml. Subsequently, the Ru(II)-2 complexes which exhibited strongest antibacterial activity were further tested against bacteria biofilms formation and toxin secretion. In addition, aimed to test whether ruthenium complexes have potential value as antimicrobial adjuvants, the synergism between Ru(Ⅱ)-2 and some antibiotics against S. aureus were examined through checkerboard method. Interestingly, Ru(Ⅱ)-2 could not only effectively inhibit biofilms formation of S. aureus and inhibit the hemolysin toxin secretion, but also selectivity show synergism with two common antibiotics. More importantly, mouse infection study also verified Ru(Ⅱ)-2 were highly effective against S. aureus in vivo.

Synthesis of ruthenium complexes functionalized with benzothiophene and their antibacterial activity against Staphylococcus aureus.

New effective antimicrobial agents with novel modes of action are urgently needed due to the continued emergence of drug-resistant bacteria. Here, three ruthenium complexes functionalized with benzothiophene: [Ru(phen)2(BTPIP)](ClO4)2 (Ru(II)-1), [Ru(dmp)2(BTPIP)](ClO4)2 (Ru(II)-2) and [Ru(dmb)2(BTPIP)](ClO4)2 (Ru(II)-3) (dmb = 4,4'-dimethyl-2,2'-bipyridine, phen = 1,10-phenanthroline, dmp = 2,9-dimethyl-1,10-phenanthroline) have been synthesized and their antimicrobial activities in vitro were assessed. Minimum inhibitory concentration (MIC) assays indicated that the three Ru(II)-1, Ru(II)-2 and Ru(II)-3 complexes all showed antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. The most active Ru(II)-3 complex was further tested against biofilms. Furthermore, it was also tested whether complex Ru(II)-3 could serve as an antibacterial adjuvant. Interestingly, the checkerboard data showed that Ru(II)-3 selectively exhibited synergism with aminoglycoside antibiotics. More importantly, the observed synergetic effect might be attributed to the inhibition of the regulatory function of SaCcpA. Finally, in vivo bacterial infection treatment studies through a murine skin infection model and skin irritation test were also conducted. All in all, these results confirmed that ruthenium complexes functionalized with benzothiophene have good antimicrobial activity against Staphylococcus aureus.

Association between PPAR-γ2 gene polymorphisms and diabetic retinopathy risk: a meta-analysis.

A close association between peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) and the development of diabetic retinopathy (DR) has been previously suggested. Herein, a meta-analysis was conducted to explore the association between PPAR-γ2 polymorphisms and DR risk by performing a systematic search and quantitative analysis. Overall, fourteen articles involving 10,527 subjects were included. The pooled results did not reveal an association between PPAR-γ2 rs1801282 C/G and DR susceptibility in the overall population (e.g., the dominant model: CG+GG vs. CC, OR=0.85, 95% CI=0.69-1.06, P=0.15, I2=62.9%). Furthermore, heterogeneity tests, cumulative analyses, sensitivity analyses, and publication bias analyses were conducted and showed that the results were robust. Similarly, race-based subgroup analyses and other subgroup analyses did not reveal an association between the rs1801282 C/G and DR susceptibility. In addition, no significant association was observed between PPAR-γ2 rs3856806 C/T polymorphism and DR risk (e.g., the dominant model: CT+TT vs. CC, OR=1.12, 95%CI=0.91-1.37, P=0.28, I2=27.0%). Overall, based on the current sample size and the level of evidence presented in the study, the results suggest that PPAR-γ2 gene polymorphisms are not associated with DR risk.

Association Between the Aldehyde Dehydrogenase-2 rs671 G>A Polymorphism and Head and Neck Cancer Susceptibility: A Meta-Analysis in East Asians.

BACKGROUND: Aldehyde dehydrogenase-2 (ALDH2) plays an important role in the alcohol detoxification and acetaldehyde metabolism. Published studies have demonstrated some inconsistent associations between ALDH2 rs671 G>A polymorphism and head and neck cancer (HNC) risk. METHODS: A meta-analysis was performed to provide pooled data on the association between the ALDH2 rs671 G>A polymorphism and HNC risk. Electronic databases were searched to identify relevant studies. Odds ratios and 95% confidence intervals (CIs) were used to examine the pooled effect size of each genetic model. In addition, heterogeneity test, accumulative analysis, sensitivity analysis, and publication bias were conducted to test the statistical power. RESULTS: Thirteen publications (14 independent case-control studies) involving 10,939 subjects were selected. The stratified analysis indicated that both light/moderated drinking (e.g., GA vs. GG: OR = 1.47, 95% CI = 1.16 to 1.86, p < 0.01, I2  = 81.1%) and heavy drinking would increase HNC risk with rs671 G>A mutation (e.g., GA vs. GG: OR = 2.30, 95% CI = 1.11 to 4.77, p = 0.03, I2  = 81.9%). CONCLUSIONS: In summary, this meta-analysis suggested that the ALDH2 rs671 G>A polymorphism may play an important synergistic effect in the pathogenesis of HNC development in East Asians.

Copper- and DMF-mediated switchable oxidative C-H cyanation and formylation of imidazo[1,2-a]pyridines using ammonium iodide.

The cyanation and formylation of imidazo[1,2-a]pyridines were developed under copper-mediated oxidative conditions using ammonium iodide and DMF as a nontoxic combined cyano-group source and DMF as a formylation reagent. Mechanistic studies indicate that the cyanation of imidazo[1,2-a]pyridines proceeds through a two-step sequence: initial iodination and then cyanation. The cyanation has a broad substrate scope and high functional group tolerance, and can be safely conducted on a gram scale. A novel copper-mediated formylation using the widely available DMF as the formylation reagent and environmentally friendly molecular oxygen as the oxidant has also been developed. This protocol also provided a convenient approach for the synthesis of clinically used saripidem.

Association between the pri-miR-26a-1 rs7372209 C>T polymorphism and cancer susceptibility: multivariate analysis and trial sequential analysis.

MiR-26 has been suggested to play a tumor-suppressive role in cancer development, which could be influenced by the mutate pri-miR-26ª-1. Molecular epidemiological studies have demonstrated some inconsistent associations between pri-miR-26ª-1 rs7372209 C>T polymorphism and cancer risk. We therefore performed this meta-analysis with multivariate statistic method to comprehensively evaluate the associations between rs7372209 C>T polymorphism and cancer risk. Eleven publications involving 6,709 patients and 6,514 controls were identified. Multivariate analysis indicated that the over-dominant genetic model was most likely. Pooled results indicated no significant association in the overall population (CC+TT vs. CT: OR=1.08, 95%CI=0.96-1.22, P=0.20, I2=54.4%), as well as the subgroup analysis according to ethnicity, control source, tumor locations, and HWE status of controls. In addition, heterogeneity, accumulative, sensitivity analysis, publication bias and trial sequential analysis (TSA) were conducted to test the statistical power. Overall, our results indicated that the pri-miR-26a-1 rs7372209 C>T polymorphism may not be a potential risk for cancer development.

Development of four ruthenium polypyridyl complexes as antitumor agents: Design, biological evaluation and mechanism investigation.

Ruthenium complexes are expected to be new opportunities for the development of antitumor agents. Herein, four ruthenium polypyridyl complexes ([Ru(bpy)2(CAPIP)](ClO4)2 (Ru(II)-1, bpy = 2,2'-bipyridine; CAPIP = (E)-2-(2-(furan-2-yl)vinyl)-1H-imidazo[4,5-f][1,10]phenanthroline), [Ru(phen)2(CA-PIP)](ClO4)2 (Ru(II)-2, phen = 1,10-phenanthroline), [Ru(dmb)2(CAPIP)](ClO4)2 (Ru(II)-3, dmb = 4,4'-dimethyl-2,2'-bipyridine), [Ru(dmb)2(ETPIP)](ClO4)2 (Ru(II)-4, ETPIP = 2-(4-(thiophen-2-ylethynyl)phenyl)-1H-imidazo[4,5-f][1,10]phen-anthroline)) have been investigated as mitochondria-targeted antitumor metallodrugs. DNA binding studies indicated that target Ru(II) complexes interacts with CT DNA (calf thymus DNA) by an intercalative mode. Cytotoxicity assay results demonstrate that Ru(II) complexes show high cytotoxicity against A549 cells with low IC50 value of 23.6 ± 2.3, 20.1 ± 1.9, 22.7 ± 1.8 and 18.4 ± 2.3 µM, respectively. Flow cytometry and morphological analysis revealed that these Ru(II) complexes can induce apoptosis in A549 cells. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were also investigated by ImageXpress Micro XLS system. The experimental results indicate that the reactive oxygen species in A549 cells increased significantly and mitochondrial membrane potential decreased obviously. In addition, colocalization studies shown these complexes could get to the cytoplasm through the cell membrane and accumulate in the mitochondria. Furthermore, Ru(II) complexes can effectively induces cell cycle arrest at the S phase in A549 cells. Finally, cell invasion assay and quantitative studies were also performed to investigate the mechanism of this process. All in together, this study suggested that these Ru(II) complexes could induce apoptosis in A549 cells through cell cycle arrest and ROS-mediated mitochondrial dysfunction pathway.

Antibacterial activity of ruthenium polypyridyl complexes against Staphylococcus aureus and biofilms.

There is clearly a need for the development of new classes of antimicrobials to fight against multidrug-resistant bacteria. Here, we designed and synthesized of three ruthenium polypyridyl complexes: [Ru(bpy)2(BTPIP)](ClO4)2 (Ru(II)-1), [Ru(bpy)2(ETPIP)](ClO4)2 (Ru(II)-2) and [Ru(bpy)2(CAPIP)](ClO4)2 (Ru(II)-3) (N-N = bpy = 2,2'-bipyridine), their antimicrobial activities against S. aureus were assessed. The lead complexes of this set, Ru(II)-1(MIC = 0.016 mg/mL), was tested against biofilm. We also investigated whether bacteria can easily develop resistance to Ru(II)-1. The result demonstrated that S. aureus could not easily develop resistance to the ruthenium complexes. In addition, aimed to test whether ruthenium complexes treatment could increase the susceptibility of S. aureus to antibiotics, the synergism between Ru(II)-1 and common antibiotics against S. aureus were investigated using the checkerboard method. Interesting, Ru(II)-1 could increased the susceptibility of S. aureus to some aminoglycoside antibiotics(kanamycin and gentamicin). Finally, in vivo bacterial infection treatment studies were also conducted through murine skin infection model. These results confirmed ruthenium complexes have good antimicrobial activity in vitro and in vivo.