Synthesis of meta-arylphenol derivatives via acid-promoted rearrangement of cyclohexadienones.

A highly effective strategy for the synthesis of meta-arylphenol derivatives through the selective rearrangement of 4-alkyl-4-aryl-2,5-cyclohexadienones under metal-free conditions was developed, in which acid-promoted [1,2]-migration of the aryl group at C-4 occurred exclusively when the alkyl group at C-4 was a methyl group. Treatment of 4-methyl-4-aryl-2,5-cyclohexadienones with 37% HCl in Ac2O at room temperature provided polysubstituted meta-arylphenyl acetates in 75-94% yields. The application of this protocol in the synthesis of polycyclic aromatic compounds was also described.

Manganese-catalyzed dehydrogenative Csp3-Csp2 coupling of imidazo[1,2-a]pyridines with methyl ketones.

A Mn(ii)-catalyzed efficient C-H alkylation of imidazoheterocycles with methyl ketones has been developed via dehydrogenative C(sp3)-C(sp2) coupling which can serve as a novel approach toward hydrocarboxylated imidazolopyridines. The merit of this strategy is illustrated by excellent functional group tolerance and the use of cheap and readily available starting materials.

Copper-catalyzed direct amination of benzylic hydrocarbons and inactive aliphatic alkanes with arylamines.

A new synthetic method toward direct C-N bond formation through saturated C-H amination of benzylic hydrocarbons and inactive aliphatic alkanes with primary aromatic amines under an inexpensive catalyst/oxidant (Cu/DTBP) system has been developed. Both aminopyridines and anilines could react smoothly with primary and secondary benzylic C-H substrates or cyclohexane to form the corresponding aromatic secondary amines in moderate to good yields. This protocol has the advantages of wide functional group tolerance and use of readily available raw materials.

Peroxide-mediated site-specific C-H methylation of imidazo[1,2-a]pyridines and quinoxalin-2(1H)-ones under metal-free conditions.

An effective approach to realize the direct methylation of imidazo[1,2-a]pyridines and quinoxalin-2(1H)-ones with peroxides under metal-free conditions is described. In this protocol, peroxides serve as both the radical initiator and methyl source. Methylated imidazopyridines and quinoxalin-2(1H)-ones were smoothly synthesized in moderate to good yields. A free radical reaction mechanism was proposed to describe the methylation process.

SO2F2-Mediated Epoxidation of Olefins with Hydrogen Peroxide.

An inexpensive, mild, and highly efficient epoxidation protocol has been developed involving bubbling SO2F2 gas into a solution of olefin, 30% aqueous hydrogen peroxide, and 4 N aqueous potassium carbonate in 1,4-dioxane at room temperature for 1 h with the formation of the corresponding epoxides in good to excellent yields. The novel SO2F2/H2O2/K2CO3 epoxidizing system is suitable to a variety of olefinic substrates including electron-rich and electron-deficient ones.

Transition Metal-Free Cross-Dehydrogenative Coupling Reaction of Coumarins with Acetonitrile or Acetone.

A transition metal-free cross-dehydrogenative coupling of coumarins with acetonitrile or acetone has been established. A series of coumarins were subjected to reaction with acetonitrile or acetone in the presence of tert-butyl benzoperoxoate and potassium fluoride for direct synthesis of 3-cyanomethyl (or acetomethyl) coumarins. The method exhibits good functional group tolerance, and desired products were obtained in moderate to good yields. Meanwhile, a radical pathway was proposed to describe the cross-dehydrogenative coupling of coumarins with acetonitrile.

Copper-Catalyzed Coupling Reactions of Cyclobutanone Oxime Esters with Sulfur Nucleophiles at Room Temperature.

A copper-catalyzed iminyl radical-mediated C-C bond cleavage/cross-coupling tandem reaction of cyclobutanone oxime esters with aryl thiols in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature was developed, and aryl cyanopropyl sulfides were smoothly synthesized in 20-88% yields. By altering the copper reagent and the molar ratio of cyclobutanone oxime ester/aryl thiol/DBU, substitutional product N-arylthio cyclobutanone imines were selectively generated in 50-91% yields. Using this protocol, C-S bond and N-S bond formations using aryl thiols as sulfur sources were realized under very mild conditions without the use of photocatalysis and electrocatalysis techniques.

Three-component difunctionalization of alkenes leading to ß-acetamido sulfides and ß-acetoxy sulfides.

A novel method for the synthesis of ß-acetamido sulfides via NBS-mediated aminosulfenylation of alkenes with thiophenols and nitriles under metal-free conditions has been described. And ß-acetamido sulfides were also synthesized with 1-(arylthio)pyrrolidine-2,5-diones as substrates and HBr as an additive. On the other hand, iodine-catalyzed 1,2-acetoxysulfenylation of alkenes by using (diacetoxyiodo)benzene as an oxygen source to synthesise various ß-acetoxy sulfides was described as well.

Copper-Mediated Oxidative Functionalization of C(sp3)-H Bonds with Isoquinolines: Two-Step Synthesis of 5-Oxaprotoberberinones.

A copper-mediated oxidative functionalization of C(sp3)-H bonds with isoquinolines via a radical process without ligands was achieved. The present system exhibits a novel pathway for the preparation of N-alkyl (benzyl) isoquinolin-1(2H)-ones in moderate to high yields. In addition, this procedure provides a simple method to afford 5-oxaprotoberberinones and their derivatives in two steps.

Three-component oxysulfenylation reaction: two simple and convenient approaches to ß-alkoxy sulfides.

An unprecedented method for the synthesis of ß-alkoxy sulfides via a NaI/HBr-mediated three-component oxysulfenylation reaction of alkenes with arylsulfinic acids and alcohols is reported. Furthermore, I2-promoted oxysulfenylation of alkenes using sodium arylsulfinates instead of arylsulfinic acids to synthesise various ß-alkoxy sulfides is also described.

Causal association of immune cells and endometriosis: a Mendelian randomization study.

Objective: To investigate the causal effect of immune cells on endometriosis (EMS), we performed a Mendelian randomization analysis. Methods: Mendelian randomization (MR) uses genetic variants as instrumental variables to investigate the causal effects of exposures on outcomes in observational data. In this study, we conducted a thorough two-sample MR analysis to investigate the causal relationship between 731 immune cells and endometriosis. We used complementary Mendelian randomization (MR) methods, including weighted median estimator (WME) and inverse variance weighted (IVW), and performed sensitivity analyses to assess the robustness of our results. Results: Four immune phenotypes have been found to be significantly associated with the risk of developing EMS: B cell %lymphocyte (WME: OR: 1.074, p = 0.027 and IVW: OR: 1.058, p = 0.008), CD14 on Mo MDSC (WME: OR: 1.056, p =0.021 and IVW: OR: 1.047, p = 0.021), CD14+ CD16- monocyte %monocyte (WME: OR: 0.947, p = 0.024 and IVW: OR: 0.958, p = 0.011), CD25 on unsw mem (WME: OR: 1.055, p = 0.030 and IVW: OR: 1.048, p = 0.003). Sensitivity analyses confirmed the main findings, demonstrating consistency across analyses. Conclusions: Our MR analysis provides compelling evidence for a direct causal link between immune cells and EMS, thereby advancing our understanding of the disease. It also provides new avenues and opportunities for the development of immunomodulatory therapeutic strategies in the future.

Causal relationships between modifiable risk factors and polycystic ovary syndrome: a comprehensive Mendelian randomization study.

Background: Polycystic Ovary Syndrome (PCOS) is a heritable condition with an as yet unclear etiology. Various factors, such as genetics, lifestyle, environment, inflammation, insulin resistance, hyperandrogenism, iron metabolism, and gut microbiota, have been proposed as potential contributors to PCOS. Nevertheless, a systematic assessment of modifiable risk factors and their causal effects on PCOS is lacking. This study aims to establish a comprehensive profile of modifiable risk factors for PCOS by utilizing a two-sample Mendelian Randomization (MR) framework. Methods: After identifying over 400 modifiable risk factors, we employed a two-sample MR approach, including the Inverse Variance Weighted (IVW) method, Weighted Median method, and MR-Egger, to investigate their causal associations with PCOS. The reliability of our estimates underwent rigorous examination through sensitivity analyses, encompassing Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots. Results: We discovered that factors such as smoking per day, smoking initiation, body mass index, basal metabolic rate, waist-to-hip ratio, whole body fat mass, trunk fat mass, overall health rating, docosahexaenoic acid (DHA) (22:6n-3) in blood, monounsaturated fatty acids, other polyunsaturated fatty acids apart from 18:2 in blood, omega-3 fatty acids, ratio of bisallylic groups to double bonds, omega-9 and saturated fatty acids, total lipids in medium VLDL, phospholipids in medium VLDL, phospholipids in very large HDL, triglycerides in very large HDL, the genus Oscillibacter, the genus Alistipes, the genus Ruminiclostridium 9, the class Mollicutes, and the phylum Tenericutes, showed a significant effect on heightening genetic susceptibility of PCOS. In contrast, factors including fasting insulin interaction with body mass index, sex hormone-binding globulin, iron, ferritin, SDF1a, college or university degree, years of schooling, household income, the genus Enterorhabdus, the family Bifidobacteriaceae, the order Bifidobacteriales, the class Actinobacteria, and the phylum Actinobacteria were determined to reduce risk of PCOS. Conclusion: This study innovatively employs the MR method to assess causal relationships between 400 modifiable risk factors and the susceptibility of PCOS risk. It supports causal links between factors like smoking, BMI, and various blood lipid levels and PCOS. These findings offer novel insights into potential strategies for the management and treatment of PCOS.

Cyanomethylation of the Benzene Rings and Pyridine Rings via Direct Oxidative Cross-Dehydrogenative Coupling with Acetonitrile.

A novel and efficient approach for the amine-directed dehydrogenative C(sp2)-C(sp3) coupling of arylamines with acetonitrile was reported by using FeCl2 as the catalyst. Substituted anilines, aminopyridines, naphthylamines, and some nitrogen-containing heterocyclic arylamines react with inactive acetonitrile to form the corresponding arylacetonitriles in moderate to good yields. This protocol features nontoxic iron catalysis, efficient atom economy, nonprefunctionalized starting materials, good regioselectivity, and excellent compatibility of functional groups and aromatic rings, providing a novel, straightforward, and green approach toward arylacetonitriles.

Preliminary Analysis of Cervical Cancer Immunotherapy.

Cervical cancer is one of the most common gynecologically malignancies worldwide. Although vaccine and cervical cancer screening including human papillomavirus testing, cytology testing, and colposcopy have developed rapidly in recent years, effectively reducing cervical cancer mortality, cervical cancer remains a malignancy with higher female fatality rates worldwide and has a high risk for socioeconomically disadvantaged groups. The combination of platinum-paclitaxel and chemotherapy, possibly with the addition of bevacizumab, is currently the treatment of choice for advanced cervical cancer, but it only has remission purposes. Therefore, new therapeutic strategies are needed for both locally advanced and metastatic cervical cancer. Here, we make a preliminary analysis of cervical cancer immunotherapy.

Involvement of p53-dependent apoptosis signal in antitumor effect of Colchicine on human papilloma virus (HPV)-positive human cervical cancer cells.

Colchicine, a plant-derived alkaloid with relatively low toxicity on normal human epidermal keratinocytes (HEKn), has selective inhibitory effect on the growth of CaSki (HPV16-positive) and HeLa (HPV18-positive) human cervical cancer cell lines via the induction of apoptosis. Colchicine (2.5, 5.0 and 10.0 ng/ml) significantly reduced the expression of human papilloma virus (HPV) 16 E6/E7 mRNA and protein in CaSki and HeLa cells. Moreover, reduced expression of E6 and E7 induced by Colchicine resulted in the up-regulation of tumor suppressor proteins, p53 and Rb, as well as down-regulation of phospho Rb (pRb) protein. In addition, Bax, cytosolic cytochrome c and cleaved caspase-3 protein were increased while Bcl-2 protein was decreased significantly by 48 h of Colchicine treatment. These results implied that Colchicine could be explored as a potent candidate agent for the treatment and prevention of HPV-associated cervical cancer without deleterious effects.

Metal-Free Site-Specific Hydroxyalkylation of Imidazo[1,2- a]pyridines with Alcohols through Radical Reaction.

An effective approach to realize the direct hydroxyalkylation of imidazo[1,2- a]pyridines with alcohols promoted by di- tert-butyl peroxide was described without any metal catalyst. It is the first time that the dehydrogenative C(sp3)-C(sp2) coupling of imidazo[1,2- a]pyridines with alcohols occurred regioselectively at the C-5 position of imidazo[1,2- a]pyridines. Multisubstituted imidazopyridine derivatives were smoothly synthesized in moderate to good yields. Through a series of control experiments, a free-radical pathway was proposed to explain the experiment.

APRIL promotes non-small cell lung cancer growth and metastasis by targeting ERK1/2 signaling.

Non-small-cell lung cancer (NSCLC) is the major subtype of lung cancer, which is the most common cause of cancer-related mortality in the world. It is a complex disease involving multiple genetic alterations. As a cytokine belonging to the Tumor Necrosis Factor-α (TNF- α) family, the - a proliferation-inducing ligand (APRIL) expression and its signaling have been studied in many human solid tumor types, but the data on APRIL signaling in NSCLC are lacking. The aim of this study was to evaluate the APRIL expression and investigate its signaling in NSCLC. The expression of APRIL and its receptors, B cell maturation antigen (BCMA) and transmembrane activator and calcium-modulatorand cyclophilin ligand interactor (TACI), was analyzed by using immunohistochemistry in NSCLC samples. Quantitative RT-PCR was performed to evaluate mRNA expression of APRIL, BCMA and TACI in human lung adenocarcinoma cell lines A549, H1299, and H1650. Cell proliferation was measured by using the cell proliferation and cytotoxicity assay kit 8 (CCK8) assay, cell migration by using wound healing assay, and cell invasion by using transwall assay. The protein level of APRIL, BCMA and TAC, and the activation of extracellular regulated protein kinases 1/2 (ERK1/2) signaling, were determined by western blot. Our results indicated, APRIL and its receptors BCMA and TACI, were overexpressed in most of human NSCLC samples and cell lines; APRIL promoted tumor proliferation, migration and metastasis in A549 and H1299 cells via BCMA and TACI. Furthermore, ERK1/2 activation was involved in APRIL signaling through TACI but not BCMA in A549 and H1299 cells. APRIL might serve as a potential prognostic biomarker for NSCLC, and APRIL related signaling pathway could be a therapeutic target for NSCLC.

Synthesis of Methylenecyclopropane Analogues of Antiviral Nucleoside Phosphonates.

Synthesis of methylenecyclopropane analogues of nucleoside phosphonates 6a, 6b, 7a and 7b is described. Cyclopropyl phosphonate 8 was transformed in four steps to methylenecyclopropane phosphonate 16. The latter intermediate was converted in seven steps to the key Z- and E-methylenecyclopropane alcohols 23 and 24 separated by chromatography. Selenoxide eliminations (15 --> 16 and 22 --> 23 + 24) were instrumental in the synthesis. The Z- and E-isomers 23 and 24 were transformed to bromides 25a and 25b which were used for alkylation of adenine and 2-amino-6-chloropurine to give intermediates 26a, 26b, 26c and 26d. Acid hydrolysis provided the adenine and guanine analogues 6a, 6b, 7a and 7b. Phosphonates 6b and 7b are potent inhibitors of replication of Epstein-Barr virus (EBV).

APRIL, BCMA and TACI proteins are abnormally expressed in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-associated mortality. Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancers. The overall survival for NSCLC is dismal, with a 5-year survival of <5% for patients. Thus, identifying an effective biomarker for early diagnosis of lung cancer is the first essential step to reduce mortality. It has been recognized that certain inflammatory and immune responses are important in lung cancer development and prevention. The present study demonstrated that, in NSCLC, a proliferation-inducing ligand (APRIL), B-cell maturation antigen (BCMA)and transmembrane activator and CAML interactor (TACI) proteins are abnormally expressed by immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blotting. In addition, the expression of APRIL, BCMA and TACI were observed to be involved in extracellular signal-regulated kinase (ERK)1/2 activation in A549 cells. Overall, the present study provides evidence that APRIL and its receptors, BCMA and TACI, may play roles in the biological processes of NSCLC tumors through the ERK1/2 signaling pathway.

Nucleotides and pronucleotides of 2,2-bis(hydroxymethyl)methylenecyclopropane analogues of purine nucleosides: synthesis and antiviral activity.

Phenylmethylphosphor-L-alaninate pronucleotides 7a, 7b, 8a, and 8b, cyclic phosphates 10a and 10b, and phosphates 11a and 11b derived from 2,2-bis(hydroxymethyl)methylenecyclopropane analogues 1a, 1b, 2a, and 2b were synthesized and evaluated for their antiviral activity. An improved protocol for the synthesis of analogues 1a, 1b, 2a, and 2b is also described. Phosphate 11a was the most effective agent against human and murine cytomegalovirus (EC(50) 0.25-1.1 microM). The Z-pronucleotides 7a and 7b had EC(50) 3.6-25.2 and 3-18.4 microM, respectively. The EC(50) of cyclic phosphate 10a was 6.0-20 microM. The activity against Epstein-Barr (EBV) was assay-dependent. Pronucleotides 7a and 7b and phosphate 11a had EC(50) 2.3-3.4 microM against EBV/H-1, but 7b was cytotoxic (CC(50) 3.8 microM). Cyclic phosphate 10a was the only compound effective against EBV/Daudi (EC(50) 0.96 microM), but it was inactive in H-1 cells. Pronucleotide 7a was active against varicella zoster virus with EC(50) 6.3 and 7.3 microM, respectively, and hepatitis B virus (HBV, EC(50) 4.1 microM). Cyclic phosphate 10a was the most effective analogue against HBV (EC(50) 0.8 microM).