Modulating Aryl Azide Photolysis: Synthesis of a Room-Temperature Phosphorescent Carboline in Cucurbit[7]uril Host.

Cucurbit[7]uril (CB7), a supramolecular host, is employed to control the pathway of photolysis of an aryl azide in an aqueous medium. Normally, photolysis of aryl azides in bulk water culminates predominantly in the formation of azepine derivatives via intramolecular rearrangement. Remarkably, however, when this process unfolds within the protective confinement of the CB7 cavity, it results in a carboline derivative, as a consequence of a C─H amination reaction. The resulting carboline caged by CB7 reveals long-lived room temperature phosphorescence (RTP) in the solid state, with lifetimes extending up to 2.1 s. These findings underscore the potential of supramolecular hosts to modulate the photolysis of aryl azides and to facilitate novel phosphorescent materials.

Enantioseparation of acetyltropic acid by countercurrent chromatography with sulfobutyl ether-ß-cyclodextrin as chiral selector.

Acetyltropic acid is an important synthetic intermediate for preparation of tropane alkaloid derivatives, which can be used as anticholinergic drugs, deliriants, and stimulants. In the present work, acetyltropic acid was successfully enantioseparated by countercurrent chromatography using sulfobutyl ether-ß-cyclodextrin as chiral selector. A biphasic solvent system composed of n-butyl acetate/n-hexane/0.1 mol/L citrate buffer at pH = 2.2 containing 0.1 mol/L of sulfobutyl ether-ß-cyclodextrin (7:3:10, v/v) was selected, which produced a suitable distribution ratio DS  = 1.14, DR  = 2.31 and a high enantioseparation factor α = 2.03. Baseline separation was achieved for preparative enantioseparation of 50 mg of racemic acetyltropic acid. A method for chiral analysis of acetyltropic acid by conventional reverse phase liquid chromatography with hydroxylpropyl-ß-cyclodextrin as mobile phase additive was established, and formation constants of inclusion complex were determined. It was found that different substituted ß-cyclodextrin should be selected for enantioseparation of acetyltropic acid by countercurrent chromatography and reverse phase liquid chromatography.

Separation and purification of intermediates for the preparation of naproxen from synthetic mixtures by countercurrent chromatography.

Three key intermediates in the preparation of the nonsteroidal anti-inflammatory drug naproxen were successfully separated and purified with high purity from synthetic mixtures by countercurrent chromatography with a selected biphasic solvent system. The biphasic solvent system composed of n-hexane/ethyl acetate/methanol/water (9:1:9:1, v/v/v/v) was selected according to partition performance of the three components using thin-layer chromatography. Fifty milligrams of the synthetic mixture after the three-step reaction was injected into a preparative countercurrent chromatography separation column and yielded 3.5, 14.0, and 8.0 mg of three key intermediates with 95.0, 99.0, and 98.0% purity, and the recovery of each component was 65.2, 71.2, and 69.6%, respectively. The results indicated that countercurrent chromatography is an efficient alternative and economical method for the separation and purification of intermediate components from synthetic mixtures.

Preparative enantioseparation of loxoprofen precursor by recycling countercurrent chromatography with hydroxypropyl-ß-cyclodextrin as a chiral selector.

Recycling countercurrent chromatography was successfully applied to the resolution of 2-(4-bromomethylphenyl)propionic acid, a key synthetic intermediate for synthesis of nonsteroidal anti-inflammatory drug loxoprofen, using hydroxypropyl-ß-cyclodextrin as chiral selector. The two-phase solvent system composed of n-hexane/n-butyl acetate/0.1 mol/L citrate buffer solution with pH 2.4 (8:2:10, v/v/v) was selected. Influence factors for the enantioseparation were optimized, including type of substituted ß-cyclodextrin, concentration of hydroxypropyl-ß-cyclodextrin, separation temperature, and pH of aqueous phase. Under optimized separation conditions, 50 mg of 2-(4-bromomethylphenyl)propionic acid was enantioseparated using preparative recycling countercurrent chromatography. Technical details for recycling elution mode were discussed. The purities of both the S and R enantiomers were over 99.0% as determined by high-performance liquid chromatography. The enantiomeric excess of the S and R enantiomers reached 98.0%. The recovery of the enantiomers from eluted fractions was 40.8-65.6%, yielding 16.4 mg of the S enantiomer and 10.2 mg of the R enantiomer. At the same time, we attempted to enantioseparate the anti-inflammatory drug loxoprofen by countercurrent chromatography and high-performance liquid chromatography using a chiral mobile phase additive. However, no successful enantioseparation was achieved so far.

Reversing the stereoselectivity of intramolecular [2+2] photocycloaddition utilizing cucurbit[8]uril as a molecular flask.

Macrocyclic hosts, such as cucurbit[8]uril (CB8), can significantly influence the outcomes of chemical reactions involving encapsulated reactive guests. In this study, we demonstrate that CB8 completely reverses the stereoselectivity of intramolecular [2+2] photo-cycloaddition reactions. Notably, it was also found that CB8 can trigger the unreactive diene to be reactive.

Tris(4-azidophenyl)methanol - a novel and multifunctional thiol protecting group.

The novel tris(4-azidophenyl)methanol, a multifunctionalisable aryl azide, is reported. The aryl azide can be used as a protecting group for thiols in peptoid synthesis and can be cleaved under mild reaction conditions via a Staudinger reduction. Moreover, the easily accessible aryl azide can be functionalised via copper-catalysed cycloaddition reactions, providing additional opportunities for materials chemistry applications.

Stereoselectiveseparation of racemic trans-paroxol, N-methylparoxetine and paroxetine containing two chiral carbon centres by countercurrent chromatography.

Racemic trans-paroxol, trans-N-methylparoxetine and trans-paroxetine containing two chiral centres were stereoselectively separated using countercurrent chromatography with hydroxypropyl-ß-cyclodextrin as the chiral selector. A two-phase solvent system composed of n-butyl acetate and 0.1 mol L-1 sodium carbonate-sodium bicarbonate buffer at pH 9.2 (1:1, v/v) was selected, and 0.10 mol L-1 hydroxypropyl-ß-cyclodextrin was added to the aqueous phase as the chiral selector. Racemic trans-N-methylparoxetine and racemic trans-paroxol (20 mg of each) were stereoselectively separated by countercurrent chromatography in an individual run, yielding 7.1-8.3 mg of enantiomers with a purity of 95-98%, where the recovery of each separated isomer reached approximately 70-83%. Racemic trans-paroxetine (20 mg) was stereoselectively separated by countercurrent chromatography using a recycling elution mode with a biphasic solvent system composed of n-hexane: n-butyl acetate: 0.1 mol L-1 sodium carbonate-sodium bicarbonate buffer at pH 9.2 (9:1:10, v/v/v), and 0.10 mol L-1 hydroxypropyl-ß-cyclodextrin was added to the aqueous phase as the chiral selector, yielding 5.0-5.6 mg of enantiomer with a high purity of over 98-99%.

Methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and risk of preeclampsia: an updated meta-analysis based on 51 studies.

BACKGROUND AND AIMS: The methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism has been considered to be associated with preeclampsia (PE), but the results from previous studies were conflicting. The present study aimed at investigating the frequency of preeclampsia according to the distribution polymorphism using a meta-analysis on the published studies. METHODS: The English and Chinese databases were searched to identify eligible studies published in English before August 2012. Data were extracted using standardized methods. The association was assessed by odds ratio (OR) with 95% confidence intervals (CI). Begg's test was used to measure publication bias. RESULTS: A total of 51 case-control studies containing 6,403 patients and 11,346 controls were involved in this meta-analysis. Significant associations were detected between MTHFR C677T polymorphism and risk of PE in the overall population for TT vs. CC (OR = 1.280, 95% CI: 1.074-1.525), recessive model (OR = 1.264, 95% CI: 1.067-1.303), and dominant genetic model (OR = 1.174, 95% CI: 1.057-1.303); in Caucasian population for dominant model (OR = 1.136, 95% CI: 1.022-1.263), and in East Asia population for TT vs. CC (OR = 2.199, 95% CI: 1.366-3.924) CT vs. CC (OR = 1.453, 95% CI: 1.001-2.109), recessive model (OR = 1.742, 95% CI: 1.202-2.525), and dominant model (OR = 1.783, 95% CI: 1.271-2.501). Conversely, no associations were detected in Latin America, South Asia, and Africa populations. CONCLUSIONS: Results of the meta-analysis suggest that the MTHFR C677T polymorphism was associated with risk of PE in overall, Caucasian, and East Asia populations. Nevertheless, the results for Latino, East Asians, South Asians and Africans should be interpreted with caution due to the small sample size.

Association between PCSK9 and LDLR gene polymorphisms with coronary heart disease: case-control study and meta-analysis.

OBJECTIVE: To explore the association of rs11206510 (PCSK9 gene) and rs1122608 (LDLR gene) polymorphisms with coronary heart disease (CHD) in Han Chinese. METHODS: A total of 813 participants (290 CHD cases, 193 non-CHD controls and 330 healthy controls) were recruited in the case-control study. DNA genotyping was performed on the SEQUENOM® Mass-ARRAY iPLEX® platform. χ(2)-test was used to compare the genotype distribution and allele frequencies. Two meta-analyses were performed to establish the association between the two polymorphisms with CHD. RESULTS: No significant associations between the two SNPs and the risk of CHD were observed in the present study. The meta-analysis of rs11206510 of PCSK9 gene comprises 11 case-control studies with a total of 69,054 participants. Significant heterogeneity was observed in Caucasian population in subgroup analysis of the association studies of rs11206510 with CHD (P=0.003, I(2)=67.2%). The meta-analysis of LDLR gene rs1122608 polymorphism comprises 7 case-control studies with a total of 20,456 participants and the heterogeneity of seven studies was minimal (P=0.148, I(2)=36.7%). CONCLUSION: The results of the meta-analyses indicated that both SNPs were associated with CHD in Caucasians (P<0.05) but not in Asians. The results from our case-control study and meta-analyses might be explained by genetic heterogeneity in the susceptibility of CHD and ethnic differences between Asians and Caucasians.

Lower ADD1 gene promoter DNA methylation increases the risk of essential hypertension.

The goal of our study is to investigate the contribution of promoter DNA methylation of α-adducin (ADD1) gene to the risk of essential hypertension (EH). Using the bisulphite pyrosequencing technology, DNA methylation levels of five CpG dinucleotides on ADD1 promoter were measured among 33 EH cases and 28 healthy controls. Significantly higher ADD1 DNA methylation levels were observed in the females than in the males (CpG1: P = 0.016; CpG2-5: P = 0.021). A breakdown analysis by gender showed that lower CpG1 methylation was associated with an increased risk of EH in females (adjusted P = 0.042). A much more significant association between lower CpG2-5 methylation levels and the increased risk of EH was found in males (adjusted P = 0.008). CpG1 methylation was inversely correlated with age in females (r = -0.407, P = 0.019) but not in males. ADD1 CpG1 and CpG2-5 methylation levels were significantly lower in post-menopausal (>50 years) women than pre-menopausal (≤50 years) women (CpG1: P = 0.006; CpG2-5: P = 0.034). A significant interaction between CpG1 methylation and age was found in females (CpG1*age: P = 0.029). CpG2-5 methylation was shown as a significant predictor of EH in males [area under curve (AUC) = 0.855, P = 0.001], in contrast that CpG1 methylation was a trend toward indicator in females (AUC = 0.699, P = 0.054). In addition, significant differences were observed between males and females for alanine aminotransferase (ALT, P = 0.001), aspartate aminotransferase (AST, P = 0.005) and uric acid (P<0.001). The concentration of AST was inversely correlated with ADD1 CpG2-5 methylation levels in female controls (r = -0.644, P = 0.024). These observations may bring new hints to elaborate the pathogenesis of EH.

Positive correlation between variants of lipid metabolism­related genes and coronary heart disease.

Four gene variants related to lipid metabolism (including the rs562338 and rs503662 variants of the APOB gene, the rs7767084 variant of the LPA gene and the rs2246942 variant of the LIPA gene) have been shown to be associated with coronary heart disease (CHD). The aim of the present study was to assess their association with CHD in the Han Chinese population and to assess the contribution of these gene variants to CHD. Using the standardized coronary angiography method, we enrolled 290 CHD patients and 193 non-CHD patients as non-CHD controls from Lihuili Hospital (Ningbo, China). In addition, we recruited 330 unrelated healthy volunteers as healthy controls from the Xi Men Community (Ningbo, China). Our results demonstrated that the rs503662 and rs562338 variants of the APOB gene were extremely rare in the Han Chinese population (minor allele frequency <1%). Genotype rs2246942-GG of the LIPA gene was associated with an increased risk of CHD [CHD cases versus healthy controls: P=0.04; odds ratio (OR)=1.63; 95% confidence interval (CI)=1.02-2.60). Genotype rs7767084-CC of the LPA gene was identified as a protective factor against CHD in females (CHD cases versus non-CHD controls: P=0.04, OR=0.21; CHD cases versus healthy controls: P=0.02, OR=0.21). The results of our meta-analysis indicated that rs7767084 was not associated with a high risk of CHD (P=0.83; combined OR=0.93; 95% CI=0.47-1.85). In the present study, two single nucleotide polymorphisms (SNPs) of genes involved in lipid metabolism (rs2246942 and rs7767084) were identified to be significantly associated with CHD in the Han Chinese population. Specifically, rs2246942-GG of the LIPA gene was a risk factor for CHD, while rs7767084-CC of the LPA gene was a protective factor against CHD in females. However, our meta-analysis indicated that rs7767084 is not associated with a higher risk of CHD.