Synthesis and Structural Revision of a Natural Tetrasaccharide from Starfish Asterias rollestoni Bell.

Starfish provide important saponins with diverse bioactivities as the secondary metabolites, among which 2-O-glycosylated glycosides are commonly found. Preparation of those 1,2-trans 2-O-glycosylated glycosides usually relies on 2-O-acyl participation requiring the selective installation and cleavage of 2-O-acyl groups. A convergent synthesis using 2-O-glycosylated oligosaccharide donors would be more straightforward but also pose greater challenges. Herein, we report a convergent synthesis of a distinctive tetrasaccharide isolated from starfish Asterias rollestoni Bell. Dual 2-(diphenylphosphinoyl)acetyl (DPPA) groups at O3 and O4 on galactose moiety led to high ß-selectivities (ß/α=12/1 or ß only) in the challenging [2+2] glycosylation, giving the desired tetrasaccharides in >90 % yields from the 2-O-glycosylated disaccharide donors. These synthetic studies have also unambiguously revised the structure of these natural tetrasaccharides. This work would facilitate further studies on new inhibitors of α-glucosidase as hypoglycemic drugs.

Safety and effectiveness of oral medium to high dose blonanserin in patients with schizophrenia: subgroup analysis from a prospective, multicenter, post-marketing surveillance study in mainland China.

BACKGROUND: Blonanserin (BNS) had been undergoing post-market surveillance (PMS) since September 2018. Using the surveillance data, we did this analysis to assess the safety and effectiveness of different doses of BNS to explore a sufficient dose range of BNS in Chinese patients with schizophrenia (SZ). METHODS: A 12-week, prospective, observational, single-arm, multicenter, open-label PMS was conducted. In this analysis, we divided the patients from PMS into low, medium to high, and high dose groups based on the dose of BNS they received, with medium to high dose group being the focus. The Brief Psychiatric Rating Scale (BPRS) scores at week 2 or 4, 6 or 8, and 12 were calculated to evaluate the effectiveness of BNS in improving psychiatric symptoms. The safety of BNS was reported as the incidence of adverse drug reactions. RESULTS: 364 patients were included in the medium to high dose group, of which 321 completed the surveillance, with a dropout rate of 11.8%. The mean daily dose was 15.1 ± 1.92 mg. The BPRS total score was 50.1 ± 11.95 at baseline and decreased to 26.6 ± 7.43 at 12 weeks (P < 0.001). When compared with other groups, the median to high dose group achieved significantly more reduction in BPRS score at week 12 (P = 0.004 versus low dose and P = 0.033 versus higher dose). Extrapyramidal symptoms [EPS (46.4%)] were the most common adverse reactions in the medium to high group. The average weight gain during the surveillance was 0.5 ± 2.56 kg and prolactin elevation occurred in 2.2% patients. Most adverse reactions were mild. CONCLUSIONS: BNS at medium to high doses (mean 15.1 mg/d) significantly improved symptoms of SZ and was well-tolerated. Most ADRs were mild, and the likelihood of causing metabolic side effects and prolactin elevations was low. Medium to high dose of BNS is a more potent treatment choice for SZ. TRIAL REGISTRATION NUMBER: ChiCTR2100048734. Date of registration: 2021/07/15 (retrospectively registered).

Effectiveness and safety of blonanserin in young and middle-aged female patients with schizophrenia: data from a post-marketing surveillance.

BACKGROUND: A post-marketing surveillance of blonanserin has been ongoing since September 2018. The aim of this study was to assess the effectiveness and safety of oral blonanserin in Chinese young and middle-aged female patients with schizophrenia in real clinical settings, using the data from the post-marketing surveillance. METHODS: A 12-week, prospective, multi-center, open-label, post-marketing surveillance was conducted. Female patients aged 18-40 years were included in this analysis. The Brief Psychiatric Rating Scale (BPRS) was used to evaluate the effectiveness of blonanserin in improving psychiatric symptoms. The incidence of adverse drug reactions (ADRs) such as of extrapyramidal symptoms (EPS), prolactin elevation and the weight gain were used to evaluate the safety profile of blonanserin. RESULTS: A total of 392 patients were included both in the safety and full analysis sets, 311 patients completed the surveillance protocol. The BPRS total score was 48.8 ± 14.11 at the baseline, decreasing to 25.5 ± 7.56 at 12 weeks (P < 0.001, compared with baseline). EPS (20.2%) including akathisia, tremor, dystonia, and parkinsonism were found as the most frequent ADRs. The mean weight gain was 0.27 ± 2.5 kg at 12 weeks from the baseline. Four cases (1%) of prolactin elevation were observed during the period of surveillance. CONCLUSION: Blonanserin significantly improved the symptoms of schizophrenia in female patients aged 18-40 years; the drug was well tolerated and had a low tendency to cause metabolic side effects, including prolactin elevation in these patients. Blonanserin might be a reasonable drug for the treatment of schizophrenia in young and middle-aged female patients.

Integrated untargeted fecal metabolomics and gut microbiota strategy for screening potential biomarkers associated with schizophrenia.

Schizophrenia (SZ) is a serious neurodevelopmental disorder. As the etiology of SZ is complex and the pathogenesis is not thoroughly understood, the diagnosis of different subtypes still depends on the subjective judgment of doctors. Therefore, there is an urgent need to develop early objective laboratory diagnostic biomarkers to screen different subtypes of patients as early as possible, and to implement targeted prevention and precision medicine to reduce the risk of SZ and improve patients' quality of life. In this study, untargeted metabolomics and 16S rDNA sequencing were used to analyze the differences in metabolites and gut microflora among 28 patients with two types of schizophrenia and 11 healthy subjects. The results showed that the metabolome and sequencing data could effectively discriminate among paranoid schizophrenia patients, undifferentiated schizophrenia patients and healthy controls. We obtained 65 metabolites and 76 microorganisms with significant changes, and fecal metabolite composition was significantly correlated with the differential genera (|r|>0.5), indicating that there was a regulatory relationship between the gut microbiota and the host metabolites. The gut microbiome, as an objective and measurable index, showed good diagnostic value for distinguishing schizophrenia patients from healthy people, especially with a combination of several differential microorganisms, which had the best diagnostic effect (AUC>0.9). Our results are conducive to understanding the complicated metabolic changes in SZ patients and providing valuable information for the clinical diagnosis of SZ.

Safety and Effectiveness of Blonanserin in Chinese Patients with Schizophrenia: An Interim Analysis of a 12-Week Open-Label Prospective Multi-Center Post-marketing Surveillance.

Schizophrenia is an unexplained, complex and serious mental illness. Blonanserin (BNS) is a new antipsychotic drug widely used in the treatment of schizophrenia. However, large-scale clinical studies have not been conducted in China. A multi-center, prospective, open-label, 12-week surveillance was carried out to evaluate the safety and effectiveness of BNS in patients with schizophrenia in China. Safety assessments included adverse drug reactions (ADRs), extrapyramidal symptoms (EPS), akathisia, concomitant medications for EPS by the end of treatment, and the changes in body weight from baseline by the end of treatment. The effectiveness was evaluated by the Brief Psychiatric Rating Scale (BPRS). From September 2018 to May 2020, of the 1,060 patients enrolled, 1,018 were included in the full analysis set (FAS) and safety set (SS), respectively. ADRs were developed in 205 patients among the included, the incidence being 20.1%. ADRs of EPS occurred in 169 patients, the incidence being 16.6%, ADRs of akathisia occurred in 90 patients, the incidence being 8.8%; concomitant therapeutic and prophylactic agents for EPS accounts for 19.2%; 4.0% of patients had a ≥7% increase in body weight from baseline at 12 weeks after initiating treatment. Using the last-observation-carried-forward (LOCF) method, the changes in total BPRS scores were -11.2 ± 10.17 (N = 1,018), -16.8 ± 12.69 (N = 1,018) and -20.6 ± 13.99 (N = 1,018) after 2/4, 6/8, or 12 weeks, respectively. 53.5% (545/1,018) patients showed response to blonanserin treatment in week 12. The post-marketing surveillance results of BNS demonstrates safety profile and effectiveness of the drug.

Direct Synthesis of 2,6-Dideoxy-ß-glycosides and ß-Rhamnosides with a Stereodirecting 2-(Diphenylphosphinoyl)acetyl Group.

Anomeric stereocontrol is usually one of the major issues in the synthesis of complex carbohydrates, particularly those involving ß-configured 2,6-dideoxyglycoside and d/l-rhamnoside moieties. Herein, we report that 2-(diphenylphosphinoyl)acetyl is highly effective as a remote stereodirecting group in the direct synthesis of these challenging ß-glycosides under mild conditions. A deoxy-trisaccharide as a mimic of the sugar chain of landomycin E was prepared stereospecifically in high yield. The synthetic potential was also highlighted in the synthesis of Citrobacter freundii O-antigens composed of a [→4)-α-d-Manp-(1→3)-ß-d-Rhap(1→4)-ß-d-Rhap-(1→] repeating unit, wherein the convergent assembly up to a nonasaccharide was realized with a strongly ß-directing trisaccharide donor. Variable-temperature NMR studies indicate the presence of intermolecular H-bonding between the donor and the bulky acceptor as direct spectral evidence in support of the concept of hydrogen-bond-mediated aglycone delivery.

More than a Leaving Group: N-Phenyltrifluoroacetimidate as a Remote Directing Group for Highly α-Selective 1,2-cis Glycosylation.

The anomeric configuration can greatly affect the biological functions and activities of carbohydrates. Herein, we report that N-phenyltrifluoroacetimidoyl (PTFAI), a well-known leaving group for catalytic glycosylation, can act as a stereodirecting group for the challenging 1,2-cis α-glycosylation. Utilizing rapidly accessible 1,6-di-OPTFAI glycosyl donors, TMSOTf-catalyzed glycosylation occurred with excellent α-selectivity and broad substrate scope, and the remaining 6-OPTFAI group can be cleaved chemoselectively. The remote participation of 6-OPTFAI is supported by the first characterization of the crucial 1,6-bridged bicyclic oxazepinium ion intermediates by low-temperature NMR spectroscopy. These cations were found to be relatively stable and mainly responsible for the present stereoselectivities. Further application is highlighted in glycosylation reactions toward trisaccharide heparins as well as the convergent synthesis of chacotriose derivatives using a bulky 2,4-di-O-glycosylated donor.

MAD1L1 and TSNARE gene polymorphisms are associated with schizophrenia susceptibility in the Han Chinese population.

BACKGROUND: Schizophrenia (SCZ) is a severe mental illness with high heritability. This study aimed to explore the correlation between MAD1L1, TSNARE polymorphisms and SCZ susceptibility. METHODS: A total of 493 SCZ patients and 493 healthy controls were included. The genotypes of MAD1L1 and TSNARE polymorphisms were identified by Agena MassARRAY platform. Odds ratio (OR) and 95% confidence intervals (CIs) were tested via logistic regression analysis in multiple genetic models and different subgroups. RESULTS: We observed that AG genotype of rs1107592, AG genotype of rs4976976, and CA genotype of rs67756423 decreased the susceptibility to SCZ (p < 0.05). Age stratification analysis showed that the TC genotype of rs12666575, AG genotype of rs1107592, and AG genotype of rs4976976 decreased the risk of SCZ individuals older than 36 years (p < 0.05). In addition, the AG and AA genotype of rs4976976, the CA genotype of rs67756423 were associated with a lower risk of SCZ in males (p < 0.05). In females, the TT genotype of rs12666575 in recessive model, the AG and AA-AG genotype of rs1107592 in heterozygote and dominant model, could reduce the susceptibility to SCZ (p < 0.05). However, no significant association was found after Bonferroni correction. CONCLUSIONS: Our results suggest that MAD1L1 and TSNARE genetic polymorphisms exert a protective role in the risk of SCZ. These findings provide evidence that MAD1L1 and TSNARE may serve as potential biomarkers of SCZ. However, a replication experiment in a cohort with large sample size are required to confirm our findings. Trial registration Not applicable.

Evaluation of the relationship between VRK2, rs4380187 polymorphisms, and genetic susceptibility to schizophrenia in the Chinese Han population.

BACKGROUND: Schizophrenia (SZ) is a serious hereditary mental disease with a low recovery rate, especially due to the lack of understanding about the cause of the disease. VRK2 is considered to be related to the pathogenesis of schizophrenia. In this study, we analyzed the correlation between VRK2, rs4380187 single-nucleotide polymorphism (SNP), and schizophrenia. METHODS: Peripheral blood DNA was extracted using a genomic DNA extraction kit. The DNA samples were genotyped using the Agena MassARRAY platform, and four genetic models were applied to compute the odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. The p value was obtained by the chi-square and t test for independent samples. RESULTS: The C allele of rs4380187 SNP was significantly (p = 0.008) associated with decreased risk of SZ. The AA genotype of rs4380187 showed significantly (p = 0.009) lower frequency in cases with SZ than in controls and was associated with decreased risk of the disease. The frequency of the CA genotype of rs4380187 correlated with a 0.73-fold decreased risk of SZ (p = 0.033). In the co-dominant genetic model, the genotype of rs4380187 was associated with a decreased risk of SZ (p = 0.010). We also found that the log-additive model of rs4380187 significantly reduced the risk of SZ disease (p = 0.007). CONCLUSION: This study provides further evidence that rs4380187 SNP is associated with SZ. This genotype variation could be associated with the psychopathology and cognitive function in SZ.

Impact of CHRNA5 polymorphisms on the risk of schizophrenia in the Chinese Han population.

BACKGROUND: Schizophrenia is a complex mental disease whose cause is still unknown. Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in various neurological disorders, including schizophrenia. The previous reports have shown that CHRNA polymorphisms were involved in schizophrenia. This study is to explore the potential association between CHRNA5 (OMIM#118505) polymorphisms and schizophrenia susceptibility in a Chinese population. METHODS AND RESULTS: A case-control study was conducted with 384 schizophrenia patients and 687 controls. We genotyped eight single nucleotide polymorphisms (SNPs) distributed in CHRNA5. Regulome DB, HaploReg, and GTEx databases were used to calculate possible functional effects of the polymorphisms. The χ2 test, genetic model analysis, and haplotype analysis were involved in assessing genetic association between variants and schizophrenia risk. The results exhibited that rs17486278 (NC_000015.10:g.78575140A>C) was associated with a decreased risk of schizophrenia on the basis of the recessive model (adjusted OR = 0.37, 95%CI: 0.15-0.93) in females. Moreover, we found that the four variants rs588765, rs6495306, rs680244, rs692780 were extremely significant after being stratified by ≥45 years. CONCLUSIONS: Overall, our findings supported that the potential association existed between CHRNA5 polymorphisms and schizophrenia susceptibility in a Chinese population. But, large sample validation is needed to enhance the accuracy of our results.

Glycosylation of a Ketone with an O-Glycosyl Trichloroacetimidate Provides an Enol Glycoside.

An enol-type glycosylation reaction has been investigated. Enol glycosides can be obtained from the reaction between O-glycosyl trichloroacetimidates and the corresponding ketones promoted by an acid. The enol glycosides derived from cyclic ketones can be afforded efficiently and isolated in good yield, while those from acyclic ketones are prepared in low conversion or are too labile for isolation. Further studies on different glycosyl donor types indicate that only the O-glycosyl trichloroacetimidate works well as a donor for enol glycosylation.