Practical synthesis of allylic amines via nickel-catalysed multicomponent coupling of alkenes, aldehydes, and amides.

Molecules with an allylic amine motif provide access to important building blocks and versatile applications of biologically relevant chemical space. The need for diverse allylic amines requires the development of increasingly general and modular multicomponent reactions for allylic amine synthesis. Herein, we report an efficient catalytic multicomponent coupling reaction of simple alkenes, aldehydes, and amides by combining nickel catalysis and Lewis acid catalysis, thus providing a practical, environmentally friendly, and modular protocol to build architecturally complex and functionally diverse allylic amines in a single step. The method is remarkably simple, shows broad functional-group tolerance, and facilitates the synthesis of drug-like allylic amines that are not readily accessible by other methods. The utilization of accessible starting materials and inexpensive Ni(ii) salt as the alternative precatalyst offers a significant practical advantage. In addition, the practicality of the process was also demonstrated in an efficient, gram-scale preparation of the prostaglandin agonist.

Ketone α-alkylation at the more-hindered site.

Control of the regioselectivity of α-alkylation of carbonyl compounds is a longstanding topic of research in organic chemistry. By using stoichiometric bulky strong bases and carefully adjusting the reaction conditions, selective alkylation of unsymmetrical ketones at less-hindered α-sites has been achieved. In contrast, selective alkylation of such ketones at more-hindered α-sites remains a persistent challenge. Here we report a nickel-catalysed alkylation of unsymmetrical ketones at the more-hindered α-sites with allylic alcohols. Our results indicate that the space-constrained nickel catalyst bearing a bulky biphenyl diphosphine ligand enables the preferential alkylation of the more-substituted enolate over the less-substituted enolate and reverses the conventional regioselectivity of ketone α-alkylation. The reactions proceed under neutral conditions in the absence of additives, and water is the only byproduct. The method has a broad substrate scope and permits late-stage modification of ketone-containing natural products and bioactive compounds.

Anti-cyclic citrullinated peptide antibody predicts the development of rheumatoid arthritis in patients with undifferentiated arthritis.

BACKGROUND: Clinical outcomes of undifferentiated arthritis (UA) are diverse, and only 40% of patients with UA develop rheumatoid arthritis (RA) after 3 years. Discovering predictive markers at disease onset for further intervention is critical. Therefore, our objective was to analyze the clinical outcomes of UA and ascertain the predictors for RA development. METHODS: We performed a prospective, multi-center study from January 2013 to October 2016 among Chinese patients diagnosed with UA in 22 tertiary-care hospitals. Clinical and serological parameters were obtained at recruitment. Follow-up was undertaken in all patients every 12 weeks for 2 years. Predictive factors of disease progression were identified using multivariate Cox proportional hazards regression. RESULTS: A total of 234 patients were recruited in this study, and 17 (7.3%) patients failed to follow up during the study. Among the 217 patients who completed the study, 83 (38.2%) patients went into remission. UA patients who developed RA had a higher rheumatoid factor (RF)-positivity (42.9% vs. 16.8%, χ = 8.228, P = 0.008), anti-cyclic citrullinated peptide (CCP) antibody-positivity (66.7% vs. 10.7%, χ = 43.897, P < 0.001), and double-positivity rate of RF and anti-CCP antibody (38.1% vs. 4.1%, χ = 32.131, P < 0.001) than those who did not. Anti-CCP antibody but not RF was an independent predictor for RA development (hazard ratio 18.017, 95% confidence interval: 5.803-55.938; P < 0.001). CONCLUSION: As an independent predictor of RA, anti-CCP antibody should be tested at disease onset in all patients with UA.

Causes of death in hospitalized patients with systemic lupus erythematosus: a 10-year multicenter nationwide Chinese cohort.

To estimate the mortality and describe the causes of death in a large multicenter cohort of hospitalized patients with SLE in China. This was a retrospective study of a nationwide SLE cohort (10 centers, 29,510 hospitalized patients) from 2005 to 2014 in China. Standardized mortality ratios (SMRs) were calculated for all death and were stratified by sex and age. Chi-square test was used to determine whether the major causes of death vary in age, sex, duration of SLE, disease activity, or medications. Comparison between dead patients and survival controls was used to identify the risk factors for mortality. Logistic regression analysis was used to evaluate the risk factors for mortality. A total of 360 patients died during the study period, accounting for 1.22%. The overall SMR was 2.13 (95% CI 1.96, 2.30), with a particularly high SMR seen in subgroups characterized by younger age. Infection (65.8%) was the most common cause of death, followed by lupus nephritis (48.6%), hematological abnormality (18.1%), neuropsychiatric lupus/NPSLE (15.8%), and interstitial pneumonia (13.1%). Cardiovascular disease and malignancy contributed little to the causes of death. Infection, in particular severe pulmonary infection, emerged as the foremost risk factor for mortality, followed by lupus encephalopathy. However, lupus nephritis and hematological abnormalities occurred more frequently in survival patients. SLE patients at a younger age of diagnosis have a poorer prognosis. Infection dominated the causes of death in recent China. Ethnicity and medications might account for the differences in causes of death compared with western populations.

Efficacy and safety of loxoprofen hydrogel patch versus loxoprofen tablet in patients with knee osteoarthritis: a randomized controlled non-inferiority trial.

This study is aimed at comparing the efficacy and safety of loxoprofen sodium hydrogel patch (LX-P) with loxoprofen sodium tablet (LX-T) in patients with knee osteoarthritis (OA). One hundred sixty-nine patients were enrolled in a randomized, controlled, double-blind, double-dummy, multicenter, non-inferiority trial of LX-P. Patients were randomly assigned to either LX-P or LX-T groups for a 4-week treatment. The primary efficacy endpoint was the proportion of patients with an overall improvement of ≥50%, and the secondary efficacy endpoint was the proportion of patients with an improvement of ≥25% from baseline in each of the seven main symptoms. The non-inferiority trial was based on a power of 80% and significance level of 2.5% with a non-inferiority margin of -10%. In both intention-to-treat (ITT) and per-protocol (PP) analyses, LX-P was as effective as LX-T in regard to the primary endpoint. In the ITT analysis, the difference between the two groups was 12.6% [95% confidence interval, -1.7 to 26.9%]. No significant differences were found between the two groups in any of the secondary efficacy outcomes. A lower incidence of adverse events was observed in LX-P group; however, the difference was not statistically significant. No serious adverse events were reported in the LX-P group, whereas one case was reported in LX-T group. Based on the present study, topical loxoprofen patch was non-inferior to oral loxoprofen in patients with knee osteoarthritis.

Primary Sjögren syndrome in Han Chinese: clinical and immunological characteristics of 483 patients.

The epidemiological characteristics of Sjögren syndrome (SS) are significantly varied in different countries. We conducted the present study to survey the epidemiological characteristics of primary SS in China. We recruited 483 primary SS patients from 16 Chinese medical centers nationwide from January 2009 to November 2011 and assessed salivary and lacrimal gland dysfunction, organ involvement, and autoimmunity in these patients. The cohort included 456 women and 27 men (ratio, 17:1; mean age at onset, 42 ±â€Š11 years; median age at diagnosis, 49 years; range, 41-56 years). Male patients showed a lower frequency of xerophthalmia (37.0% vs 60.7%) and a higher frequency of arthritis (40.7% vs 16.4%). Young-onset patients showed a higher frequency of low C3 levels (57.7% vs 36.3%) and pancytopenia (22.2% vs 8.8%). Patients with systemic involvement had a higher frequency of immunoglobulin A (IgA) (39.4% vs 22.5%) and immunoglobulin M (IgM) (12.4% vs 37.9%). Patients with pulmonary involvement had a higher parotid enlargement (21.4% vs 10.2%), purpura (12.1% vs 5.7%) and higher anti-La/SS-B (61.7% vs 41.8%), immunoglobulin G (IgG) (80.7% vs 64.6%) and IgA (48.9% vs 30.6%) levels. Patients with anti-Ro/SSA antibodies had more frequent exocrine gland symptoms and some extraglandular symptoms and immunological alterations. Compared with previous studies performed in other countries, SS patients in China showed particular clinical manifestation, systemic involvement, and immunological alterations.

Serum nerve grow factor and brain-derived neurotrophic factor profiles in Sjögren's syndrome concomitant with interstitial lung disease.

The aim of this study is to investigate the serum levels and clinical significance of nerve grow factor (NGF) and brain-derived neurotrophic factor (BDNF) in Sjogren's syndrome (SS) with interstitial lung disease (ILD). Fifty two untreated patients with SS were enrolled in the study. Of them, 25 patients only displayed salivary glands damage and/or lacrimal gland injury (simple SS group). The other 27 patients were lacrimal and/or salivary gland involvement as well as being concomitant only with intestinal lung disease (ILD group). Twenty-five serum samples from healthy volunteers were examined as controls. We measure serum NGF and BDNF levels by ELISA and correlate them with clinical data. Serum NGF levels were significantly higher in ILD patients (372 ± 129 pg/ml) and simple SS patients (293 ± 72 pg/ml) when compared with healthy controls (187 ± 47 pg/ml) (both p < 0.01). Significant difference were also found between the two patient groups (p < 0.01). In contrast, BDNF were significantly decreased in ILD patients (1,005 ± 143 pg/ml) when compared with either simple SS patients (1,204 ± 176 pg/ml, p < 0.01) or healthy controls (1,217 ± 155 pg/ml, p < 0.01). Correlation analysis showed NGF levels in ILD patient were positively correlated with serum levels of C-reactive protein and IgG (both p < 0.05). The abnormal NGF and BDNF in sera may be a potential character of ILD secondary to pSS.

[Clinical study of total glucosides of paeony in patients with systemic lupus erythematosus].

OBJECTIVE: To study the therapeutic efficacy and adverse reaction of total glucosides of paeony (TGP, extracted from Paeonia lactiflora Pall.) in patients with systemic lupus erythematosus (SLE). METHODS: Clinical data of patients with SLE were analyzed. Those who orally took TGP continuously for five years or more were taken as TGP1 group (29 cases). Those who orally took TGP continuously or intermittently for more than one year but less than five years were taken as TGP2 group (47 cases). Twenty patients matched with the TGP1 group and the TGP2 group in age, affected duration, urine protein, and SLE disease activity index (SLEDAI) were selected as the control group. The average daily dose of prednisone, total cyclophosphamide (CTX) dose, urine protein, SLEDAI score, recurrent case, and episodes of infection were compared among the three groups after five-year treatment. RESULTS: The average daily dose of prednisone, total CTX dose, and SLEDAI score were obviously lower in the TGP1 group than in the control group (P<0.01). The average daily dose of prednisone, total CTX dose, and SLEDAI score were obviously lower in the TGP1 group than in the TGP2 group, Significant difference was shown (P <0. 05). The average daily dose of prednisone and total CTX dose were lower in the TGP2 group than in the control group (P<0.05, P<0.01). There was no statistical difference in the urine protein among the three groups. As for the recurrence, one case occurred in the TGP1 group, nine in the TGP2 group, and seven in the control group. As for episodes of infection, there were three cases in the TGP1 group, seventeen in the TGP2 group, and eighteen in the control group during the five years. No adverse reaction correlated to TGP was found in the three groups. CONCLUSIONS: TGP had definite therapeutic efficacy in treatment of patients with SLE. It could reduce the average daily dose of prednisone and the total CTX dose, lower the recurrent cases and episodes of infection, especially for the medication of more than five years.

[The effect of secondary lymphoid tissue chemokine and its receptor on chemotaxis of peripheral blood lymphocytes in the patients with Sjögren's syndrome].

AIM: To investigate the effect of secondary lymphoid tissue chemokine (SLTC) and its receptor CCL21/CCR7 on chemotaxis of peripheral blood lymphocytes in the patients with Sjögren's syndrome (SS) and explore their roles in the SS pathogenesis. METHODS: Thirty-one SS patients were selected, including 18 primary SS patients (pSS) and 13 secondary SS (sSS) patients. In addition, 20 healthy persons were selected as normal controls. Peripheral blood lymphocytes were isolated from all the SS patients and normal controls. The cell trans-membrane test with 24-well transwells was used to detect the effect of CCL21/CCR7 on the lymphocyte migration. RESULTS: In the presence of CCL21, the chemotactic indexes (CIs) of lymphocytes from pSS and sSS patients were 2.92±0.12 and 2.80±0.28, respectively. Both of them were significantly higher than that of normal controls (CI=1.32±0.11, P<0.01), while there was no difference between pSS and sSS patients. After anti-CCR7 mAb pretreatment, the lymphocyte CIs of pSS and sSS patients respectively, decreased significantly to 1.04±0.05 and 1.03±0.08 as compared with untreated controls. CONCLUSION: CCR7 is the one of the important factors resulting in lymphocyte migration. CCL21/CCR7 interaction mediates the migration of peripheral lymphocytes in SS patients and may be involved in the gland damage due to the infiltration of massive lymphocytes in exocrine glands in SS patients.

Vascular endothelial growth factor gene polymorphisms and rheumatoid arthritis.

OBJECTIVE: To investigate polymorphisms of the vascular endothelial growth factor (VEGF) gene in patients with rheumatoid arthritis (RA) and their relationship to clinical features. METHOD: A total of 198 unrelated Chinese individuals were enrolled in this study, including 98 patients with RA and 100 healthy controls. Eight different polymorphisms of the VEGF gene were analyzed using Sequenom MassArray platform. RESULT: All 8 polymorphisms were in Hardy-Weinberg equilibrium in controls. The frequencies of rs833070 A allele and rs325010 C allele were elevated in the patients with RA compared with the controls. There were increased genotype frequencies in GA of rs833070, GC of rs3025030, CT of rs3025039 and decreased genotype frequencies in GG of rs833070, GG of rs3025030, CC of rs3025039 in the patients with RA compared with the controls. The frequencies of haplotype GA in rs2010963 and rs833070 were higher in the patients with RA than in the controls. There was no significant difference in the genotype or allele frequencies in the RA group sorted by complications, serum markers, or age of onset. CONCLUSION: Our data suggested a trend of association between VEGF gene polymorphisms and RA, and patients who carried the haplotype GA of rs2010963 and rs833070 were more susceptible to RA. Our study was performed in a small population, and further studies in other populations are needed to confirm these results.

[The expression of TWEAKR/Fn14 in Rheumatoid arthritis fibroblast-like synoviocytes].

AIM: To investigate the mechanism of TWEAK on Rheumatoid arthritis fibroblast-like synoviocytes (RA FLS) activation and articular destruction by analyzing expression of TWEAKR/Fn14 on RA FLS. METHODS: FLS was co-cultured with rhTWEAK, with TNF-alpha or IL-1beta as a synergistic stimulator. Expression of TWEAKR/Fn14 protein on RA FLS was detected by Immunocytochemistry and Western blotting. The fn14 mRNA was measured by RT-PCR. RESULTS: TWEAKR/Fn14 was expressed on the cell membrane and in the cytoplasm of RA FLS. TWEAKR/Fn14 mRNA and protein induced by 100 microg/L TWEAK were higher than the control group. TNF-alpha and IL-1beta had synergistic effect on expression of TWEAKR/Fn14 in RA FLS. CONCLUSION: TWEAKR/Fn14 was expressed on the cell membrane and in the cytoplasm of RA FLS, and recombinant TWEAK further enhanced the TWEAKR/Fn14 expression. TNF-alpha and IL-1beta had synergistic effect on the biological activity of TWEAK by increasing the expression of TWEAKR/Fn14 on RA FLS.

[Effects of TWEAK on the synthesis of MMP-3 in fibroblast-like synoviocytes of rheumatoid arthritis].

AIM: To investigate the effects of TWEAK on the synthesis of MMP-3 in RA FLS at different concentrations and to discuss the relative mechanism of how TWEAK involves in the destruction of articular bone and cartilage. METHODS: RA FLS were primarily cultured and stimulated with TWEAK. ELISA was used to detect the concentration of MMP-3 in cell-cultured fluid. The gene mRNA expression of MMP-3 was measured by RT-PCR. RESULTS: The level of MMP-3 induced by TWEAK at 50 and 100 microg/L was higher than that in control group, which had significant statistic difference (P<0.05).The expression level of MMP-3mRNA induced by TWEAK at 100 microg/L was 1.26 times higher than that in the control group, which had significant statistic difference (P<0.05).TNF-alpha and IL-1beta had synergetic effect on the synthesis and mRNA expression of MMP-3. The level in the synergetic group was significantly higher than that in the simple TWEAK group , which had significant statistic difference (P<0.05). CONCLUSION: TWEAK can induce RA FLS to synthesize MMP-3 and damage the articular bone and cartilage directly. TNF-alpha, IL-1beta and TWEAK had synergetic effects during the synthesis of MMP-3 in RA FLS.

[Clinical observation of Shuxuetong Injection in treating patients with active rheumatoid arthritis].

OBJECTIVE: To observe the efficacy and adverse reaction of Shuxuetong Injection (SXTI, the extracted liquor from Pheretima and Hirudo) in treating patients with active rheumatoid arthritis (RA). METHODS: Ninety-seven patients with active RA assigned in the SXTI group were treated with high or low dose SXTI (6 mL/d or 8 mL/d) combined with conventional therapy and the 30 in the control group treated with conventional therapy alone. Thompson index, Ritchie index, time of morning stiffness (TMS), erythrocyte sedimentation rate (ESR) and plasma fibrinogen (Fib) in patients were determined before treatment (T0), by the end of the 1st (T1), second (T2) and 4th (T3) week of treatment, respectively, as well as the SXTI associated adverse reaction monitored. RESULTS: Marked improvement of all indexes, including Thompson index, Ritche index, TMS, ESR and Fib, was shown in the SXTI groups at T1 (P < 0.01), but in the control group, it only appeared at T3 (P < 0.01). Compared with the control group, TMS, ESR and Fib at T1, Thompson index and Ritche index at T2 in the SXTI groups were significantly improved (P < 0.01), especially significant in the high dose group (P < 0.01). However, hands edema appeared in 2 patients, foot edema in 1 and fullness sensation of head in 1 in the high dose SXTI group. The dose was forced to redue to 6 mL/d, and then all the symptoms were improved. CONCLUSION: SXTI shows good efficacy with less adverse reaction in treating patients with active RA, and better efficacy was obtained at the dose of 8 mL/d.

[Clinical observation on effect of total glucosides of paeony in treating patients with non-systemic involved Sjögren syndrome].

OBJECTIVE: To investigate the efficacy and adverse reaction of total glucosides of paeony (TGP) in treating patients with non-systemic involved Sjögren syndrom (NSI-SS). METHODS: Retrospective study was conducted on 27 patients with NSI-SS who received TGP treatment for over two years as the TGP group, and 20 patients received hydroxychloroquine sulfate (HCQs) for over two years in the HCQs group for positive control. Salivary flow, Schirmer's test and serum gamma-globulin at different time points, i.e. before treatment, and at the end of 1st, 3rd, 6th, 12th and 24th month respectively, were compared between groups, and adverse reactions associated with TGP and HCQ were also observed. RESULTS: In the TGP group, saliva secretion was significantly increased and serum gamma-globulin decreased significantly from the 6th month (P <0.01), Schirmer's test improved significantly after 12 months (P< 0.01). While in the HCQs group serum gamma-globulin was significantly decreased from the 3rd month (P <0.01), saliva secretion and Schirmer's test improved significantly after six months (P<0.01). However, the 3 indexes determined at the end of the 3rd month were insignificantly different from those before treatment. Mild diarrhea occurred in 4 cases in the TGP group, they were improved two weeks later, but one case with severe diarrhea was dropped. While in the HCQs group, 2 patients were dropped, one for the raising of alanine aminotransferase at the 6th month and the other for decreased vision at the 9th month. CONCLUSION: Efficacy of TGP is equivalent to that of HCQs in treating NSI-SS, but with higher safety and the effect initiating time being about 6 - 12 months.

[Effect of neutralizing anti-VEGF antibody on genesis of murine type II collagen-induced arthritis].

AIM: To understand the effect of neutralizing anti-vascular endothelial growth factor (VEGF) antibody on the genesis of murine type II collagen (CO II)-induced arthritis (CIA). METHODS: mice DBA/1J (8-10 weeks) were given intradermal injection chick tape II collagen to set up the murine CIA model. The incidence of CIA and arthritis index were measured and the pathologic changes of articular tissue were observed after the injection of neutralizing anti-VEGF antibody. RESULTS: The anti-VEGF antibody could notably inhibit the genesis and severity of arthritis (P<0.05) at the early stage of CIA formation; while it made no difference after CIA was completely formed. CONCLUSION: Anti-VEGF neutralizing antibody can significantly inhibit synovial fibroblast proliferation, neovascularization and angeitis genesis, which made it a promising agent for RA treatment.

[A study of susceptibility genes mapping for aberrant B1 cell proliferation in New Zealand mice].

OBJECTIVE: To map the susceptibility genes for aberrant B1 cell proliferation in New Zealand mice. METHODS: New Zealand Black (NZB) x New Zealand White (NZW) F1 x NZW backcross mice model was set up and polymorphic microsatellite markers and quantitative trait locus (QTL) analysis was used. RESULTS: Susceptibility genes of aberrant B1 cell proliferation was linked to the microsatellite markers on chromosome 1, 4, 19 in NZB and on chromosome 17 in NZW such as D1Mit115, D4Mit58, D19Mit73 and D17Mit61 nearby which there existed Fcgr2b, c-jun, Fas and tumor necrosis factor (TNF)alpha, H-2 genes according to the QTL analysis. CONCLUSION: B1 cell proliferation in New Zealand mice was controlled by multiple genes and the candidate susceptibility genes were Fcgr2b, c-jun, Fas derived from NZB strain and TNF alpha, H-2 genes derived from NZW strain.