An organophosphorus-mediated cross-Rauhut-Currier/Wittig domino reaction for the efficient synthesis of trisubstituted cyclopentenes.

An efficient organophosphorus-mediated cross-Rauhut-Currier/Wittig domino reaction of vinyl ketones with chalcones has been developed for the synthesis of trisubstituted cyclopentenes. The new synthetic method has the advantages of mild reaction conditions, high efficiency, environmental friendliness and satisfactory yields.

Chemical synthesis and functional characterization of a new class of ceramide analogues as anti-cancer agents.

Deregulation of ceramide metabolism is a hallmark of human cancer. Ceramide analogues thereby represent a new class of anti-cancer agents. We aimed at developing effective and low toxic ceramide analogues and synthesized a new class of ceramide analogues starting from l-threonine. Several analogues exhibit potent cytotoxicity against human cancer cells in vitro with IC50 as low as 4.8 µM. These ceramide analogues decreased xIAP and Bcl-xL level and exhibited significant sensitization activity to overcome human cancer cell resistance to TRAIL, a cancer-selective agent that are being tested in human clinical trials. Furthermore, we determined that these ceramide analogues effectively suppress human cancer xenograft growth in vivo with no significant toxicity at the efficacious dose. Therefore, we have developed a simple and effective method to synthesize functional ceramide analogues using l-threonine as starting material and these analogues have the great potential to be further developed as anti-cancer agents in human cancer therapy.

A cascade C-H functionalization/cyclization reaction of N-arylpyridin-2-amines with α,ß-unsaturated aldehydes for the synthesis of dihydroquinolinone derivatives under rhodium catalysis.

A novel cascade C-H functionalization/cyclization reaction of N-arylpyridin-2-amines with α,ß-unsaturated aldehydes has been developed under rhodium catalysis, affording dihydroquinolinone derivatives in moderate to excellent yields. A plausible mechanism of dual catalytic cycles by rhodium(iii) catalysis is also proposed.

Morita-Baylis-Hillman Reaction of α,ß-Unsaturated Ketones with Allylic Acetates by the Combination of Transition-Metal Catalysis and Organomediation.

An intermolecular Morita-Baylis-Hillman (MBH) reaction of α,ß-unsaturated ketones with allylic acetates under the catalysis of 10 mol % of tetrakis(triphenylphosphine)palladium(0) and mediation of tributylphosphine has been developed in the presence of acetic acid, affording the desired α-coupling products. The MBH reaction has the advantages of good tolerance to many functional groups, excellent regioselectivity and E-stereoselectivity, and moderate to good yields.

Domino Reactions Containing Different Types of Heck Reactions for Selective 3,3- and 1,3-Diarylations of Propenol with Aryl Halides by Triple Catalysis.

A new domino Heck-isomerization/Saegusa/Heck reaction of propenol with aryl iodides has been developed for the synthesis of 3,3-diaryl propenals by triple transition-metal catalysis. Moreover, we also developed the domino Heck-isomerization/Heck-type reaction of propenol with aryl iodides for the synthesis of 1,3-diaryl propanones by double transition-metal catalysis and the mediation of secondary amine or triple transition metal catalysis and aminocatalysis.

A dehydrogenative cross-coupling reaction between aromatic aldehydes or ketones and dialkyl H-phosphonates for formyl or acylphenylphosphonates.

A novel DCC reaction between aromatic aldehydes or ketones and H-phosphonates has been developed for the synthesis of p-formyl or p-acylphenylphosphonates. The synthetic method has excellent para regioselectivities, good yields, and broad substrate scopes and is more benign to the environment. The DCC reaction also tolerates many functional groups, and results in a series of new p-formyl and p-acylphenylphosphonates, which should be important building blocks for the synthesis of versatile arylphosphonate derivatives.

Copper-catalyzed dehydrogenative cross-coupling reaction between allylic C-H bonds and α-C-H bonds of ketones or aldehydes.

A dehydrogenative cross-coupling reaction between allylic C-H bonds and the α-C-H bond of ketones or aldehydes was developed using Cu(OTf)2 as a catalyst and DDQ as an oxidant. This synthetic approach to γ,δ-unsaturated ketones and aldehydes has the advantages of broad scope for both ketones and aldehydes as reactants, mild reaction conditions, good yields and atom economy. A plausible mechanism using Cu(OTf)2 as a Lewis acid catalyst was also proposed (DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone; Tf=trifluoromethanesulfonate).

A cascade alkylarylation reaction of 2-isocyanobiphenyls with simple alkanes for 6-alkyl phenanthridines via dual C(sp3)-H/C(sp2)-H functionalizations.

A cascade alkylarylation reaction of 2-isocyanobiphenyls with simple alkanes for 6-alkyl phenanthridines has been developed through dual C(sp(3))-H/C(sp(2))-H functionalizations. The synthetic method has the advantages of high yields, good compatibility of functional groups and mild reaction conditions, although very unreactive alkanes were involved in the reaction. A plausible mechanism through both copper-catalyzed and DTBP mediated pathways has also been proposed.

Synthesis of imides by palladium-catalyzed C-H functionalization of aldehydes with secondary amides.

An efficient palladium-catalyzed C-H functionalization of aldehydes with various N-substituted N-heteroarene-2-carboxamides has been developed for the synthesis of secondary imides. The reaction tolerates various functionalities, such as methoxy, fluoro, chloro, and bromo groups. A tentative radical mechanism for a Pd(II)/Pd(IV) catalytic cycle is proposed.

High urea induces anxiety disorders associated with chronic kidney disease by promoting abnormal proliferation of OPC in amygdala.

Chronic kidney disease (CKD) with anxiety disorder is of a great concern due to its high morbidity and mortality. Urea, as an important toxin in CKD, is not only a pathological factor for complications in patients with CKD, but also is accumulated in the brain of aging and neurodegenerative diseases. However, the pathological role and underlying regulatory mechanism of urea in CKD related mood disorders have not been well established. We previously reported a depression phenotype in mice with abnormal urea metabolism. Since patients with depression are more likely to suffer from anxiety, we speculate that high urea may be an important factor causing anxiety in CKD patients. In adenine-induced CKD mouse model and UT-B-/- mouse model, multiple behavioral studies confirmed that high urea induces anxiety-like behavior. Single-cell transcriptome revealed that down-regulation of Egr1 induced compensatory proliferation of oligodendrocyte progenitor cells (OPC). Myelin-related signaling pathways of oligodendrocytes (OL) were change significant in the urea accumulation amygdala. The study showed that high urea downregulated Egr1 with subsequent upregulation of ERK pathways in OPCs. These data indicate that the pathological role and molecular mechanism of high urea in CKD-related anxiety, and provide objective serological indicator and a potential new drug target for the prevention and treatment of anxiety in CKD patients.

Transesterification for synthesis of carboxylates using aldehydes as acyl donors via C-H and C-O bond activations.

A new type of transesterification between aryl, heteroaryl, alkyl N-heteroarene-2-carboxylates and various aldehydes by C-H and C-O bond activations has been developed for the synthesis of versatile carboxylates. A possible mechanism containing oxidative addition of acyl-O bond in parent ester and radical cleavage of sp(2) C-H bond in aldehyde is proposed.

Coupling reactions of heteroarenes with phosphites under silver catalysis.

A silver-catalyzed dehydrogenative cross-coupling reaction of substituted furans, thiophene, thioazole, and pyrrole 1a-e with dialkyl phosphites 2 was first developed to afford corresponding phosphonated products 3a-h with up to 89% yield and good regioselectivities. Moreover, an unprecedented coupling of various substituted pyridines 1f-k with dialkyl phosphites 2 using AgNO(3) as a catalyst and K(2)S(2)O(8) as an oxidant, followed by reduction with Na(2)S(2)O(3), was also realized to furnish desired pyridine phosphonates 3i-q in satisfactory yields with good regioselectivities.

Oridonin Delays Aging Through the AKT Signaling Pathway.

Aging is a major risk factor for chronic diseases and disability in humans. Nowadays, no effective anti-aging treatment is available clinically. In this study, oridonin was selected based on the drug screening strategy similar to Connectivity MAP (CMAP) but upon transcriptomes of 102 traditional Chinese medicines treated cell lines. Oridonin is a diterpenoid isolated from Rabdosia rubescens. As reported, Oridonin exhibits a variety of pharmacological activities, including antitumor, antibacterial and anti-inflammatory activities. Here, we found that oridonin inhibited cellular senescence in human diploid fibroblasts (2BS and WI-38), manifested by decreased senescence-associated ß-galactosidase (SA-ß-gal) staining. Compared with the elderly control group, the positive cell rate in the oridonin intervention group was reduced to 48.5%. Notably, oridonin prolonged the lifespan of yeast by 48.9%, and extended the average life span of naturally aged mice by 21.6%. Our mice behavior experiments exhibited that oridonin significantly improved the health status of naturally aged mice. In addition, oridonin also delayed doxorubicin-induced cellular senescence and mouse senescence. Compared with the model group, the percentage of SA-ß-gal positive cells in the oridonin treatment group was reduced to 59.8%. It extended the average lifespan of mice by 53.8% and improved healthspan. Mechanistically, we showed that oridonin delayed aging through the AKT signaling pathway and reversed the genetic changes caused by doxorubicin-induced cell senescence. Therefore, oridonin is a potential candidate for the development of anti-aging drugs.

3,5-Dimethyl-H-furo[3,2-g]chromen-7-one as a potential anticancer drug by inducing p53-dependent apoptosis in human hepatoma HepG2 cells.

BACKGROUND/AIMS: Coumarins are natural compounds found in many plants that possess medical value by itself and its modified derivatives. METHOD: Six novel coumarin derivatives were synthesized and examined for their potential anticancer cytotoxicity. RESULT: Among the 6 derivatives, 3,5-dimethyl-(7)H-furo[3,2-g]chromen-7-one (DMFC) presented the strongest cytotoxicity against human hepatoma HepG2 cells in vitro with an IC(50) value of 8.46 ± 0.28 µM in a 48-hour treatment. Further experiments revealed that DMFC induced apoptosis in HepG2 cells through both extrinsic and intrinsic apoptotic pathways in a p53-dependent manner. Mechanistically, DMFC activated caspases 3, 8 and 9, depolarized mitochondrial membrane potential and induced cytochrome c and apoptosis-inducing factor release. DMFC-induced apoptosis was also characterized by DNA fragmentation, phosphatidylserine externalization and sub-G1 peak in DNA histograms. Moreover, both caspase 8 and 9 inhibitors suppressed the apoptosis induced by DMFC. Western blot analyses revealed that DMFC also significantly increased the expression levels of p53, Fas death receptor, Fas-associated death domain protein and proapoptotic Bcl-2 family members such as Bax, Bad and tBid, as well as decreased the levels of pro-survival members such as Bcl-2 and Bcl-xl. CONCLUSION: DMFC is potentially an effective therapeutic agent in liver cancer therapy.

Synthesis and antiproliferative activities of novel 5'-Schiff-base group substituted psoralen derivatives.

It was found that psoralen derivative could perform a Friedel-Crafts acylation smoothly with acetic anhydride to give 5'-acetylpsoralen in a 73% yield. In the presence of boron trifluoride etherate, 5'-acetylpsoralen reacted with both aromatic amines and aliphatic amine smoothly to afford 5'-Schiff-base group substituted psoralen derivatives in 72%-92% yields. The novel synthetic method has the advantages of cheap materials, mild reaction conditions, good yields and high regioselectivity in the Friedel-Crafts acylation. Cell viability assay by MTT demonstrates that some of the psoralen derivatives 6 have antiproliferative activities.

The BRD4 inhibitor JQ1 protects against chronic obstructive pulmonary disease in mice by suppressing NF-κB activation.

OBJECTIVE: To examine the effect of the BRD4 inhibitor JQ1 on mice with chronic obstructive pulmonary disease (COPD) via NF-κB. METHODS: COPD models constructed by exposure to cigarette smoke and intratracheal instillation of lipopolysaccharides (LPS) in mice were treated with JQ1 (15, 25 or 50 mg/kg). HE staining was performed to observe histopathological changes in the lung tissues. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the levels of IL-10, IFN-γ, IL-17, IL-1ß, IL-6, TNF-α, MMP-2, MMP-9, MDA, SOD, T-AOC and HO-1, and gelatin zymography assays were used to examine MMP-2 and MMP-9 activity. A TransAMTM NF-κB p65 detection kit was used to test NF-κB p65/DNA binding activity. Western blotting was conducted to analyze NF-κB p65 in the nucleus and its acetylation. RESULTS: JQ1 dose-dependently improved the histopathological changes in the lung tissues and decreased the mean linear intercept (MLI), destructive index and inflammatory score of the mice with COPD. The mice with COPD showed increased levels of MMP-2, MMP-9, IFN-γ, IL-17, IL-1ß, IL-6 and TNF-α with decreased IL-10 level; these changes were reversed by JQ1 in a dose-dependent manner. In addition, JQ1 reduced the MDA level and increased the SOD, HO-1 and T-AOC levels in mice with COPD, with suppression of NF-κB p65 expression in the nucleus, NF-κB/p65 (Lys310) acetylation and NF-κB p65/DNA binding activity in the lung tissues. CONCLUSION: The BRD4 inhibitor JQ1 can downregulate MMP-2 and MMP-9 expression, reduce inflammatory responses, and alleviate oxidative stress in mice with COPD, and this mechanism might be related to the inhibition of NF-κB.

Cleavage factor Im 25 as a potential biomarker for prognosis of colorectal cancer.

BACKGROUND: Cleavage factor Im 25 (CFIm25) affects the prognosis and progression of cancer by regulating alternative polyadenylation; however, its role in colorectal cancer remains unclear. METHODS: A standard EnVision tissue microarray was used to evaluate the expression of CFIm25 by immunohistochemistry in 363 patients with colorectal cancer. The correlation between CFIm25 expression and clinicopathological characteristics was analyzed using the χ2 test. Univariate analysis was used to study the relationship between clinicopathological characteristics and patient prognosis. Multivariate analysis was performed using the Cox regression model to identify independent prognostic factors for patients with colorectal cancer. RESULTS: Statistical analysis revealed that CFIm25 expression was significantly associated with vascular invasion (P=0.000), serous invasion (P=0.007), pT stage (P=0.016), and clinical stage (P=0.007). Age, vascular invasion, nerve invasion, serosal invasion, differentiation, clinical stage, recurrence, and CFIm25 expression were significantly correlated with the survival time of colorectal cancer patients (P<0.05). The mean overall survival rate in colorectal cancer patients with decreased CFIm25 expression was only 88.53 months, compared with 110.69 months in the high expression group (P=0.000). Decreased CFIm25 expression indicated a worse prognosis in patients with colorectal cancer. Further analysis by the Cox multivariate model showed that CFIm25 (HR, 0.543; 95% CI: 0.372-0.792; P=0.002) and serosa invasion (HR, 1.470; 95% CI: 1.032-2.094; P=0.033) are independent prognostic factors for colorectal cancer. CONCLUSIONS: Decreased CFIm25 expression indicates a worse prognosis of colorectal cancer patients and could be a novel target for the treatment of colorectal cancer in the future. KEYWORDS: Polyadenylation; survival analysis; colorectal cancer (CRC); CFIm25.

Ganoderic acid improves 5-fluorouracil-induced cognitive dysfunction in mice.

5-Fluorouracil (5-FU) is a chemotherapeutic drug with a good anti-cancer effect on various types of cancers, such as colorectal cancer and breast cancer. However, previous studies have found that 5-FU could induce cognitive deficit in clinics. As ganoderic acid, isolated from Ganoderma lucidum, has a protective effect on neurons, this study investigated the effects of ganoderic acid (GA) against 5-FU-induced cognitive dysfunction with a series of behavioral tests and related indicators. Experimental results showed that GA significantly prevented the reduction of spatial and non-spatial memory in 5-FU-treated mice. In addition, GA not only ameliorated the damage to hippocampal neurons and mitochondrial structure, but also significantly improved abnormal protein expression of mitochondrial biogenesis related marker PGC-1α, and mitochondrial dynamics related markers MFN2, DRP1 and FIS1 in the hippocampi of 5-FU-treated mice. Moreover, GA could up-regulate the expression of neuronal survival and growth-related proteins, such as BDNF, p-ERK, p-CREB, p-Akt, p-GSK3ß, Nrf2, p-mTOR, and p-S6, in the hippocampi of 5-FU-treated mice. These results suggest that GA could prevent cognitive dysfunction in mice treated with 5-FU via preventing mitochondrial impairment and enhancing neuronal survival and growth, which provide evidence for GA as a promising adjunctive therapy for chemotherapy related cognitive impairment in clinics.

Association between Interleukin-10 Gene Polymorphisms and Behcet's Disease Susceptibility: Evidence from a Meta-Analysis.

Epidemiological studies have demonstrated that interleukin-10 (IL-10) polymorphisms may be associated with the development of Behcet's disease (BD). However, the published results were inconsistent. Therefore, this meta-analysis was conducted to derive a more precise relationship between IL-10 polymorphisms and BD susceptibility. Online databases (PubMed, Embase, Science Citation Index (SCI), CNKI, and WanFang) were searched to identify eligible studies. Odds ratio (OR) and a 95% confidence interval (CI) were applied to assess the relationship strength between IL-10 -1082A>G (rs1800896), -819T>C (rs1800871), and -592A>C (rs1800872) polymorphisms and BD susceptibility. Publication bias, sensitivity, and cumulative analyses were conducted to measure the robustness of our findings. Finally, fifteen articles (36 independent case-control studies) involving 5,971 patients and 8,913 controls were included. Overall, significant associations between -819T>C polymorphisms and BD risk were observed in the total population (C vs. T: OR = 0.72, 95%CI = 0.67-0.77, P < 0.01, I 2 = 36.6%; TC vs. TT: OR = 0.73, 95%CI = 0.66-0.80, P < 0.01, I 2 = 23.0%; CC vs. TT: OR = 0.52, 95%CI = 0.39-0.70, P < 0.01, I 2 = 53.7%; TC+CC vs. TT: OR = 0.67, 95%CI = 0.61-0.71, P < 0.01, I 2 = 22.1%; and CC vs. TT+TC: OR = 0.66, 95%CI = 0.53-0.82, P < 0.01, I 2 = 57.8%). Moreover, the IL-10 -592 A>C polymorphism and the ACC haplotype exhibited a significant, protective effect against BD susceptibility. In summary, our meta-analysis suggested that IL-10 gene polymorphisms may play a salient role for BD development.

First example of highly stereoselective synthesis of 1,2,3-trisubstituted cyclopropanes via chiral selenonium ylides.

As the first example of the application of chiral selenonium ylides in asymmetric cyclopropanation, a new strategy for the highly stereoselective synthesis of chiral 1,2,3-trisubstituted cyclopropanes via selenonium ylides is described. The reaction afforded three stereoisomers of chiral 1,2,3-trisubstituted cyclopropanes with good yields, excellent diastereoselectivities, very high enantioselectivities (up to >99% ee), good generality and recyclability of chiral selenides. The possible pathways and models of the asymmetric cyclopropanation via the chiral selenonium ylides were also proposed to rationalize the excellent enantioselectivities and diastereoselectivities.