Insights into the role played by modified cinchona alkaloids in the Sharpless asymmetric dihydroxylation inspired studies of modified cinchona alkaloids as chiral organic catalysts that lead to the development of highly enantioselective alcoholyses for the desymmetrization, kinetic resolution, and dynamic kinetic resolution of cyclic anhydrides, cyanation of ketones, and 1,4-addition of thiols to cylic enones. These studies demonstrate the potential of modified cinchona alkaloids as broadly useful chiral organic catalysts for asymmetric synthesis.

BackgroundRobust and precise molecular prognostic predictors for luminal breast cancer are required. This study aimed to identify key methylation sites in luminal breast cancer, as well as precise molecular tools for predicting prognosis.MethodsWe compared methylation levels of normal and luminal breast cancer samples from The Cancer Genome Atlas dataset. The relationships among differentially methylated sites, corresponding mRNA expression levels and prognosis were further analysed. Differentially expressed genes in normal and cancerous samples were analysed, followed by the identification of prognostic signature genes. Samples were divided into low- and high-risk groups based on the signature genes. Prognoses of low- and high-risk groups were compared. The Gene Expression Omnibus dataset were used to validate signature genes for prognosis prediction. Prognosis of low- and high-risk groups in Luminal A and Luminal B samples from the TCGA and the Metabric cohort dataset were analyzed. We also analysed the correlation between clinical features of low- and high- risk groups as well as their differences in gene expression.ResultsFourteen methylation sites were considered to be related to luminal breast cancer prognosis because their methylation levels, mRNA expression and prognoses were closely related to each other. The methylation level of SOSTDC1 was used to divide samples into hypo- and hyper-methylation groups. We also identified an mRNA signature, comprising eight transcripts, ESCO2, PACSIN1, CDCA2, PIGR, PTN, RGMA, KLK4 and CENPA, which was used to divide samples into low- and high-risk groups. The low-risk group showed significantly better prognosis than the high-risk group. A correlation analysis revealed that the risk score was an independent prognostic factor. Low- and high- risk groups significantly correlated with the survival ratio in Luminal A samples, but not in Luminal B samples on the basis of the TCGA and the Metabric cohort dataset. Further functional annotation demonstrated that the differentially expressed genes were mainly involved in cell cycle and cancer progression.ConclusionsWe identified several key methylation sites and an mRNA signature for predicting luminal breast cancer prognosis. The signature exhibited effective and precise prediction of prognosis and may serve as a prognostic and diagnostic marker for luminal breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4314-9) contains supplementary material, which is available to authorized users.

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Acyl-transfer reactions use cheap reagents to transform readily available starting materials into useful and easily purified products. These characteristics, in combination with high enantioselectivity, enable acyl-transfer reactions catalyzed by enzymes such as lipases and esterases to become highly valuable methods for asymmetric synthesis. 1 The development of synthetic catalysts to mimic lipases/esterases with the goal of further expanding the scope of asymmetric acyl transfer catalysis is of both conceptual and practical significance for asymmetric catalysis. 2 Although effective phosphorus and nitrogen synthetic catalysts for the kinetic resolution of racemic alcohols have emerged, 3,4 efforts to develop small molecule-catalyzed kinetic resolutions of racemic carbonyl derivatives have met with limited success despite their great potential in asymmetric synthesis. 5 We report here an exceedingly general and highly enantioselective kinetic resolution of urethane-protected R-amino acid N-carboxyanhydrides (UNCA) that generates optically active R-amino acid derivatives suitable for further synthetic elaboration such as peptide synthesis.Encouraged by our discovery of modified cinchona alkaloids as efficient catalysts for asymmetric alcoholysis of meso and racemic cyclic anhydrides, 6-8 we became interested in the kinetic resolution of urethane-protected R-amino acid N-carboxyanhydrides (UNCA, 2) via cinchona alkaloid-catalyzed alcoholysis (Scheme 1). UNCAs (2) can be easily prepared from the readily available racemic amino acids (1). 9 Their alcoholysis generates the carbamate-protected amino ester 3 and CO 2 . When suitably protected, amino ester 3 will not interfere with the cinchona alkaloid-catalyzed alcoholysis. Furthermore, the unreacted enantiomerically enriched UNCA (2) can be hydrolyzed to protected amino acid (4) (Scheme 1). The resulting mixture of the basic amine catalyst, the acidic amino acid (4) and the neutral amino ester (3), can be separated using simple extractive procedures to give 3, 4, and the recovered amine catalyst in desired chemical and optical purity. We initially utilized racemic N-Cbz-phenylalanine NCA (2a) as a model substrate. Reaction of 2a with methanol (0.55 equiv) in ether at room temperature with (DHQD) 2 AQN (10 mol %) and molecular sieves (4 Å) afforded ester 3a in 80% ee at 42% conversion, corresponding to a selectivity factor (s) of 16 for the kinetic resolution (entry 1, Table 1). Importantly, the enantioselectivity of the kinetic resolution could be dramatically improved at low temperature and, at -60°C, reached a level (s ) 79, entry 2, Table 1) comparable to that of an enzyme-catalyzed resolution. Further catalyst screening studies revealed that (DHQD) 2 AQN is the most effective catalyst. Notably, high enantioselectivity is also achieved with the monocinchona alkaloids, DHQD-PHN, and quinidine (entries 3, 4, Table 1). Interestingly, under the same conditions, other related amines such as (DHQD) 2 PYR, (DHQD) 2 -PHAL, DHQD-MEQ, DHQD-CLB, and quinuclidine afforded o...

Background Glutamate metabotropic receptors (GRM) play a variety of roles in neuronal cells. However, their clinical significance and biological functions in breast cancer remain unknown. Methods RNA sequencing data of breast cancer was obtained from the TCGA dataset (v2) and mined for the expression profiles of GRM family according to cancer subtypes. mRNA expression of GRM family in breast cancer tissues and para-cancerous tissue samples as well as breast cancer cell lines were measured by qPCR. The effects of over- and under-expression of GRM4 on cell capabilities to survive, migrate and invade were determined by colony formation, transwell migration and invasion assays. To explore the upstream regulation pattern of GRM4, miRNAs that target GRM4 were predicted and validated by dual luciferase reporter assay. In addition, the mRNA and protein expression of GRM4 regulated by these miRNAs were further measured by qPCR and western blot assay. Results GRM4 was the only GRM member that expressed in breast cancer tissues. Ectopic expression of GRM4 was correlated with better prognosis of breast cancer patients. Overexpression of GRM4 could significantly inhibit cell proliferation, migration and invasion capacity in MDA-MB-231, while knockdown of GRM4 could promote these processes. miR-328-3p and miR-370-3p were predicted to regulate the expression of GRM4 and dual luciferase reporter assay demonstrated that miR-328-3p and miR-370-3p directly bound to the 3′ UTR of GRM4 and mutations on the binding regions on GRM4 significantly decreased the luciferase activity. qPCR demonstrated that expression of miR-328-3p and miR-370-3p was significantly decreased in breast cancer tissues and cells compared with that in control samples. However, there were no correlations between the expression of miR-328-3p and GRM4, as well as the expression of miR-370-3p and GRM4. Moreover, overexpression of miR-328-3p and miR-370-3p counteracted the inhibitory effect of GRM4-induced cell proliferation, migration and invasion. Conclusions Our results suggest that GRM4 might be a tumor suppressor gene in breast cancer under the direct regulation of miR-328-3p and miR-370-3p.

A flexible SbO/carbon cloth (CC) composite is synthesized using a simple solvothermal method. The SbO/CC composite exhibits higher capacity and capacity retention of alloying and conversion reactions as an anode for sodium ion batteries, attributed to the good conductivity of CC and strong chemical bonds between SbO and CC.

[reaction: see text] A rapid, highly efficient and general dynamic kinetic resolution (DKR) of racemic alpha-aryl UNCAs with the dual-function catalysis of modified cinchona alkaloid was accomplished at room temperature. This DKR led to the development of a highly enantioselective catalytic method for the practical synthesis of a wide range of alpha-aryl and alpha-heteroaryl amino acids in 89-92% ee and 86-95% yield from racemic UNCAs.

The saponin fraction QS-21 from Quillaja saponaria has been demonstrated to be a potent immunological adjuvant when mixed with keyhole limpet hemocyanin conjugate vaccines, as well as with other classes of subunit antigen vaccines. QS-21 adjuvant is composed of two isomers that include the apiose and xylose forms in a ratio of 65:35, respectively. The chemical syntheses of these two isomers in pure form have recently been disclosed. Herein we describe detailed in vivo immunological evaluations of these synthetic QS-21 isomeric constituents, employing the GD3-KLH melanoma antigen. With this vaccine construct, high antibody titers against GD3 ganglioside and KLH were elicited when GD3-KLH was co-administered with adjuvant, either as the individual separate synthetic QS-21 isomers (SQS-21-Api or SQS-21-Xyl), or as its reconstituted 65:35 isomeric mixture (SQS-21). These antibody titer levels were comparable to that elicited by vaccinations employing naturally derived QS-21 (PQS-21). Moreover, toxicities of the synthetic saponin adjuvants were also found to be comparable to that of naturally derived PQS-21. These findings demonstrate unequivocally that the adjuvant activity of QS-21 resides in these two principal isomeric forms, and not in trace contaminants within the natural extracts. This lays the foundation for future exploration of structure-function correlations to enable the discovery of novel saponins with increased potency, enhanced stability, and attenuated toxicity.