Synthesis of Chiral 1,2-Amino Alcohol-Containing Compounds Utilizing Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Unprotected α-Ketoamines.

Herein, we disclose a facile synthetic strategy to access an important class of drug molecules that contain chiral 1,2-amino alcohol functionality utilizing highly effective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-ketoamines. Recently, the COVID-19 pandemic has caused a crisis of shortage of many important drugs, especially norepinephrine and epinephrine, for the treatment of anaphylaxis and hypotension because of the increased demand. Unfortunately, the existing technologies are not fulfilling the worldwide requirement due to the existing lengthy synthetic protocols that require additional protection and deprotection steps. We identified a facile synthetic protocol via a highly enantioselective one-step process for epinephrine and a two-step process for norepinephrine starting from unprotected α-ketoamines 1b and 1a, respectively. This newly developed enantioselective ruthenium-catalyzed asymmetric transfer hydrogenation was extended to the synthesis of many 1,2-amino alcohol-containing drug molecules such as phenylephrine, denopamine, norbudrine, and levisoprenaline, with enantioselectivities of >99% ee and high isolated yields.

Design and Discovery of Water-Soluble Benzooxaphosphole-Based Ligands for Hindered Suzuki-Miyaura Coupling Reactions with Low Catalyst Load.

We report a new class of highly effective, benzooxaphosphole-based, water-soluble ligands in the application of Suzuki-Miyaura cross-coupling reactions for sterically hindered substrates in aqueous media. The catalytic activities of the coupling reactions were greatly enhanced by the addition of catalytic amounts of organic phase transfer reagents, such as tetraglyme and tetrabutylammonium bromide. The optimized general protocol can be conducted with a low catalyst load, thereby providing a practical solution for these reactions. The viability of this new Suzuki-Miyaura protocol was demonstrated with various substrates to generate important building blocks, including heterocycles, for the synthesis of biologically active compounds.

Synthesis of a Series of Trimeric Branched Glycoconjugates and Their Applications for Supramolecular Gels and Catalysis.

Carbohydrate-derived molecular gelators have found many practical applications as soft materials. To better understand the structure and molecular gelation relationship and further explore the applications of sugar-based gelators, we designed and synthesized eight trimeric branched sugar triazole derivatives and studied their self-assembling properties. These included glucose, glucosamine, galactose, and maltose derivatives. Interestingly, the gelation properties of these compounds exhibited correlations with the peripheral sugar structures. The maltose derivative did not form gels in the tested solvents, but all other compounds exhibited gelation properties in at least one of the solvents. Glucose derivatives showed superior performance, followed by glucosamine derivatives. They typically formed gels in toluene and alcohols; some formed gels in ethanol-water mixtures or DMSO water mixtures. The glycoclusters 9 and 10 demonstrated rate acceleration for the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. These were further studied for their metallogels formation properties, and the copper metallogels from compound 9 were successfully utilized to catalyze click reactions. These metallogels were able to form a gel column, which was effective in converting the reactants into the triazole products in multiple cycles. Moreover, the same gel column was used to transform a second click reaction using different reactants. The synthesis and characterization of these compounds and their applications for catalytic reactions were discussed.

A de novo mutation of ADAMTS8 in a patient with Wiedemann-Steiner syndrome.

BACKGROUND: Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant disorder caused by mutations in the KMT2A gene and is usually characterized by hairy elbows, short stature, developmental delay, intellectual disability and obvious facial dysmorphism. CASE PRESENTATION: Here, we report a 5-year-old girl with clinical features similar to WDSTS, including postnatal growth delay, retarded intellectual development, and ocular hypertelorism. Through whole-exome sequencing (WES), a frameshift variant of KMT2A was found in the patient but not in her parents' genomic DNA. By bioinformatics analysis, the KMT2A variant was demonstrated to be the top candidate pathogenic variant for the clinical phenotype consistent with WDSTS. Moreover, a duplication of exon 1 in ADAMTS8 (belonging to the zinc metalloproteinase family) was found in the genomic DNA of this patient, which may be responsible for the characteristics that are different from those of WDSTS, including early teething, rapid tooth replacement, and dysplastic enamel. CONCLUSIONS: From the above results, we propose that in our patient, the frameshift variant in KMT2A is the main reason for the WDSTS phenotype, and the unreported mutation in ADAMTS8 may be the candidate reason for other characteristics that are different from those of WDSTS. Therefore, this study not only provides a new KMT2A variant associated with WDSTS but is also a reminder that combined mutations may be present in a case with more characteristics than those seen in WDSTS.

Design and Synthesis of α-Anomeric Diacetylene-Containing Glycosides as Photopolymerizable Molecular Gelators.

Glycolipids with diacetylene functional groups are fascinating compounds with many practical uses. Among these, diacetylene-containing gelators are especially important because they can form photopolymerizable gels, which are useful stimuli-responsive materials. Inspired by the unique properties of diacetylene-containing gelators and to understand the structural influences especially the location of the diacetylene functional groups on the self-assembling properties, a series of 15 novel N-acetyl-d-glucosamine derivatives with the diacetylene functional group introduced at the anomeric position were designed and synthesized. The diacetylene function is attached to the sugar through α-glycosylation with the distance from the anomeric oxygen being varied from one, two, and three methylene groups, and the other side contains hydroxyl, carboxyl, phenyl, and alkyl substituents. Remarkably, all compounds can form self-assembled gels in one or more selected solvents. A majority of these synthesized diacetylene glycosides are effective gelators for ethanol/water (v/v 1:1), dimethyl sulfoxide/water (v/v 1:1), and toluene, and one compound also formed a hydrogel at 1.0 wt %. Typically, these glycosides form gels that are photopolymerizable to afford red-colored gels. Scanning electronic microscopy indicated that the gelators formed helices, fibers, and planar sheet-like morphologies. The chemical structures of the derivatives affected their gelation properties and responses to UV treatment. The carboxylic acid-functionalized derivative 17 was able to immobilize basic solutions and form transparent gels. We expect that these diacetylene glycosides especially the hydroxyl and carboxylic acid derivatives will be useful as stimuli-responsive glycolipids for biomedical research.

Synthesis of Carbohydrate Based Macrolactones and Their Applications as Receptors for Ion Recognition and Catalysis.

Glycomacrolactones exhibit many interesting biological properties, and they are also important in molecular recognitions and for supramolecular chemistry. Therefore, it is important to be able to access glycomacrocycles with different sizes and functionality. A new series of carbohydrate-based macrocycles containing triazole and lactone moieties have been designed and synthesized. The synthesis features an intramolecular nucleophilic substitution reaction for the macrocyclization step. In this article, the effect of some common sulfonate leaving groups is evaluated for macrolactonization. Using tosylate gave good selectivity for monolactonization products with good yields. Fourteen different macrocycles have been synthesized and characterized, of which eleven macrocycles are from cyclization of the C1 to C6 positions of N-acetyl D-glucosamine derivatives and three others from C2 to C6 cyclization of functionalized D-glucosamine derivatives. These novel macrolactones have unique structures and demonstrate interesting anion binding properties, especially for chloride. The macrocycles containing two triazoles form complexes with copper sulfate, and they are effective ligands for copper sulfate mediated azide-alkyne cycloaddition reactions (CuAAC). In addition, several macrocycles show some selectivity for different alkynes.

Synthesis of Dendritic Glycoclusters and Their Applications for Supramolecular Gelation and Catalysis.

Glycoclusters with three, four, and six arms of glycosyl triazoles were designed, synthesized, and characterized. The self-assembling properties of these molecules and their catalytic activity as ligands in copper-catalyzed azide and alkyne cycloaddition (CuAAC) reactions were studied. The compounds with a lower number of branches exhibit excellent gelation properties and can function as supramolecular gelators. The resulting gels were characterized using optical microcopy and atomic force microscopy. The glycoconjugates containing six branches showed significant catalytic activity for copper sulfate mediated cycloaddition reactions. In aqueous solutions, 1 mol % of glycoclusters to substrates was efficient at accelerating these reactions. Several trimeric compounds were found to be capable of forming co-gels with the catalytically active hexameric compounds. Using the organogels formed by the glycoconjugates as supramolecular catalysts, efficient catalysis was demonstrated for several CuAAC reactions. The metallogels with CuSO4 were also prepared as gel columns, which can be reused for the cycloaddition reactions several times. These include the preparation of a few glycosyl triazoles and aryl triazoles and isoxazoles. We expect that these sugar-based soft biomaterials will have applications beyond supramolecular catalysis for copper-catalyzed cycloaddition reactions. They may also be useful as ligands or gel matrixes for other metal-ion catalyzed organic reactions.

Anti-fibrosis activity of quercetin attenuates rabbit tracheal stenosis via the TGF-ß/AKT/mTOR signaling pathway.

AIMS: This study aimed to explore the possible mechanism of trauma-induced laryngotracheal stenosis and potential protective and therapeutic efficacy of quercetin on trauma-induced laryngotracheal stenosis. MAIN METHODS: The expression and activity of fibrotic factors [interleukin (IL)-6, IL-8, autophagy related 5 (ATG5), collagen (COL)-1, tumor growth factor (TGF)-ß COL-3, microtubule-associated proteins 1A/1B light chain 3A (LC3), and vascular endothelial growth factor (VEGF)] and fibrotic signaling mediators [mammalian target of rapamycin (mTOR) and phosphorylated AKT (pAKT)] were detected by real-time quantitative PCR (qRT-PCR), ELISA, Western blot, and immunohistochemical staining, respectively, in the lipopolysaccharide (LPS)-induced WI-38 (a human embryonic lung fibroblast cell line) cellular fibrotic model and a trauma-induced rabbit tracheal stenosis model, with and without quercetin treatment. KEY FINDINGS: Pre-treatment with quercetin significantly reversed the LPS-induced upregulation of pro-fibrotic factors (IL-6, IL-8, COL-1, COL-3, LC3) and fibrotic signaling mediators (mTOR and AKT), and it induced the downregulation of ATG5 in the WI-38 cells. Furthermore, the anti-fibrotic activity of quercetin was confirmed in the trauma-induced rabbit tracheal stenosis model. Thus, the nasogastric administration of quercetin attenuated the tracheal stenosis of the rabbit tracheal stenosis model, in addition to effectively reversing an increase in pro-fibrotic factors (VEGF, IL-6, TGF-ß, COL-1, and COL-3) and fibrotic signaling mediators (mTOR and AKT), as well as downregulating ATG5 of the rabbit tracheal stenosis model. SIGNIFICANCE: Quercetin exhibits anti-fibrotic activity by inhibiting pro-fibrotic factors and AKT/mTOR signaling pathway, in addition to activating autophagy activity. This study provided experimental evidence supporting the application of quercetin in tracheal stenosis, clinically.

Stimuli-responsive gelators from carbamoyl sugar derivatives and their responses to metal ions and tetrabutylammonium salts.

Carbohydrate-based low molecular weight gelators (LMWGs) are interesting compounds with a variety of applications. In this research, a library of nineteen carbamate derivatives of N-acetyl-d-glucosamine were synthesized and characterized, and several derivatives were found to be effective LMWGs. They formed gels in pump oils as well as mixtures of water with ethanol or water with DMSO. The structures of the carbamoyl chains played an important role in the gelation properties, short chain aliphatic derivatives and phenyl carbamates formed gels in more solvents than certain aromatic and dimeric carbamates. The phenyl carbamate gelator was also selected for the encapsulation of naproxen sodium, and the drug slowly diffused from the gel to the aqueous phase as indicated by UV-vis spectroscopy. In addition, we also found that the p-methoxyl benzyl carbamate derivative showed interesting stimuli-responsive gelation properties in the presence of metal salts and tetrabutylammonium salts. The gels were characterized using optical microscopy, scanning electron microscopy, rheology and other methods. The self-assembling mechanisms of the gelators were studied using 1H NMR spectroscopy. The preparation, characterization, and molecular assembling properties of these compounds are reported. The results obtained from this study are useful for the design of other LMWGs and the sugar derivatives can be explored for different biological applications. The formation of spontaneous ionic gels can be applicable for a plethora of applications including catalysis and environmental remediation.

Synthesis and characterization of pentaerythritol derived glycoconjugates as supramolecular gelators.

Carbohydrate based self-assembling supramolecular systems are important classes of new materials with many potential applications. In this study, a series of twelve glycoconjugates were synthesized and characterized in order to obtain effective supramolecular gelators. These glycoconjugates are mono-, di-, tri-, and tetra-functionalized pentaerythritol derivatives synthesized by using copper(i) catalyzed azide alkyne cycloaddition reactions (CuAACs). The properties of these twelve compounds gave insight into the rational design of covalently linking multiple units of sugars. We found that the trivalent and tetravalent glycoclusters were effective molecular gelators, but the monovalent and divalent derivatives were typically not able to form gels in the tested solvents. The gels were characterized using rheology, optical microscopy, and atomic force microscopy. The tris-triazole derivative 21 was discovered to be a suitable gelator for the encapsulation of naproxen, vitamin B2, and vitamin B12. The strategy of covalently linking three or four small molecules to form trimeric or tetrameric branched compounds is a valid approach in designing useful self-assembling materials. The glycocluster based organogels and hydrogels obtained in this study have potential applications in biomedical research and as advanced functional materials.

Inhibition of mouse RM-1 prostate cancer and B16F10 melanoma by the fusion protein of HSP65 & STEAP1 186-193.

The research of tumor vaccine plays a crucial role in tumor immunotherapy. This study has constructed and prepared a fusion protein vaccine of heat shock protein 65 (HSP65) and the octapeptide epitope 186-193 of the six transmembrane epithelial antigen of the prostate 1 (STEAP1 186-193), and investigated the inhibitory effect of the fusion protein on mouse RM-1 prostate cancer and B16F10 melanoma xenografts. The fusion protein His-HSP65-STEAP1 186-193 (HHST1), His-HSP65-2×STEAP1 186-193 (HHST2) and His-HSP65-6×STEAP1 186-193 (HHST6) were obtained by setting different copy number of STEAP1 186-193 and adding His purification tag before HSP65. Firstly the inhibitory effect of fusion protein on mouse RM-1 prostate cancer xenografts has been studied, which could be the basis of the study the inhibitory effect of the best fusion protein on mouse B16F10 melanoma xenografts. All studies compared with the fusion protein His-HSP65 (HHSP65), the fusion proteins HHST1, HHST2 and HHST6 all could significantly inhibit the growth of mouse RM-1 prostate cancer xenografts. In addition, the fusion protein HHST2 was proved to be the best compared with the fusion proteins HHST1 and HHST6 (P<0.05). Apart from this, compared with the fusion protein HHSP65, the fusion protein HHST2 also significantly inhibited the growth of mouse beared B16F10 melanoma. The results above indicate that HSP65 and STEAP1 186-193 can significantly inhibit the growth of mouse RM-1 prostate cancer and B16F10 melanoma xenografts, and the appropriate increase of copy number can effectively improve that the fusion protein has an excellent anti-tumor ability.

Synthesis and self-assembling properties of 4,6-O-benzylidene acetal protected D-glucose and D-glucosamine ß-1,2,3-triazole derivatives.

Sugar based low molecular weight gelators (LMWGs) are useful small molecules that can form reversible supramolecular gels with many applications. Selective functionalization of common monosaccharides has resulted in several classes of effective LMWGs. Recently we found that certain peracetylated sugars containing anomeric triazole functional groups were effective gelators. In this study we synthesized two series of 4,6-O-benzylidene acetal protected ß-1,2,3-triazolyl glycoside of D-glucose and N-acetyl D-glucosamine derivatives and evaluated their self-assembling properties in a few solvents. Several gelators were obtained and the gelation properties of these compounds rely on the structures of the 4-triazolyl substituents. Typically, alkyl derivatives resulted in effective gelation in organic solvents and aqueous mixtures of ethanol and dimethyl sulfoxide. But further acetylation of these compounds resulted in loss of gelation properties. The gels were characterized using optical microscopy, rheology, and FTIR spectroscopy. We also analyzed the molecular assemblies, using 1H NMR spectroscopy to probe the influences of the hydroxyl, amide, and triazole functional groups. Naproxen was used as a model drug and it formed co-gels with compound 25 in DMSO water mixtures. Using UV spectroscopy, we found that naproxen was slowly released from the gel to aqueous solution. The general structure and gelation trend obtained here can be useful in designing sugar based biomaterials. We expect that further structural optimization can lead to more effective gelators that are compatible with different drug molecules for encapsulation and sustained release.

Synthesis and Study of Molecular Assemblies Formed by 4,6-O-(2-Phenylethylidene)-Functionalized d-Glucosamine Derivatives.

Low-molecular-weight gelators are interesting small molecules with potential applications as advanced materials. Carbohydrate-based small molecular gelators are especially useful because they are derived from renewable resources and are more likely to be biocompatible and biodegradable. Various 4,6-benzylidene acetal protected α-methyl 2-d-glucosamine derivatives have been found to be effective low-molecular-weight gelators. To understand the influence of the 4,6-benzylidene acetal functional group toward molecular self-assembly and to obtain effective molecular gelators, we synthesized and analyzed a new series of d-glucosamine derivatives in which the phenyl group of the acetal is replaced by a benzyl group. The homologation of the acetal protection from aromatic to aliphatic functional groups allows us to probe the effect of increasing structural flexibility on molecular self-assembly and gelation. In this study, nine representative amides and nine urea analogs were synthesized, and their gelation properties were analyzed in a series of organic solvents and aqueous solutions. The resulting amide and urea derivatives are versatile organogelators forming gels in toluene, ethanol, isopropanol, ethylene glycol, and aqueous mixtures of organic solvents. More interestingly, the amide analogs are also effective gelators for pump oil and engine oil. NMR spectroscopy at variable temperatures was used to analyze the molecular assemblies and intermolecular forces. The selected gelators with several drug and dye molecules in DMSO and water were studied for their effectiveness of encapsulation and release of these agents.

Preoperative Antihypertensive Medication in Relation to Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery: A Meta-Analysis.

Background. We undertake a systematic review and meta-analysis to evaluate the effect of preoperative hypertension and preoperative antihypertensive medication to postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery. Methods. We searched PubMed, Embase, and Cochrane Library (from inception to March 2016) for eligible studies. The outcomes were the effects of preoperative hypertension, preoperative calcium antagonists regimen, preoperative ACE inhibitors regimen, and preoperative beta blocking agents regimen with POAF. We calculated pooled risk ratios (OR) and 95% CIs using random- or fixed-effects models. Results. Twenty-five trials involving 130087 patients were listed. Meta-analysis showed that the number of preoperative hypertension patients in POAF group was significantly higher (P < 0.05), while we found that there are no significant differences between two groups in Asia patients by subgroup analysis, which is in contrast to other outcomes. Compared with the Non-POAF group, the number of patients who used calcium antagonists and ACE inhibitors preoperatively in POAF group was significantly higher (P < 0.05). And we found that there were no significant differences between two groups of preoperative beta blocking agents used (P = 0.08). Conclusions. Preoperative hypertension and preoperative antihypertensive medication in patients undergoing cardiac operations seem to be associated with higher risk of POAF.

Efficient asymmetric synthesis of structurally diverse P-stereogenic phosphinamides for catalyst design.

The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P-stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P-stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis.

Synthesis of phosphaguanidines by hydrophosphination of carbodiimides with phosphine boranes.

The direct addition of anionic secondary phosphine boranes to carbodiimides yields both chiral and achiral phosphaguanidine boranes under ambient temperature conditions. An analogous preparation of menthol-derived phosphinite boranes is also described. These products can be deborinated to give the corresponding phosphines, and subsequently oxidized to give phosphine oxides. The robustness of this method was further demonstrated in the synthesis of structurally novel cyclic phosphaguanidines.