Borane-Catalyzed Tandem Cyclization/Hydrosilylation Towards Enantio- and Diastereoselective Construction of trans-2,3-Disubstituted-1,2,3,4-Tetrahydroquinoxalines.

Recent years have witnessed marked progress in the efficient synthesis of various enantioenriched 1,2,3,4-tetrahydroquinoxalines. However, enantio- and diastereoselective access to trans-2,3-disubstituted 1,2,3,4-tetrahydroquinoxalines remains much less explored. Herein we report that a frustrated Lewis pair-based catalyst generated via in situ hydroboration of 2-vinylnaphthalene with HB(C6 F5 )2 allows for the one-pot tandem cyclization/hydrosilylation of 1,2-diaminobenzenes and 1,2-diketones with commercially available PhSiH3 to exclusively afford trans-2,3-disubstituted 1,2,3,4-tetrahydroquinoxalines in high yields with excellent diastereoselectivities (>20 : 1 dr). Furthermore, this reaction can be rendered asymmetric by using an enantioenriched borane-based catalyst derived from HB(C6 F5 )2 and a binaphthyl-based chiral diene to give rise to enantioenriched trans-2,3-disubstituted 1,2,3,4-tetrahydroquinoxalines in high yields with almost complete diastereo- and enantiocontrol (>20 : 1 dr, up to >99 % ee). A wide substrate scope, good tolerance of diverse functionality and up to 20-gram scale production are demonstrated. The enantio- and diastereocontrol are achieved by the judicious choice of borane catalyst and hydrosilane. The catalytic pathway and the origin of the excellent stereoselectivity are elucidated by mechanistic experiments and DFT calculations.

Ligand-Promoted RhI -Catalyzed C2-Selective C-H Alkenylation and Polyenylation of Imidazoles with Alkenyl Carboxylic Acids.

The first RhI -catalyzed, directed decarbonylative C2-H alkenylation of imidazoles with readily available alkenyl carboxylic acids is reported. The reaction proceeds in a highly regio- and stereoselective manner, providing efficient access to C2-alkenylated imidazoles that are generally inaccessible by known C-H alkenylation methods. This transformation accommodates a wide range of alkenyl carboxylic acids, including challenging conjugated polyene carboxylic acids, and diversely decorated imidazoles with high functional group compatibility. The presence of a removable pyrimidine directing group and the use of a bidentate phosphine ligand are pivotal to the success of the catalytic reaction. This process is also suitable for benzimidazoles. Importantly, the scalability and diversification of the products highlight the potential of this protocol in practical applications. Detailed experimental and computational studies provide important insights into the underlying reaction mechanism.

Regioselectivity-reversed asymmetric aldol reaction of 1,3-dicarbonyl compounds.

Reverse regioselectivity: The first catalytic asymmetric C-1 functionalization of 1,3-dicarbonyl compounds by an aldol reaction is described, which regioselectively affords 6-hydroxyhexane-2,4-dione derivatives as the only product with high optical purity of up to 93 % ee. Furthermore, this method provides a facile access to enantioenriched oxygen-containing spirooxindoles and spirobutyrolactones from simple commercial available starting materials (see scheme).

Ion-specific effect on dynamics of polyelectrolyte chains.

The sedimentation of quaternized poly(4-vinyl pyridine) (QP4VP) or poly(N-methyl 4-vinyl pyridine iodide) in aqueous solution has been investigated by using an analytical ultracentrifuge (AUC) via sedimentation velocity (SV). When NaI is introduced, either the sedimentation coefficient (s) or apparent molar mass (Mw) of QP4VP increases with NaI concentration because the polyelectrolyte chains aggregate or even form precipitates due to hydrophobic interaction. Upon addition of NaCl, either s or Mw exhibits a maximum as NaCl concentration increases. The sedimentation in NaBr solution falls in between. Besides, the diffusion coefficient (D) shows a minimum as the added salt concentration increases when either of the salts is added. Isothermal titration calorimetry (ITC) measurements show that the enthalpy change increases from NaI over NaBr to NaCl when each of them is mixed with QP4VP, revealing that the order of the strength of the anion-pyridinium interaction is I(-) > Br(-) > Cl(-). When I(-) ions are added, they only screen the electrostatic interaction and no counterion competition happens. Upon addition of Cl(-) or Br(-) ions, the original counterions (I(-)) win the competition at low Cl(-) or Br(-) concentration, so that the added anions only screen the electrostatic interaction. When the concentration of Cl(-) or Br(-) ions is high enough, they replace I(-) ions to interact with the polyelectrolyte chains due to osmotic pressure. The present study demonstrates that the complex dynamics of the polyelectrolyte is greatly influenced by the ion-specific effect.

Cobalt(III)-Catalyzed Regioselective C6 Olefination of 2-Pyridones Using Alkynes: Olefination/Directing Group Migration and Olefination.

Co(III)-catalyzed highly regio- and stereoselective direct C6 olefination of 2-pyridones with alkynes has been developed with the assistance of chelation. Upon variation of the reaction conditions, 2-pyridones react well with diaryl alkynes via a C6 olefination/directing group migration pathway to give the tetrasubstituted 6-vinyl-2-pyridones, but the C6-H olefination with terminal alkynes works effectively to afford only the C6-olefinated 2-pyridones. A judicious choice of a solvent and an additive is crucial for catalysis. The protocols feature 100% atom economy, excellent site selectivity, high stereoselectivity, an ample substrate scope, and good compatibility of functional groups. Synthetic applications are demonstrated, and experimental studies and density functional theory calculations are conducted to gain mechanistic insight into the two transformations.

Scaling for sedimentation and diffusion of poly(ethylene glycol) in water.

The sedimentation and diffusion of poly(ethylene glycol) (PEG) with weight average molecular weight (M(w)) from 5 x 10(2) to 2 x 10(5) g/mol have been investigated by use of an analytical ultracentrifuge (AUC). The sedimentation velocity analysis based on the Lamm equation gives the sedimentation coefficient (s) and diffusion coefficient (D). Our study reveals that the sedimentation coefficient (s(0)) and diffusion coefficient (D(0)) at infinite dilution scale to molecular weight (M(w)), namely, s(0) = K(s)M(w)(alpha), with K(s) = 6.14 x 10(-3) and alpha = 0.469 +/- 0.008, and D(0) = K(D)M(w)(-beta), with K(D) = 1.43 x 10(-8) and beta = 0.576 +/- 0.007.

Effects of microbubble-enhanced ultrasound combined with prothrombin on microwave ablation in rabbit VX2 liver tumor.

OBJECTIVE: This study aimed to investigate effects of microbubble-enhanced ultrasound (MEUS) combined with prothrombin on microwave ablation (MWA) on VX2 liver tumors in a rabbit model. METHODS: 80 rabbits with VX2 liver tumors were randomly divided into Group A (sham + NS), Group B (sham + NS + P), Group C (MEUS), and Group D (PMEUS). After treatment, targeted liver tumors were ablated with MWA. On 0, 3, 7 and 14 d, volume of coagulated area was measured. Tissues in ablated area, transition area and surrounding area were collected. RESULTS: On 0, 3, 7 and 14 d, coagulated volume in Group D was larger than remaining three groups (P<0.05). On 7 d and 14 d, tumor volume in Group D was smaller than remaining three groups (P<0.05). Fibrotic band in Group D was wider than in remaining three groups (P<0.05). Cellular ultrastructure injury in ablated area on 0 d and mitochondrial injury in transition area on 7 d were more severe in Group D than in remaining three groups. On 0, 3, 7 and 14 d, proliferative cellular nuclear antigen-positive index in transition area in Group C and Group D was lower than Group A and Group B (P<0.05). On 0, 3 and 7 d, apoptosis index in transition area in Group D was higher than remaining three groups (P<0.05). CONCLUSIONS: MEUS combined with prothrombin on MWA can significantly expand ablation volume, enhance the necrosis of ablated tissues, inhibit tumor growth/metastasis and improve therapeutic effect of MWA on rabbit VX2 liver tumors.

Rhodium(i)-catalyzed C6-selective C-H alkenylation and polyenylation of 2-pyridones with alkenyl and conjugated polyenyl carboxylic acids.

A versatile Rh(i)-catalyzed C6-selective decarbonylative C-H alkenylation of 2-pyridones with readily available, and inexpensive alkenyl carboxylic acids has been developed. This directed dehydrogenative cross-coupling reaction affords 6-alkenylated 2-pyridones that would otherwise be difficult to access using conventional C-H functionalization protocols. The reaction occurs with high efficiency and is tolerant of a broad range of functional groups. A wide scope of alkenyl carboxylic acids, including challenging conjugated polyene carboxylic acids, are amenable to this transformation and no addition of external oxidant is required. Mechanistic studies revealed that (1) Boc2O acts as the activator for the in situ transformation of the carboxylic acids into anhydrides before oxidative addition by the Rh catalyst, (2) a decarbonylation step is involved in the catalytic cycle, and (3) the C-H bond cleavage is likely the turnover-limiting step.

Rhodium(III)-Catalyzed Oxidative Annulation of 2,2'-Bipyridine N-Oxides with Alkynes via Dual C-H Bond Activation.

Rh(III)-catalyzed switchable annulation of 2,2'-bipyridine N-oxides with internal alkynes via dual C-H bond activation has been developed. Tuning the reaction conditions enabled the reaction pathway to be switched between rollover and nonrollover annulation, delivering 5,6-disubstituted-1,10-phenanthrolines and 5,6,7,8-tetrasubstituted-1-(pyridin-2-yl)isoquinoline 2-oxides in high yields, respectively. The procedures feature excellent regioselectivity, broad substrate scope, and high tolerance of functional groups. The synthetic utilities of these obtained products were demonstrated in the catalytic reactions.

Ruthenium(II)-Catalyzed Regioselective C-8 Hydroxylation of 1,2,3,4-Tetrahydroquinolines.

Ru(II)-catalyzed chelation-assisted highly regioselective C8-hydroxylation of 1,2,3,4-tretrahydroquinolines has been developed. Various 1,2,3,4-tetrahydroquinolines underwent smooth C8-H hydroxylation with cheap and safe K2S2O8 as the oxidant and oxygen source to furnish the corresponding products in good to excellent yields with high tolerance of the functional groups. The choice of a readily installable and removable N-pyrimidyl directing group is the key to catalysis. Mechanistic studies suggest the involvement of a six-membered ruthenacycle intermediate in the catalytic cycle. The method can also be extended to the direct hydroxylation of other (hetero)arene C-H bonds.

Chitosan/silk fibroin modified nanofibrous patches with mesenchymal stem cells prevent heart remodeling post-myocardial infarction in rats.

Poor functional survival of the engrafted stem cells limits the therapeutic efficacy of stem-cell-based therapy for myocardial infarction (MI). Cardiac patch-based system for cardiac repair has emerged as a potential regenerative strategy for MI. This study aimed to design a cardiac patch to improve the retention of the engrafted stem cells and provide mechanical scaffold for preventing the ventricular remodeling post-MI. The patches were fabricated with electrospinning cellulose nanofibers modified with chitosan/silk fibroin (CS/SF) multilayers via layer-by-layer (LBL) coating technology. The patches engineered with adipose tissue-derived mesenchymal stem cells (AD-MSCs) (cell nano-patch) were adhered to the epicardium of the infarcted region in rat hearts. Bioluminescence imaging (BLI) revealed higher cell viability in the cell nano-patch group compared with the intra-myocardial injection group. Echocardiography demonstrated less ventricular remodeling in cell nano-patch group, with a decrease in the left ventricular end-diastolic volume and left ventricular end-systolic volume compared with the control group. Additionally, left ventricular ejection fraction and fractional shortening were elevated after cell nano-patch treatment compared with the control group. Histopathological staining demonstrated that cardiac fibrosis and apoptosis were attenuated, while local neovascularization was promoted in the cell nano-patch group. Western blot analysis illustrated that the expression of biomarkers for myocardial fibrosis (TGF-ß1, P-smad3 and Smad3) and ventricular remodeling (BNP, ß-MHC: α-MHC ratio) were decreased in cell nano patch-treated hearts. This study suggests that CS/SF-modified nanofibrous patches promote the functional survival of engrafted AD-MSCs and restrain ventricular remodeling post-MI through attenuating myocardial fibrosis. STATEMENT OF SIGNIFICANCE: First, the nanofibrous patches fabricated from the electrospun cellulose nanofibers could mimic the natural extracellular matrix (ECM) of hearts to improve the microenvironment post-MI and provide three dimensional (3D) scaffolds for the engrafted AD-MSCs. Second, CS and SF which have exhibited excellent properties in previous tissue engineering research, such as nontoxicity, biodegradability, anti-inflammatory, strong hydrophilic nature, high cohesive strength, and intrinsic antibacterial properties further optimized the biocompatibility of the nanofibrous patches via LBL modification. Finally, the study revealed that beneficial microenvironment and biomimetic ECM improve the retention and viability of the engrafted AD-MSCs and the mechanical action of the cell nano-patches for the expanding ventricular post-MI leads to suppression of HF progression by inhibition of ventricular remodeling.

Moderate Autophagy Inhibits Vascular Smooth Muscle Cell Senescence to Stabilize Progressed Atherosclerotic Plaque via the mTORC1/ULK1/ATG13 Signal Pathway.

In order to investigate the effects of autophagy induced by rapamycin in the development of atherosclerosis plaque we established murine atherosclerosis model which was induced in ApoE-/- mice by high fat and cholesterol diet (HFD) for 16 weeks. Rapamycin and 3-Methyladenine (MA) were used as autophagy inducer and inhibitor respectively. The plaque areas in aortic artery were detected with HE and Oil Red O staining. Immunohistochemical staining were applied to investigate content of plaque respectively. In contrast to control and 3-MA groups, rapamycin could inhibit atherosclerosis progression. Rapamycin was able to increase collagen content and a-SMA distribution relatively, as well as decrease necrotic core area. Then we used MOVAS and culture with ox-LDL for 72 h to induce smooth muscle-derived foam cell model in vitro. Rapamycin and 3-MA were cultured together respectively. Flow cytometry assay and SA-ß-Gal staining experiments were performed to detect survival and senescence of VSMCs. Western blot analysis were utilized to analyze the levels of protein expression. We found that rapamycin could promote ox-LDL-induced VSMCs autophagy survival and alleviate cellular senescence, in comparison to control and 3-MA groups. Western blot analysis showed that rapamycin could upregulate ULK1, ATG13 and downregulate mTORC1 and p53 protein expression.

The impact of microbubble-enhanced therapeutic ultrasound combined with prothrombin on microwave ablation in the rabbit liver.

AIM: This study aimed to investigate the effect of microbubble-enhanced ultrasound (MEUS) combined with prothrombin on regional hepatic circulation and microwave ablation (MWA) in rabbit livers. MATERIALS AND METHODS: High-pressureamplitude therapeutic ultrasound (TUS) was used to treat 52 surgically exposed livers of healthy New Zealand rabbits: 13 livers were treated with MEUS alone, 13 with MEUS and prothrombin (PMEUS), 13 with ultrasound plus normal saline and 13 with ultrasound plus prothrombin as controls. Contrast-enhanced ultrasound (CEUS) imaging was performed on the exposed livers before and after treatment, and acoustic quantification was done to assess liver perfusion. Then, the liver was divided into two parts, one was used for pathologic examination and the other was ablated with microwave (MWA) and then processedfor pathologic examination. RESULTS: The CEUS images and Peak value after treatment in the PMEUS group were significantly reduced as compared to the remaining 3 groups (p<0.05). Occasional piecemeal hemorrhage was evidenced in the pathological examination in the MEUS group. Obvious cellular degeneration and necrosis with thrombosis were observed in the PMEUS group. Electron microscopy showed endothelial damage in both the MEUS group and PMEUS group. After MWA, coagulated volumes (V) in the PMEUS group were larger than in the remaining 3 groups (p<0.05). The cell ultrastructure disorder wasmore severe in the PMEUS group than in remaining 3 groups. CONCLUSION: PMEUS promotes endothelial injury and produces more obvious thrombotic occlusion, improving the therapeutic effect of MWA on the rabbit liver.

Preclinical modeling and multimodality imaging of chronic myocardial infarction in minipigs induced by novel interventional embolization technique.

BACKGROUND: This study was designed to establish a chronic myocardial infarction (MI) model in minipigs with a novel coronary sequential balloons-sponge embolism technique. METHODS: Eighteen healthy minipigs (25-30 kg) were randomly divided into three groups for left anterior descending artery (LAD) occlusion: conventional balloon occlusion group (BO group, temporary balloon occlusion for 60 mins), half-balloon embolism group (HB group), and sequential balloon-balloon-sponge embolism group (BBS group, two half-balloons with one sponge as the embolism clot). The incidence of ventricular fibrillation (VF), total mortality, operating time, and vascular recanalization 3 months post-MI was recorded and compared. Echocardiography, multimodality nuclear medical imaging, and histology staining were applied for the evaluation of infarction. RESULTS: Thirteen out of 18 minipigs survived after the operation, while 5 animals died with VF (3 in the BO group, 1 in the HB group, and 1 in the BBS group), with an 83.3 % (5/6 minipigs) acute procedural survival rate in embolism groups. The operating duration was 60.0 ± 0.5 mins, 21.4 ± 5.2 mins, and 31.2 ± 4.7 mins in the three groups, respectively. LAD recanalization was found in three animals of the HB group but none in the BBS group by angiography follow-up. The infarct sizes were more stable and larger in the HB group and BBS group than that in the BO group (P < 0.05, n = 13). CONCLUSIONS: The method of sequential balloons-sponge embolization could induce myocardial infarction with consistent and sustained embolization and gain higher operation success rate and better repeatability in minipigs, which holds a promising method for preclinical MI study.

Direct Catalytic Asymmetric Synthesis of ß-Hydroxy Acids from Malonic Acid.

A nickel(II) catalyzed asymmetric synthesis of ß-hydroxy acids from malonic acid and ketones was developed, revealing for the first time the synthetic utility of malonic acid in the construction of chiral carboxyl acids; importantly, the synthetic potential of this strategy was further demonstrated by the rapid construction of cephalanthrin A, phaitanthrin B, cruciferane, and rice metabolites.

Amino acid salts catalyzed asymmetric aldol reaction of tryptanthrin: a straightforward synthesis of phaitanthrin A and its derivatives.

The first asymmetric synthesis of (S)-Phaitanthrin A and its derivatives via a catalytic aldol reaction of Tryptanthrin and ketones is described, in which the cheap, easily prepared natural amino acid salts exhibited unique catalytic ability; importantly, this methodology tolerates a range of substrates with different substitution patterns. Moreover, the synthetic utility of this strategy was further illustrated by a gram-scale synthesis of Phaitanthrin A.