Asymmetric Total Synthesis of the Highly Strained 4ß-Acetoxyprobotryane-9ß,15α-diol.

The first and asymmetric total synthesis of 4ß-acetoxyprobotryane-9ß,15α-diol, containing a rare and highly strained trans-fused bicyclo[3.3.0]octane ring system, has been achieved. The synthetically challenging [6-5-5] tricyclic ring system in the final product was efficiently and diastereoselectively synthesized via an asymmetric rhodium-catalyzed [4 + 2] cycloaddition reaction, followed by a unique benzilic acid type rearrangement under very mild conditions. The seven contiguous stereocenters were installed efficiently and diastereoselectively.

Microwave-Assisted Intramolecular Ullmann Diaryl Etherification as the Post-Ugi Annulation for Generation of Dibenz[b,f][1,4]oxazepine Scaffold.

A sequence of the Ugi four-component reaction (U-4CR) and microwave-assisted intramolecular Ullmann etherification has been established for efficient generation of a dibenz[b,f][1,4]oxazepine scaffold. The U-4CR, using 2-aminophenols and 2-bromobenzoic acids or 2-bromobenzaldehydes as the inputs, was carried out in MeOH at 50-60 °C for 2-3 days to form a collection of 22 linear products in 46-90% yields. A microwave-assisted intramolecular Ullmann etherification was then used to transform these acyclic U-4CR products into the cleft-shaped 6/7/6-fused tricyclic heterocycles. The intramolecular Ullmann diaryl ether formation was catalyzed by 10 mol % of CuI and 30 mol % of N,N-dimethylglycine hydrochloride (DMG·HCl) in the presence of Cs2CO3 with microwave irradiation (150 °C, 30 min) to furnish dibenz[b,f][1,4]oxazepin-11(10H)-ones and dibenz[b,f][1,4]oxazepin-11(10H)-carboxamides in 64-100% yields.

Ertapenem prophylaxis of surgical site infections in elective colorectal surgery in China: a multicentre, randomized, double-blind, active-controlled study.

OBJECTIVES: Our purpose was to evaluate ertapenem versus ceftriaxone/metronidazole for prophylaxis of surgical site infections (SSIs) following elective colorectal surgery in Chinese adult patients. METHODS: Eligible Chinese adults aged 18-80 years scheduled to undergo elective colorectal surgery by laparotomy were randomized to receive a 30 min infusion of 1 g of ertapenem/metronidazole placebo or 2 g of ceftriaxone/500 mg of metronidazole within 2 h before initial incision. The study endpoint was the proportion of patients with successful prophylaxis at 4 weeks after treatment. The primary analysis was based on the evaluable population (PP population) and the pre-specified non-inferiority margin was set at -15%. ClinicalTrials.gov: NCT01254344. RESULTS: Of 599 patients randomized, 499 (251 ertapenem and 248 ceftriaxone) were eligible for inclusion in the PP population. The proportions of patients with successful prophylaxis in the ertapenem and ceftriaxone groups were 90.4% (227/251) and 90.3% (224/248), respectively. The difference in the proportion of successful outcomes was 0.1% (95% CI -5.2%, 5.5%). Unexplained antibiotic use was the most frequent reason for prophylaxis failure in both groups [ertapenem 4.8% (12/251), ceftriaxone 4.4% (11/248); difference 0.3%; 95% CI -3.6, 4.3]. Pathogen species isolated from SSI sources were consistent with previously conducted studies and the product package insert. The incidence of adverse events (AEs) was similar between the groups, with the most common AE being pyrexia [ertapenem 7.6% (22/290), ceftriaxone 5.7% (17/297)]. CONCLUSIONS: Ertapenem is as effective as ceftriaxone/metronidazole for SSI prophylaxis in patients undergoing elective colorectal surgery, and is well tolerated.

Synthesis of the Macrolactone Cores of Maltepolides via a Diene-Ene Ring-Closing Metathesis Strategy.

Synthesis of the C19-truncated maltepolide E has been accomplished via a diene-ene ring-closing metathesis (RCM) strategy without damage to the C11-C14 alkenyl epoxy unit. Upon release of the C17-OH group, it attacked at the C14 position with double bond migration and epoxide ring opening to furnish the C19-truncated maltepolides A and B as proposed for the biosynthesis of maltepolides.

Predictive value of serum visinin-like protein-1 for early neurologic deterioration and three-month clinical outcome in acute primary basal ganglia hemorrhage: A prospective and observational study.

BACKGROUND: Visinin-like protein 1 (VILIP-1) appears as a biomarker of neuronal injury. We investigated the correlation of serum VILIP-1 concentrations with severity, early neurologic deterioration (END) and functional outcome of intracerebral hemorrhage (ICH). METHODS: In this prospective and observational study, serum VILIP-1 concentrations were quantified in 106 patients with basal ganglia hemorrhage. Univariate and multivariable logistic regression analyses were used to analyze the relationship between serum VILIP-1 concentrations and END plus worse prognosis (modified Rankin Scale score of 3 or greater) at post-injury 3 months. RESULTS: Serum VILIP-1 concentrations of patients were closely correlated with hematoma volume and National Institutes of Health Stroke Scale score. Serum VILIP-1 concentrations were substantially elevated in patients with END or worse 3-month prognosis, as compared to other remainders. Also, serum VILIP-1 concentrations were independently associated with END and worse 3-month prognosis. Under ROC curve analysis, serum VILIP-1 concentrations exhibited marked accuracy for distinguishing patients with the development of END or worse 3-month prognosis. Its predictive ability was in the range of hematoma volume and National Institutes of Health Stroke Scale score. CONCLUSIONS: Serum VILIP-1 may be a good biomarker for assessing hemorrhagic severity and clinical outcomes after ICH.

2-Amino-6-methyl-pyridinium 4-nitro-benzoate.

In the crystal structure of the title salt, C(6)H(9)N(2) (+)·C(7)H(4)NO(4) (-), the cations and anions are linked by N-H⋯O hydrogen bonds, forming chains running parallel to the b axis.

[Preliminary application study of Ligasure in video-assisted thoracic pulmonary surgery].

OBJECTIVE: To investigate the application and techniques of Ligasure in video-assisted thoracic pulmonary surgery. METHODS: Use Ligasure to dissect lung parenchyma, small pulmonary vessel and stop bleeding in 15 cases spontaneous pneumothorax and 20 cases peripheral single lung node who undertaken video-assisted thoracic surgery during October 2008 to June 2010. RESULT: All the procedures were successful, no severe complications, as active bleeding, continuous air leak occurred. A period of 9.3 months (2 - 18 months) follow-up of all patients shows no delayed bleeding or recurrence pneumothorax. CONCLUSION: Ligasure is safe, easy to use. It can optimize operation and reduce the operation time.

Measuring serum melatonin concentrations to predict clinical outcome after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Oxidative stress has a key role in brain injury and melatonin possesses antioxidant effects. We aimed to ascertain the potential relationship between serum melatonin concentrations and functional outcome following aneurysmal subarachnoid hemorrhage (aSAH). METHODS: This prospective and observational study was conducted of 169 aSAH patients. Baseline serum melatonin concentrations were determined. A worse 6-month functional outcome was defined as a Glasgow Outcome Scale score of 1-3. RESULTS: Patients with a worse outcome (56 cases) compared to those with a good outcome (113 cases) exhibited significantly higher concentrations of serum melatonin (P < 0.001). An area under the receiver operating curve of 0.819 was revealed for the prediction of 6-month worse outcome by serum melatonin concentrations. Multiple logistic regression analysis showed an independent association of serum melatonin concentrations with 6-month worse outcome (odds ratio = 1.204). An intimate correlation existed between serum melatonin concentrations and World Federation of Neurological Surgeons subarachnoid hemorrhage scale scores as well as between serum melatonin concentrations and modified Fisher scores (P < 0.001). CONCLUSIONS: Patients with higher serum melatonin concentrations are more likely to have a poor prognosis. Serum melatonin can be considered as an independent predictor of functional outcome after aSAH.

A concise total synthesis of amphidinolide T2.

RCM + AD = T2: In the presence of the C16-methylene group, regioselective ring-closing metathesis (RCM) formed the (12E)-endocyclic double bond, which underwent Os-catalyzed asymmetric dihydroxylation (AD) to give the desired 12,13-diol intermediate required for the total synthesis of amphidinolide T2 in 16 linear steps in 8.0% overall yield.

Intramolecular Diels-Alder Cycloaddition Approach toward the cis-Fused Δ5,6-Hexahydroisoindol-1-one Core of Cytochalasins.

Synthesis of the cis-fused Δ5,6-hexahydroisoindol-1-one core of cytochalasins B2-B5, K, Z8, Z9, Z12-Z15, and Z17 has been established starting from an intramolecular Diels-Alder reaction of the amide-tethered (8 E)-1,3,8-nonatriene. The trans-fused 5/6-bicyclic adduct was then subjected to highly stereoselective C9-ß-hydroxylation and epimerization of the C7-α-OH group.

Total Synthesis of Laingolide B Stereoisomers and Assignment of Absolute Configuration.

Total synthesis of (-)-(2 R,9 S)- and (+)-(2 S,9 S)-stereoisomers of laingolide B has been accomplished by using sequential ring-closing metathesis (RCM) and alkene isomerization to construct the macrocyclic trans- N-methyl enamide moiety. The Myers alkylation was used to secure the C2 stereochemistry of the two RCM precursors from a common (9 S)-C3-C9 alkyl iodide. The absolute configuration of laingolide B has been assigned as (2 S,9 R) by comparison of the optical rotation data.

Total synthesis of amphidinolide Y by formation of trisubstituted (E)-double bond via ring-closing metathesis of densely functionalized alkenes.

Amphidinolide Y, a 17-membered cytotoxic macrolide isolated from marine dinoflagellates, has been synthesized via ring-closing metathesis to assemble the congested trisubstituted (E)-double bond. The seco precursor was prepared from readily available chiral synthons with the tetrahydrofuran ring formed via 5-endo epoxide ring-opening cyclization. It was found that the C6-keto seco substrate showed higher reactivity toward Grubbs' second generation catalyst while Schrock's Mo catalyst was completely inactive for formation of the macrocycle.

Diversity-oriented synthesis and solid-phase organic synthesis under controlled microwave heating.

Diversity-oriented organic synthesis (DOS) and solid-phase organic synthesis (SPOS) are proven technologies for generating small molecule libraries for chemical genetics studies. Integration of controlled microwave heating with DOS and SPOS not only speeds up the library preparation process but also offers unique opportunities in tackling issues which are hardly addressed by thermal heating. Microwave-assisted synthesis is illustrated for (a) highly regioselective Wittig olefination of cycloalkanones by accurate regulation of temperature; (b) tandem Wittig-IMDA sequence toward stereochemical diversity of gamma-butyrolactones; (c) one-pot alkylation-amidation approach toward appendage diversity through use of building blocks; and (d) one-pot U-4CR-annulation strategy toward skeletal diversity via careful reaction design. Microwave-assisted solid-phase organic synthesis (MASPOS) is highlighted by incorporating with split-pool combinatorial synthesis (SPCS) of indole sulfonamides via a key on-resin Cu(II)- or Pd(II)-catalyzed heteroannulation under microwave heating. Design and fabrication of a novel diglycine-derived catlinker are described and its role in facilitating on-resin reaction is evaluated. A traceless synthesis of indole sulfonamides via microwave-assisted Cu(II)-catalyzed heteroannulation of the catlinker-tethered substrates is also given.

Anti-epileptic Effects of Valepotriate Isolated from Valeriana jatamansi Jones and Its Possible Mechanisms.

OBJECTIVE: This work aimed to investigate the anti-epileptic effects of valepotriate isolated from Valeriana jatamansi Jones and studied its possible mechanisms. METHODS: The anti-epileptic effects of valepotriate were studied using maximal electroshock-induced seizure (MES), pentylenetetrazole (PTZ)-induced epilepsy, and pentobarbital sodium-induced sleeping model in mice. The possible anti-epileptic mechanisms of valepotriate were investigated by analyzing the expressions of GABAA, GABAB, glutamic acid decarboxylase (GAD65), Bcl-2, and caspase-3 in the brain using Western blot assay. RESULTS: The results indicated that valepotriate showed significant anti-epileptic activity against MES- and PTZ-induced epilepsy at doses of 5, 10, and 20 mg/kg, and ED50 values for MES- and PTZ-induced epilepsy were 7.84 and 7.19 mg/kg, respectively. Furthermore, valepotriate (10 and 20 mg/kg) can significantly prolong sleeping time and shorten the latency time on the pentobarbital sodium-induced sleeping time test. Furthermore, valepotriate (5, 10, and 20 mg/kg) could significantly up-regulate the expression of GABAA, GAD65, and Bcl-2 and down-regulate the expression of caspase-3, but had no significant effect on the expression of GABAB. CONCLUSION: The results indicated that valepotriate had anti-epileptic activity and the mechanisms might be associated with regulation of GABA and inhibition of neuronal apoptosis. SUMMARY: Anti-epileptic effect of valepotriate was investigated for the 1st timeValepotriate showed notable anti-epileptic activityValepotriate can significantly increase the expression of GABAA, glutamic acid decarboxylase 65, and Bcl-2 and reduce the expression of caspase-3.

Effects of microRNA-26b on proliferation and invasion of glioma cells and related mechanisms.

Neuroglioma is the most common primary malignant tumor in neurosurgery. Due to its short survival period and high patient mortality rate, neuroglioma is a major challenge in clinics. Elucidating the pathogenic mechanisms and associated molecular targets of neuroglioma can therefore benefit diagnosis and treatment of glioma. Previous studies have established the role of microRNA (miR)­26b in various tumors, including breast cancer, lymphoma and glioma. Its function and mechanism in neuroglioma, however, remains to be elucidated. In the present study, in vitro cultured U87 glioma cells were randomly divided into miR­26b mimic, miR­26b inhibitor and respective control (NC) groups. MTT assay was performed to detect the effect of miR­26b on cell proliferation, while a cell invasion assay detected its effects on cell invasion. Caspase­3 activity was also quantified to test cell apoptosis, followed by reverse transcription-quantitative polymerase chain reaction and western blotting to detect the variation of Bcl­2 expression under the effect of miR­26b. miR­26b mimics transfection upregulated its expression in U87 cells, which had significantly reduced Bcl­2 mRNA and protein expression levels and higher casapse3 activity, and inhibited cell proliferation and invasion compared with the control group. The transfection of miR­26b inhibitor, in contrast, facilitated U87 cell proliferation and invasion, inhibited caspase­3 activity and elevated Bcl­2 mRNA/protein expression. In conclusion, miR­26 could facilitate apoptosis and inhibit proliferation/invasion of neuroglioma cells via downregulating Bcl­2 expression and potentiating caspase-3 activity.

Role of galectin-3 in plasma as a predictive biomarker of outcome after acute intracerebral hemorrhage.

OBJECTIVE: Inflammation is involved in pathophysiological mechanisms underlying secondary brain injury after intracerebral hemorrhage. Enhanced circulating levels of galectin-3, a proinflammatory cytokine, have close relation to poor prognosis of some inflammatory illnesses. This study was designed to investigate whether plasma galectin-3 levels are related to the inflammation, severity and prognosis following intracerebral hemorrhage. METHODS: In this observational, prospective study, plasma galectin-3 levels of 110 patients and 110 controls were determined. We further assessed the association of galectin-3 levels with inflammation reflected by systemic C-reactive protein levels, severity indicated by hematoma volumes and National Institutes of Health Stroke Scale (NIHSS) scores, and endpoints including 1-week mortality, 6-month mortality, 6-month overall survival and 6-month unfavorable outcome (modified Rankin Scale score>2). RESULTS: Plasma galectin-3 levels of patients were significantly higher than those of controls. Galectin-3 was identified as an independent prognostic predictor for 1-week mortality, 6-month mortality, 6-month overall survival and 6-month unfavorable outcome, as well as had strong relation to C-reactive protein levels, hematoma volumes and NIHSS scores. Compared with NIHSS scores and hematoma volumes, plasma galectin-3 levels had similar areas under receiver operating characteristic curve (AUC). Moreover, galectin-3 levels significantly improved AUCs of NIHSS scores or hematoma volumes alone for prediction of 6-month mortality and 6-month unfavorable outcome. CONCLUSIONS: Elevated plasma galectin-3 levels are strongly associated with the inflammation, severity and poor prognosis after intracerebral hemorrhage, indicating galectin-3, involved in brain inflammation, might have the potential to be a prognostic biomarker for hemorrhagic stroke.

Structures and total syntheses of the plecomacrolides.

The plecomacrolides are a large family of natural products typically featured with a 16- or 18-membered macrolactone possessing two conjugated diene units and a hemiacetal side chain. The macrocycle skeleton is connected with the side chain through a three-carbon linker, forming a biologically important intramolecular hydrogen bonding network among the lactone/linker/hemiacetal structural motif. Many members of the plecomacrolides act as selective inhibitors of vacuolar H+-ATPases (V-ATPases) and they are considered to have the potential for treatment of postmenopausal osteoporosis. Significant progress has been achieved in recent years in the area of plecomacrolide total synthesis. These include the total synthesis of bafilomycin A1 by Evans, Toshima, Hanessian, and Roush, of bafilomycin V1 by Marshall, of hygrolidin by Hashimoto and Yonemitsu, of concanamycin F by Paterson and Toshima, and of formamicin by Roush. The synthetic strategies and key transformations used in the total synthesis are discussed.

Natural product inspired design of enediyne prodrugs via rearrangement of an allylic double bond.

Cyclodeca-1,5-diyn-3-ene, the parent core of naturally occurring 10-membered ring enediyne antitumor antibiotics, decomposes at 37 degrees C with a t(1/2) value of 18 h. A prodrug approach was envisaged by in situ formation of the core structure via rearrangement of an allylic double bond. Three synthetic methods including intramolecular lithium acetylide addition to aldehyde, intramolecular Nozaki-Hiyama-Kishi reaction, and intramolecular Sonogashira cross-coupling have been established for synthesis of the enediyne precursors, (E)-3-acyloxy-4-(arylmethylidene)cyclodeca-1,5-diynes. The latter are transformed into 10-membered ring enediynes in the presence of a catalytic amount of Ln(fod)(3) under mild reaction conditions. Alternatively, the enediyne precursor dissociates in buffer solution into an allylic cation or a quinone methide intermediate, which reacts with a nucleophile (such as H(2)O) to form the bioactive enediyne. LC-MS data confirmed formation of the 10-membered ring enediyne from the precursor, which exhibits DNA cleavage activity and cytotoxicity against P388 cancer cell line.

DNA cleavage potency, cytotoxicity, and mechanism of action of a novel class of enediyne prodrugs.

We have discovered a novel class of (E)-3-acyloxy-4-(arylmethylidene)cyclodeca-1,5-diynes which exhibit promising enediyne-like DNA cleavage and cytotoxic activities. LC-MS analysis of the incubation mixture (pH 8.5, 37 degrees C) confirmed formation of 10-membered ring enediyne presumably via an allylic cation and suggested that the 1,4-benzenoid diradical might be one of the active species for DNA damage and cytotoxicity.