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Vorapaxar is an approved drug for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Subsequent to the discovery of Vorapaxar, medicinal chemistry efforts were continued to identify structurally differentiated leads. Toward this goal, extensive structure-activity relationship studies using a C-ring-truncated version of Vorapaxar culminated in the discovery of three leads, represented as

Anti-programmed cell death-ligand 1 (Anti-PD-L1) blockades have become the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC) from CASPIAN and IMpower133 trials. SCLC has a high incidence of brain metastasis (BM) and brain radiotherapy (BRT) is the main local treatment method, but there is limited data on the BRT-immunotherapy scheme. The aim of the retrospective study is to investigate the clinical efficacy and safety of the first-line anti-PD-L1 blockades combined with BRT in ES-SCLC with BM.Patients with newly diagnosed ES-SCLC with baseline BMs at Shandong Cancer Hospital and Research Institute between 2017 and 2021 were selected. Patients were divided into the anti-PD-L1+BRT group and BRT group. We also assessed the leukoencephalopathy in both groups.A total of 46 patients were selected. Fifteen were divided into anti-PD-L1+BRT group and 31 to BRT group. The median overall survival (OS) was not reached (NR) vs 15.9 m (P = 0.172). Progression-free survival (PFS) was numerically prolonged with anti-PD-L1 blockades, but the significance was not reached (median: 9.4 m vs 7.4 m, P = 0.362). The median intracranial PFS was not improved, neither (median: 8.2 m vs 8.9 m, P = 0.620). Objective response rate (ORR) in the two groups was 73.33% vs 77.42% (P = 0.949) and disease control rate (DCR) was both 100%. Intracranial ORR and DCR were 53.33% vs 70.97% (P = 0.239) and 73.33% vs 80.65% (P = 0.855), respectively. There was no significant difference in leukoencephalopathy incidence between the two groups.The combination of first-line anti-PD-L1 blockades with BRT did not confer a significant survival benefit in ES-SCLC with BM, without enhancing cranial neurotoxicity.

In-clinic dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling for improved logistical feasibility and decreased blood volume burden. However, an interim PK analysis revealed verubecestat concentrations in DBS samples declined with time to assay in both trials. An investigation revealed wide variation in implementation practices for DBS sample handling procedures resulting in insufficient desiccation which caused verubecestat instability. High-resolution mass spectrometry evaluations of stressed and aged verubecestat DBS samples revealed the presence of two hydrolysis degradants. To minimize instability, new DBS handling procedures were implemented that provided additional desiccant and minimized the time to analysis. Both verubecestat hydrolysis products were previously discovered and synthesized during active pharmaceutical ingredient stability characterization. A liquid chromatography-mass spectrometry assay to quantitate the dominant verubecestat degradant in DBS samples was developed and validated. The application of this method to stressed and aged verubecestat DBS samples confirmed that degradant concentrations accounted for the observed decreases in the verubecestat concentration. Furthermore, after increasing desiccant amounts, degradant concentrations accounted for approximately 7% of the verubecestat concentration in DBS clinical samples, indicating that issues with sample handling were minimized with new storage and shipping conditions. This case study illustrates the challenges with employing new sampling techniques in large, global trials, and the importance of anticipating and mitigating implementation risks.

Background: Percutaneous transforaminal endoscopic discectomy (PTED) is a minimally invasive surgical method for the treatment of spinal diseases. However, the operation procedure relied on the radiative interventional technology, and was conducted under local anesthesia. Method: From June 2016 to December 2019, we performed a newly developed full-endoscopic visualized foraminoplasty and discectomy under general anesthesia in 30 patients with L5/S1 LDH. In this retrospective study, the outcomes and neurological complications of this approach were evaluated. Results: The mean visual analog scale (VAS) and Oswestry Disability Index (ODI) were significantly improved after surgery. The postoperative MRI reexamination revealed that the degree of intervertebral disc degeneration of each subject was improved significantly to different degrees as compared with that before surgery. The learning curve showed operative time rapidly decreased over the earlier cases, and then tapered to a steady state in the latter cases. Conclusions: Full-endoscopic foraminoplasty and discectomy under general anesthesia is efficient and safe for the treatment of the L5-S1 disc herniation.Trial registration: N/A

We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.

Utilizing data from the China Health and Nutrition Survey (CHNS) from 1991 to 2011, we aim to analyze the effects of income distribution on two risks for chronic diseases: body mass index (BMI) and blood pressure. Unlike the previous studies, we consider two different kinds of indicators of income distribution: inequality and polarization. Different from relative inequality indicators such as the Gini index, which measure income gaps only, the recently developed polarization indicator captures group clustering and social alienation, in addition to income gaps. Our empirical results demonstrate that both BMI and blood pressure are positively correlated with income polarization, while inequality is a weaker predictor of these health outcomes. Thus, polarization, rather than inequality, should be used when analyzing the relationship between health outcomes and income distribution. We also examine the polarization-to-health transmission mechanism using mediation and moderation analytic frameworks. The results suggest that social networks mediate the effect of polarization on BMI and neutralize the effect on blood pressure.

In microbial electrolysis cells (MECs), methanogenic communities were sensitively affected both by hydrogen production rate, which were regulated by external voltages, and by initial cathodes, which were determined by reactor startup mode. Hydrogenotrophic methanogens, such as Methanobacterium, Methanococcus, Methanocorpusculum, and Methanoculleus, were enriched in the anode biofilm with a high voltage (0.7 V), which promoted a hydrogen production rate of 0.99–1.10 mL H2 per mL reactor in a 24 h batch operation, compared to 0.08–0.09 mL H2 per mL reactor at low applied voltage (0.3 V). Acetoclastic methanogens were only obtained from Methanosarcina, which competed with anode respiring bacteria in the anode biofilm, and they were largely detected in open circuit reactors (control). GeoChip analysis revealed that MECs with the largest hydrogen yields had the highest microbial diversity of methanogens. The cathodic products (hydrogen, methane) can simultaneously make the anodophilic community structure comprehensive and diverse despite the use of only a single substrate (acetate) in MECs. The results indicated that the evolution of microbial communities was substantially affected by external voltage and initial operational modes, but methanogen communities were inevitably affected by cathodic products. Higher applied voltage positively affected the relative abundance of cytochrome gene among the overall detected genes, and methanogens were consequently promoted by high coulombic efficiency and fast hydrogen production rate. This research can help in understanding of improving or regulating the quality of products from MEC reactors in the future.

Relebactam, a potent β-lactamase inhibitor, in combination with Primaxin is an FDA-approved (Recarbrio) treatment for serious and antibiotic-resistant bacterial infections. An efficient synthesis of key chiral piperidine intermediate

Sediments and their associated microbial communities are a vital part of riverine ecosystems. In order to understand the effects of ecology-types on microbial communities in the riverine sediments, the sediments and water samples were collected from several ecology-types along the Songhua River, and characterized in several ways. We analyzed the microbial communities in the sediments using denaturing gradient gel electrophoresis (DGGE). Furthermore, we determined environmental parameters, such as organic matter, nutrients (total N and P) and particle size distribution. The results revealed that the sediments are grouped by ecology-types along the river, but not by their geographical location. Longitude, latitude and elevation were also partially correlated with microbial community composition. This study suggests that sites of similar ecology-types affect the microbial communities in a similar manner, and result in increased heterogeneity in ecological landscapes.

Objective Psoralen is a natural plant toxin which has the function of protecting fungi, insects, and herbivores. In this study, we aim to investigate the effect and mechanism of psoralen on steroid-induced avascular necrosis of femoral head (SANFH). Methods Thirty rabbits were randomly divided into blank group (n = 10), model group (n = 10), and experimental group (n = 10). Rabbits in blank and model groups were treated with normal saline, and rabbits in experimental group were treated with psoralen. Total RNA of bone marrow was extracted by trizol, and the mRNA expression of PPARγ and osteocalcin were detected by q-PCR. Then, the mRNA expression of PPARγ and osteocalcin in the three groups were compared. Western blot was used to detect the PPARγ protein expression in the bone of rabbits. ELISA was used to measure the osteocalcin protein. Results The mRNA expression of PPARγ in model group significantly increased compared with blank group. The mRNA expression of osteocalcin in model group decreased compared with blank group. However, the mRNA and protein expressions of PPARγ in experimental group were significantly decreased compared with the model group. The protein expressions of osteocalcin increased compared with the model group. There was no significant difference of trabecular bone area (TBA) between experimental and blank groups (P > 0.05). TBA in model group was lower than the experimental group (P 0.05). Conclusion This research confirms that psoralen plays a positive role in the rehabilitation of SANFH.

An enantioselective arylation reaction catalyzed by palladium complexed with substituted phosphinooxazoline (PHOX) ligands is described. Aza-quaternary stereocenters are readily accessible through the arylation reaction between cyclic iminosulfates and a wide variety of arylboronic acids, including electron-poor and ortho-substituted arylboronic acids. This reaction was applied to the preparation of verubecestat, which is currently undergoing clinical evaluation for the treatment of Alzheimer’s disease.

Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

Orally bioavailable inhibitors of β-(1,3)- d -glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein.

Rhodobacter sphaeroides W16 and Acinetobacter lwoffii DNS32 which were isolated from soil in cold area subjected to a long-term atrazine application in Heilongjiang Province (China) can degrade atrazine efficiently. The investigation of their antioxidant properties will be useful for bioremediation and engineering applications of atrazine-degrading bacteria. Superoxide dismutase (SOD) and catalase (CAT) from two atrazine-degrading bacteria and one non-atrazine-degrading bacterium were tested for response to the oxidative stress caused by atrazine. Atrazine produced a greater inhibition of growth in Bacillus subtilis B19. The three bacteria apparently produced two activity peaks of SOD and CAT. The results demonstrated all three bacteria possessed a mechanism for atrazine tolerance that may include controlling the cellular redox balance by producing reactive oxygen species (ROS) and the subsequent scavenging of the ROS, but such response was more rapid and at lower levels in the two atrazine-degrading bacteria, suggesting less oxidative damage in these cells upon atrazine exposure. Compared to B. subtilis B19, atrazine-degrading bacteria had relatively high tolerance to atrazine stress, especially R. sphaeroides W16. Therefore, R. sphaeroides W16 and A. lwoffii DNS32 have a good application prospect of bioremediation project for soil contaminated by atrazine in cold area in Heilongjiang Province.

Statistical experimental designs provided by statistical analysis system (SAS) software were applied to optimize the fermentation medium composition for the production of atrazine-degradingAcinetobactersp. DNS32in shake-flask cultures. A “Plackett-Burman Design” was employed to evaluate the effects of different components in the medium. The concentrations of corn flour, soybean flour, and K2HPO4were found to significantly influenceAcinetobactersp. DNS32production. The steepest ascent method was employed to determine the optimal regions of these three significant factors. Then, these three factors were optimized using central composite design of “response surface methodology.” The optimized fermentation medium composition was composed as follows (g/L): corn flour 39.49, soybean flour 25.64, CaCO33, K2HPO43.27, MgSO4·7H2O 0.2, and NaCl 0.2. The predicted and verifiable values in the medium with optimized concentration of components in shake flasks experiments were7.079×108 CFU/mL and7.194×108 CFU/mL, respectively. The validated model can precisely predict the growth of atrazine-degraing bacterium,Acinetobactersp. DNS32.

Supplemental Digital Content is available in the text, Background: Total knee arthroplasty (TKA) is one of the most common joint replacement surgeries in the United States. Postoperative pain is still a major complication after TKA. Electroacupuncture (EA) has been commonly used in clinical practice for pain after TKA, but its effects and safety remain uncertain. This protocol is described for a systematic review to investigate the beneficial effects and safety of EA for postoperative pain after TKA. Methods: Randomized controlled trials (RCTs) related to EA treatment of pain after TKA will be collected from 3 databases of English literature, namely PubMed, Embase, and Cochrane Library, and 4 databases of Chinese literatures, namely CBM, CNKI, VIP and Wanfang database. The retrieved trials will be those published from the time when the respective databases were built to January 2018. The therapeutic effects according to the change from baseline in the amount of pain measured by the visual analogue scale (VAS) or numerical rating scale, will be accepted as the primary outcomes. We will use RevMan V.5.3 software as well to compute the data synthesis carefully when a meta-analysis is allowed. Results: This systematic review and meta-analysis will provide a high-quality synthesis of current evidence of EA for pain after TKA. Conclusion: The conclusion of our systematic review will provide evidence to judge whether EA is an effective intervention for patient with postoperative pain after TKA. PROSPERO registration number: PROSPERO CRD 42018082407.

Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

Several tetrahydrofluorenones with a triazole fused across C7-C8 showed high levels of ERbeta-selectivity and were found to be potent ERbeta-agonists. As a class they demonstrate improved oral bioavailability in the rat over a parent class of 7-hydroxy-tetrahydrofluorenones. The most selective agonist displayed 5.7 nM affinity and 333-fold selectivity for ERbeta.

Sometimes a surprise can occur in a total synthesis. The preparative investigation of the title compound CP-263,114 and of CP-225,917 (1)—both natural products that were first isolated in 1997 by Pfizer—has shown that CP compounds of the 7R series can be converted into the 7S series (for example, 2); (7S)-CP-263,114 is itself apparently a fermentation product.

A reaction sequence made up of a Sakurai reaction, ketene cyclization, sulfur-directed Baeyer–Villiger reaction, and tandem lactone cleavage/isomerization provided the fully functionalized core of the CP compounds. Key steps were the methanolysis of 1, which leads via 2 to the CP precursor 3.

Epothilones are a new class of natural products that bind to tubulin and prevent the depolymerization of microtubules, although they have no structural similarity to paclitaxel. Taxanes are only marginally effective in the treatment of disseminated prostate cancer, although they may have useful activity when administered in combination with estramustine. Unlike paclitaxel, epothilones are not substrates for P-glycoprotein and are active in multidrug resistant cells. Epothilones A and B (EA, EB) have recently been synthesized in toto. In this report, we examine the effects of synthetic epothilones and their desoxy derivatives, as well as paclitaxel, on prostate cancer cell lines. EB was the most active of these compounds in tissue culture (IC(50): 50-75 pM), four to ten-fold more potent than paclitaxel. EA and the desoxyderivatives of EA and EB (dEA, dEB) were also active, but less potent than EB. Each of these compounds causes mitotic block followed by apoptotic cell death. The relative potencies for cell cycle arrest and cytotoxicity directly correlate with the ability of the drugs to bind microtubules, stabilize mitotic spindles and induce the formation of interphase microtubule bundles. Therefore, synthetic epothilones are potent inhibitors of prostate cancer cell lines and work in a fashion similar to paclitaxel. Recently, we showed that farnesyl transferase inhibitors sensitize tumor cells to paclitaxel-induced mitotic arrest. We now have extended these observations to show that paclitaxel and the epothilones synergize with FTI to arrest the growth of prostate cancer cells. Moreover, this occurs in DU145, a cell line that is not particularly sensitive to the FTI. The combination of FTI and epothilone represent a new potential clinical strategy for the treatment of advanced prostatic cancer.

The reactions of a series of enamines generated from a range of cyclic ketones with chloromethyl and iodomethyl vinyl ketone have been studied. The principal products are bridged ring diketones. The four carbon bridge, bearing a 2-oxobutyl function, spans the α and α′ carbons of the original cyclanone. Presumptive evidence as to the pathway of this novel one step bridging annulation is provided.

A new class of 16-membered macrolides, the epothilones (Epos), has been synthesized and evaluated for antitumor potential in vitro and in vivo. Recent studies in these and other laboratories showed that epothilones and paclitaxel (paclitaxel) share similar mechanisms of action in stabilizing microtubule arrays as indicated by binding-displacement studies, substitution for paclitaxel in paclitaxel-dependent cell growth, and electron microscopic examinations. The present study examined cell growth-inhibitory effects in two rodent and three human tumor cell lines and their drug-resistant sublines. Although paclitaxel showed as much as 1,970-fold cross-resistance to the sublines resistant to paclitaxel, adriamycin, vinblastine, or actinomycin D, most epothilones exhibit little or no cross-resistance. In multidrug-resistant CCRF-CEM/VBL 100 cells, IC 50 values for EpoA (1), EpoB (2), desoxyEpoA (3) (dEpoA), desoxyEpoB (4) (dEpoB), and paclitaxel were 0.02, 0.002, 0.012, 0.017, and 4.14 μM, respectively. In vivo studies, using i.p. administration, indicated that the parent, EpoB, was highly toxic to mice and showed little therapeutic effect when compared with a lead compound, dEpoB. More significantly, dEpoB (25–40 mg/kg, Q2Dx5, i.p.) showed far superior therapeutic effects and lower toxicity than paclitaxel, doxorubicin, camptothecin, or vinblastine (at maximal tolerated doses) in parallel experiments. For mammary adenocarcinoma xenografts resistant to adriamycin, MCF-7/Adr, superior therapeutic effects were obtained with dEpoB compared with paclitaxel when i.p. regimens were used. For ovarian adenocarcinoma xenografts, SK-OV-3, dEpoB (i.p.), and paclitaxel (i.v.) gave similar therapeutic effects. In nude mice bearing a human mammary carcinoma xenograft (MX-1), marked tumor regression and cures were obtained with dEpoB.

Important progress towards the total syntheses of the title compounds, potent inhibitors of squalene synthase and farnesyl transferase, has been accomplished by the construction of the highly functionalized compound 1.

Ein entscheidender Schritt auf dem Weg zur Totalsynthese der Titelverbindungen, die die Squalen-Synthase und Farnesyl-Transferase inhibieren, gelang durch den Aufbau der hochfunktionalisierten zentralen Ausgangsverbindung 1.

Convergent, stereocontrolled total syntheses of the microtubule-stabilizing macrolides epothilones A (2) and B (3) have been achieved. Four distinct ring-forming strategies were pursued (see Scheme...

The title compounds have been synthesized in a convergent way by recourse to a Weiler type dianion construction.

Bacteria are present extensively in the environment. Investigation of their antioxidant properties will be useful for further study on atrazine stress tolerance of bacteria and the defense mechanism of antioxidant enzymes against atrazine or other triazine herbicides. Superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and total antioxidant capacity (T-AOC) from one Gram-negative representative strain Escherichia coli K12 and one Gram-positive representative strain Bacillus subtilis B19, respectively, were tested for response to atrazine stress. The results indicated that SOD, CAT, GST and T-AOC were induced upon exposure to atrazine. The growth of two bacteria was better in the absence than in the presence of atrazine, indicating that atrazine can decrease bacterial growth. The changes of enzyme activities indicate the presence of oxidative stress. Oxidative stress induced by atrazine may be due to imbalance of redox potential in bacterial cells, which leads to bacterial metabolic disorder.

The title compounds have been synthesized in a convergent way by recourse to a Weiler type dianion construction.

Convergent, stereocontrolled total syntheses of the microtubule-stabilizing macrolides epothilones A (2) and B (3) have been achieved. Four distinct ring-forming strategies were pursued (see Scheme...

Important progress towards the total syntheses of the title compounds, potent inhibitors of squalene synthase and farnesyl transferase, has been accomplished by the construction of the highly functionalized compound 1.

The reactions of a series of enamines generated from a range of cyclic ketones with chloromethyl and iodomethyl vinyl ketone have been studied. The principal products are bridged ring diketones. The four carbon bridge, bearing a 2-oxobutyl function, spans the α and α′ carbons of the original cyclanone. Presumptive evidence as to the pathway of this novel one step bridging annulation is provided.

Put dead immobilized saccharomyces cerevisiae biomass into column of continuous upflowing reactor. Study the influence of temperature, quantity of saccharomyces cerevisiae in column and initial Cu 2+ concentration on Cu 2+ adsorption. Determine optimal operating parameters of initial pH values, flow rates and quantities of saccharomyces cerevisiae in column through orthogonal experiment. Analyse adsorption mechanisms on Cu 2+ by saccharomyces cerevisiae powder through SEM. The results show optimal conditions are normal temperature, quantity of saccharomyces cerevisiae in column 80 g/L and initial Cu 2+ concentration 20 mg/L. The orthogonal experiment indicates that the optimal test condition was initial pH value 6, flow rate 5 mL/min, quantity of saccharomyces cerevisiae in column 80 g/L. SEM figures indicate that inorganic precipitation mechanism and redox mechanism might work in the process, and that the cell wall plays an important role in Cu 2+ adsorption.

Tetrahydrofluorenones which possess a C9a-fluoroalkyl substituent were efficiently converted to tetrahydrofluorenones which contain a ring bridging C9a−C2. Conditions include a stepwise sequence of...

Tetrahydrofluorenones which possess a C9a-fluoroalkyl substituent were efficiently converted to tetrahydrofluorenones which contain a ring bridging C9a-C2. Conditions include a stepwise sequence of conversion to an alkyl bromide followed by treatment with base, and a direct cyclization by treatment with lithium chloride in DMF heated to 150 degrees C.

Das quartare Stereozentrum an C7 einer Vorstufe der Titelverbindungen konnte durch Addition des von Trost beschriebenen Ylids an 1 aufgebaut werden. Dies und eine Photooxidation, die die Maleinsaureanhydrid-Einheit liefert, sind zwei weitere wichtige Schritte fur die Totalsynthese der beiden Verbindungen.

Synthesis of a series of fused pyrazole tetrahydrofluorenone analogs which are potent, ERbeta subtype selective ligands is described. Analogs possessing subnanomolar ERbeta binding, greater than 100-fold ERbeta-selectivity, and oral bioavailability are reported.