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Charlotte E Coomber, Laure Benhamou, Dejan-Krešimir Bučar, Peter D Smith, Michael J Porter, Tom David Sheppard
Herein we report a silver-free Pd(II)-catalyzed C(sp3)-H arylation of saturated bicyclic and tricyclic amine scaffolds. The reaction provides good yields using a range of aryl iodides and aryl bromides including functionalized examples bearing aldehydes, ketones, esters, free phenols and heterocycles. The methodology has been applied to medicinally relevant scaffolds. Two of the intermediate palladium complexes in the catalytic cycle have been prepared and characterized, and a mechanism proposed. Removal of the directing group proceeded with good yield under relatively mild conditions...
December 14, 2017: Journal of Organic Chemistry
Federica Pollastro, Diego Caprioglio, Patrizia Marotta, Aniello Schiano Moriello, Luciano De Petrocellis, Orazio Taglialatela-Scafati, Giovanni Appendino
Treatment with iodine cleanly converts various p-menthane-type phytocannabinoids and their carboxylated precursors into cannabinol (CBN, 1a). The reaction is superior to previously reported protocols in terms of simplicity and substrate range, which includes not only tricyclic tetrahydrocannabinols such as Δ9-THC (2a) but also bicyclic phytocannabinoids such as cannabidiol (CBD, 3a). Lower homologues from the viridin series (2c and 3c, respectively) afforded cannabivarin (CBV), a non-narcotic compound that, when investigated against a series of ionotropic (thermo-TRPs) biological end-points of phytocannabinoids, retained the submicromolar TRPA1-activating and TRPM8-inhibiting properties of CBN, while also potently activating TRPV2...
December 14, 2017: Journal of Natural Products
Yujia Qing, Gökçe Su Pulcu, Nicolas Bell, Hagan Bayley
Tetrazine- and sydnone-based click chemistries have emerged as important bioconjugation strategies with fast kinetics and N2 or CO2 as the only by-product. Mechanistic studies of these reactions have focused on the initial rate-determining cycloaddition steps. The subsequent N2 or CO2 release from the bicyclic intermediates has been approached mainly through computational studies, which have predicted lifetimes of femtoseconds. In the present study, bioorthogonal cycloadditions involving N2 or CO2 extrusion have been examined experimentally at the single-molecule level by using a protein nanoreactor...
December 14, 2017: Angewandte Chemie
Eric Bourdon, Matthew Mavor, Dean C Hay
Independent cranks (IC) are recently introduced bicycle cranks that are decoupled; therefore allowing each leg to pedal independent of the other. Despite this introduction, limited research has been conducted assessing biomechanical changes when cycling with IC. Therefore, the purpose of this study was to evaluate and compare trunk kinematics and surface electromyography (sEMG) during IC and normal crank (NC) cycling during a graded exercise test to volitional fatigue. Ten healthy, physically active men performed two tests (IC and NC) on a cycling ergometer on separate days...
December 2017: Journal of Sports Science & Medicine
Therese E Johnston, Tiara A Baskins, Rachael V Koppel, Samuel A Oliver, Donald J Stieber, Lisa T Hoglund
Background: The knee is susceptible to injury during cycling due to the repetitive nature of the activity while generating torque on the pedal. Knee pain is the most common overuse related injury reported by cyclists, and intrinsic and extrinsic factors can contribute to the development of knee pain. Purpose: Due to the potential for various knee injuries, this purpose of this systematic review of the literature was to determine the association between biomechanical factors and knee injury risk in cyclists...
December 2017: International Journal of Sports Physical Therapy
Michael Blumer, Sabina Kumalic, Thomas Gander, Martin Lanzer, Claudio Rostetter, Martin Rücker, Heinz-Theo Lübbers
PURPOSE: Zygomaticomaxillary complex (ZMC) fractures are frequent in facial trauma; only fractures of the mandible are more common. Although the frequency of these fractures is geographically consistent, the aetiology differs widely among countries and even regions. Differences in socio-economic status and the ageing population seem to be two causes. This retrospective epidemiological study evaluates patients who were surgically treated for ZMC fractures at a Swiss university clinic. MATERIALS AND METHODS: This study included 471 patients who were surgically treated for ZMC fractures in an oral and maxillofacial surgery clinic at a Swiss university hospital between January 2004 and December 2012...
November 23, 2017: Journal of Cranio-maxillo-facial Surgery
Hua Gong, David S Weinstein, Zhonghui Lu, James J-W Duan, Sylwia Stachura, Lauren Haque, Ananta Karmakar, Hemalatha Hemagiri, Dhanya Kumar Raut, Arun Kumar Gupta, Javed Khan, Dan Camac, John S Sack, Andrew Pudzianowski, Dauh-Rurng Wu, Melissa Yarde, Ding-Ren Shen, Virna Borowski, Jenny H Xie, Huadong Sun, Celia D'Arienzo, Marta Dabros, Michael A Galella, Faye Wang, Carolyn A Weigelt, Qihong Zhao, William Foster, John E Somerville, Luisa M Salter-Cid, Joel C Barrish, Percy H Carter, T G Murali Dhar
We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies...
December 5, 2017: Bioorganic & Medicinal Chemistry Letters
Lanying Wang, Yunfei Zhang, Delong Wang, Mei Wang, Yong Wang, Juntao Feng
Carabrone, a botanical bicyclic sesquiterpenic lactone, has broad-spectrum antifungal activities, and is particularly efficient against the devastating phytopathogen Gaeumannomyces graminis var.tritici (Ggt). The antifungal mechanism of carabrone against Ggt, however, remains unclear. The main objective of this study was to investigate the subcellular localization of carabrone in Ggt to make a better understanding of the mechanism of action. When Ggt was exposed to carabrone (EC50 value, 28.45 μg/mL) for 7 days, the decline of mitochondrial concentration, together with some obvious alternations in the mitochondrial structure including hazy outline, medullary transition, excess accumulation of unclear settlings, and vacuolar degeneration were observed, indicating that carbrone may act on the mitochondria directly...
December 12, 2017: Journal of Agricultural and Food Chemistry
Ryo Mizojiri, Moriteru Asano, Daisuke Tomita, Hiroshi Banno, Noriyuki Nii, Masako Sasaki, Hiroyuki Sumi, Yoshihiko Satoh, Yukiko Yamamoto, Takeo Moriya, Yoshinori Satomi, Hironobu Maezaki
We initiated our structure-activity relationship (SAR) studies for selective ACC1 inhibitors from 1a as a lead compound. SAR studies of bicyclic scaffolds revealed many potent and selective ACC1 inhibitors represented by 1f, however most of them had physicochemical issues, particularly low aqueous solubility and potent CYP inhibition. To address these two issues and improve the drug-likeness of this chemical series, we converted the bicyclic scaffold into a monocyclic framework. Ultimately, this lead us to discover a novel monocyclic derivative 1q as a selective ACC1 inhibitor, which showed highly potent and selective ACC1 inhibition as well as acceptable solubility and CYP inhibition profiles...
December 12, 2017: Journal of Medicinal Chemistry
Yan Ge, Hong Yao, Juan Tong, Ying He, Guiyuan Li, Xiang'ao Kong
OBJECTIVE: To explore the effects of acupuncture on improving the peripheral skeletal muscle exercise ability in patients with chronic obstructive pulmonary disease (COPD) at stable phase. METHODS: Forty-four patients were randomly divided into an observation group (24 cases) and a control group (20 cases). Based on regular western medication treatment and aerobic training, acupuncture was used in the observation group and placebo acupuncture was used in the control group...
April 12, 2017: Zhongguo Zhen Jiu, Chinese Acupuncture & Moxibustion
Yuki Yokouchi, Shintaro Ishida, Tsunenobu Onodera, Hidetoshi Oikawa, Takeaki Iwamoto
A fascinating but still rare bicyclic siloxane, bicyclo[3.3.3]pentasiloxane, was synthesized by the oxidation of a bicyclic silicon cluster and characterized using a combination of NMR spectroscopy and X-ray diffraction analysis. The bridgehead OSiMe3 groups of the siloxane were selectively and efficiently converted to O-K+ (siloxide) by treating with tBuOK in the presence of 18-crown-6-ether. The resulting siloxides provided various bridgehead-functionalized bicyclo[3.3.3]pentasiloxanes after treatment with electrophiles...
December 12, 2017: Chemical Communications: Chem Comm
George G Zhanel, Courtney K Lawrence, Heather Adam, Frank Schweizer, Sheryl Zelenitsky, Michael Zhanel, Philippe R S Lagacé-Wiens, Andrew Walkty, Andrew Denisuik, Alyssa Golden, Alfred S Gin, Daryl J Hoban, Joseph P Lynch, James A Karlowsky
Relebactam (formerly known as MK-7655) is a non-β-lactam, bicyclic diazabicyclooctane, β-lactamase inhibitor that is structurally related to avibactam, differing by the addition of a piperidine ring to the 2-position carbonyl group. Vaborbactam (formerly known as RPX7009) is a non-β-lactam, cyclic, boronic acid-based, β-lactamase inhibitor. The structure of vaborbactam is unlike any other currently marketed β-lactamase inhibitor. Both inhibitors display activity against Ambler class A [including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemases (KPCs)] and class C β-lactamases (AmpC)...
December 12, 2017: Drugs
Chelsea Williams, Raquel Weston, Joe Feinglass, Marie Crandall
BACKGROUND: Bicycling is one of the most popular forms of play and exercise for children in the US. However, over 200,000 children per year are injured in bicycle crashes, and an estimated 22,000 pediatric bicycle-related traumatic brain injuries (TBIs) occur annually. Bicycle helmets are known to decrease the risk of head injury, but efficacy and magnitude of the effect of helmet legislation have not been fully elucidated. METHODS: This was a retrospective, observational study of children aged <18, who presented after a bicycle crash in Illinois from 1999 to 2009...
December 8, 2017: Journal of Surgical Research
Xiaohua Liu, Yu Zhang, Wenjing Huang, Wenfu Tan, Ao Zhang
The antiapoptotic protein Bcl-2, overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, we report a different structural modification approach on ABT-263 by merging the piperazinyl-phenyl fragment into a bicyclic framework leading to a series of novel analogues, among which tetrahydroisoquinoline 13 was nearly equally potent against Bcl-2 as ABT-263. Further SAR in the P4-interaction pocket affored the difluoroazetidine substituted analogue 55, which retained good Bcl-2 activity with improved Bcl-2/Bcl-xL selectivity...
December 5, 2017: Bioorganic & Medicinal Chemistry
Thomas A Alanine, Stephen Stokes, Craig A Roberts, James S Scott
A palladium mediated C-H aziridination reaction of 3,3,5,5-substituted-piperazin-2-ones has been developed using phenyliodonium diacetate (PIDA) and succinic acid to give synthetically useful bicyclic aziridines, in moderate to good yields. Succinic acid was found to be key for selectively promoting C-N bond formation (aziridination) and suppressing competitive acetoxylation. Analysis of the reaction kinetics revealed the role of succinic acid in promoting an equilibrium between monomeric and dimeric palladium species in the rate determining step of the reaction...
December 11, 2017: Organic & Biomolecular Chemistry
Mengmeng Chen, Guohua Zhu, Jiaxiang Xu, Huarong Zhang, Jinsong Liu, Kezhi Jiang
RATIONALE: Carcinogenic o-methylaniline is one of the banned aromatic amines in azo dyes, but it is very difficult to distinguish it from its noncarcinogenic isomers due to their identical retention time on chromatography and similar mass spectra. METHODS: Imidization of the isomeric methylanilines was carried out by treatment with benzaldehyde under mild conditions. The formed derivatives were analyzed by gas chromatography-mass spectrometry. Theoretical calculations were carried out on the Gaussian 03 program by using the density functional theory method at the B3LYP/6-311+G(d,p) level...
December 10, 2017: Rapid Communications in Mass Spectrometry: RCM
Bo Cao, Huan-Yu Ni, Jun Li, Ying Zhou, Xin-Lan Bian, Yan Tao, Cheng-Yun Cai, Cheng Qin, Hai-Yin Wu, Lei Chang, Chun-Xia Luo, Dong-Ya Zhu
Fear- and anxiety-related psychiatric disorders have been one of the major chronic diseases afflicting patients for decades, and new compounds for treating such disorders remain to be developed. (+)-Borneol, a bicyclic monoterpene found in several species of Artemisia and Dipterocarpaceae, is widely used for anxiety, pain and anesthesia in Chinese medicine. Meanwhile, it can potentiate GABA (γ-aminobutyric acid) activity directly in recombinant GABAA receptors. The present study was to investigate the effects of (+)-Borneol on both contextual and cued fear recall...
December 6, 2017: Biochemical and Biophysical Research Communications
Elias M Neeman, Juan Ramón Avilés Moreno, Thérèse R Huet
The gas phase structure of the bicyclic atmospheric aerosol precursor α-pinene was investigated employing a combination of quantum chemical calculation and Fourier transform microwave spectroscopy coupled to a supersonic jet expansion. The very weak rotational spectra of the parent species and all singly substituted 13C in natural abundance have been identified, from 2 to 20 GHz, and fitted to Watson's Hamiltonian model. The rotational constants were used together with geometrical parameters from density functional theory and ab initio calculations to determine the rs, r0, and rm(1) structures of the skeleton, without any structural assumption in the fit concerning the heavy atoms...
December 7, 2017: Journal of Chemical Physics
Shweta Bisht, Rashmi Rani, Rama Krishna Peddinti
An efficient [3 + 2]/[4 + 2] or double [4 + 2] cycloaddition strategy has been established for the synthesis of heterocyclic systems under mild conditions. The reaction pathway is governed by the nature of reaction partner. Several dihydrofurocoumarin, furopyranocoumarin, dihydrofuran, dihydrobenzopyran, and dihydrobenzofuran derivatives were obtained as single diastereomers from cyclic or acyclic enol ethers and styrenes. This one-pot transformation constructed C-C and C-O bonds and generated molecular complexity by domino/tandem process to produce the heterocyclic systems in good yields...
December 8, 2017: Journal of Organic Chemistry
Toshimune Nomura, Satoshi Yokoshima, Tohru Fukuyama
A total synthesis of huperzine R was accomplished. Intramolecular cycloaddition of a nitrile oxide and reductive cleavage of the resulting isoxazoline induced sequential cleavage of the C-C and C-O bonds to form the characteristic bicyclic lactam core with an enone moiety. Construction of the butenolide moiety from the enone afforded huperzine R.
December 8, 2017: Organic Letters
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