Evidence has accumulated that reactive oxygen species and inflammation play crucial roles in the development of chronic pain, including radicular low back pain. Nonsteroid anti-inflammatory drugs (NSAIDs), for example, salicylic acid, aspirin, provided analgesic effects in various types of pain. However, long-term use of these drugs causes unwanted side effects, which limits their implication. Stable nitronyl (NIT) nitroxide radicals have been extensively studied as a unique and interesting class of new antioxidants for protection against oxidative damage. The present study synthesized a novel NIT nitroxide radical with salicylic acid framework (SANR) to provide synergistic effect of both antioxidation and antiinflammation. We demonstrated for the first time that both acute and repeated SANR treatment exerted dramatic analgesic effect in radicular low back pain mimicked by chronic compression of dorsal root ganglion in rats. This analgesic potency was more potent than that produced by classical NSAIDs aspirin and traditional nitroxide radical Tempol alone. Furthermore, SANR-induced behavioral analgesia is found to be mediated, at least in partial, by a reduction of ectopic spontaneous discharges in injured DRG neurons. Therefore, the synthesized NIT nitroxide radical coupling with salicylic acid framework may represent a novel potential therapeutic candidate for treatment of chronic pain, including radicular low back pain.

Infrasound causes functional disorders and structural injury to the central nervous system. However, few anti-infrasound drugs exist, and they are inefficient. Nitronyl nitroxide radicals have been reported to be good antioxidants that act as superoxide dismutase mimics and directly react with reactive oxygen species, such as ·OH, H2O2, and O 2 ∙ −. Our previous research showed that the nitronyl nitroxide radical L-NNNBP has good protective effects against β-amyloid deposition and memory deficits in an AD rat model of APP/PS1. The objective of the present study was to find a new group of anti-infrasound drugs and determine the underlying pharmacological actions of nitronyl nitroxide radicals against infrasound-induced neuronal impairment in vivo. We synthesized a new stable nitronyl nitroxide radical, NRbt, and characterized its crystal structure. The results of the anti-oxidative damage effects of NRbt and the positive control drug tempol showed that they could significantly increase the SOD activity, CAT activity and GSH level and decrease the MDA level in rat hippocampi compared with infrasound exposure without pretreatment. Moreover, the ability of NRbt to regulate the activity or level of these biochemical markers was better than that of tempol. Our results showed that both NRbt and tempol significantly protected against the learning and memory impairments induced by infrasound exposure in a Morris water maze, but there were no significant differences in the path length or escape latency between the rats in the tempol group and the three NRbt groups (P > 0.05). In addition, the infrasound-induced neuronal apoptosis in rat hippocampi was significantly suppressed by NRbt and tempol. The results demonstrated that compared with the infrasound exposure group, the expression of Bcl-2 was up-regulated and the expressions of Bax and caspase-3 were down-regulated in rats pretreated with NRbt (40 mg/kg) or tempol (40 mg/kg). These results showed that the newly synthesized nitronyl nitroxide radical, NRbt, may be an effective anti-infrasound drug because of its capacity to inhibit the oxidative damage of free radicals induced by infrasound exposure.

Ionizing radiation can directly attack biological macromolecules including DNA, protein and lipids. Radiation can also damage cells indirectly by the formation of lots of free radicals through the radiolysis of surrounding water molecules. As the result, ion-izing radiation may make serious injury in human immune system, reproductive system and nervous system. Several synthetic radiopro-tectors have been used in clinic. However, most of them have some undesirable side effects. Hence, natural radioprotectors with high efficiency and low toxicity have been the focus of radioprotection field in recent years. In the paper, the recent research progress in the protection and repair effects of polysaccharides on radiation damage was reviewed.

C31H33N2O3, orthorhombic, P212121 (no. 19), a = 7.8122(11) Å, b = 12.2682(18) Å, c = 28.837(4) Å, V = 2763.8(7) Å3, Z = 4, Rgt(F) = 0.0574, wRref(F2) = 0.1189, T = 273 K.

Phytochemical investigation of the n-BuOH extract of the rhizomes of Anemone rivularis var. flore-minore led to the isolation of five new oleanane-type triterpenoid saponins 1–5, together with five known saponins 6–10. Their structures were determined by the extensive use of 1D and 2D NMR experiments, along with ESIMS analyses and acid hydrolysis. The aglycone of 4 and 5 was determined as 21α-hydroxyoleanolic acid, which was reported in this genus for the first time. The cytotoxicity of these compounds was evaluated against four human cancer cell line, including HL-60 (promyelocytic leukemia), HepG2 (hepatocellular carcinoma), A549 (lung carcinoma) and HeLa (cervical carcinoma). The monodesmosidic saponins 6–8 exhibited cytotoxic activity toward all tested cancer cell lines, with IC50 values in the 7.25–22.38 μM range.

目的:研究新型氮氧自由基(N1)对心脑缺血/再灌注(I/R)损伤模型大鼠的保护作用.方法:取大鼠分别建立脑I/R模型和心肌I/R(MI/R)模型,将两种模型大鼠分别分为假手术(0.9％氯化钠注射液)组、模型(0.9％氯化钠注射液)组、阳性对照(传统的氧自由基清除剂Tempol,100 mg/kg)组和高、中、低剂量(N1,100、50、10 mg/kg)组,每组6只,均在建模前腹腔注射相应药物.就脑I/R模型,通过神经功能评分和脑梗死容积百分率评价N1的脑保护功能;就MI/R模型,通过左室收缩压(LVSP)、左室等容收缩/舒张期压力上升或下降最大速率(±dp/dtmax)和血清中肌酸激酶(CK)活性、丙二醛(MDA)的水平评价N1的心脏保护功能.结果:脑I/R模型中,与模型组比较,阳性对照组和各剂量组大鼠神经功能评分均明显增加,脑梗死容积百分率明显减小(P＜0.05或P＜0.01);与阳性对照组比较,中、高剂量组大鼠脑梗死容积百分率明显减小(P＜0.05).MI/R模型中,与模型组比较,阳性对照组和各剂量组大鼠的LVSP、±dp/dtmax均明显升高(P＜0.05或P＜0.01),各剂量组大鼠血清中CK活性、MDA水平均明显降低(P＜0.05或P＜0.01);与阳性对照组比较,高、中剂量组大鼠的LVSP、±dp/dtmax均明显升高(P＜0.05或P＜0.01),血清中CK活性、MDA水平均明显降低(P＜0.05或P＜0.01).结论:N1对大鼠的心脑I/R损伤均具有明显的保护作用,且保护作用强于Tempol.

Investigation of the n-BuOH extract of the rhizomes of Anemone taipaiensis led to the isolation of five new oleanane-type triterpenoid saponins (1-5), together with seven known saponins (6-12). Their structures were determined by the extensive use of D-1 and D-2 NMR experiments along with ESIMS analyses and acid hydrolysis. The aglycone of 1, 2 and 4 was determined as siaresinolic acid, which was reported in this genus for the first time. The cytotoxicities of the saponins 1-12, prosapogenins 4a, 5a, 10a-12a and sapogenins siaresinolic acid (SA), oleanolic acid (OA), hederagenin (HE) were evaluated against five human cancer cell lines, including HepG2, HL-60, A549, HeLa and U87MG. The monodesmosidic saponins 6-8, 5a, 10a-12a and sapogenins SA, OA, HE exhibited cytotoxic activity toward all cancer cell lines, with IC50 values ranging from 2.25 to 57.28 mu M. Remarkably, the bisdesmosidic saponins 1-4 and 9 showed selective cytotoxicity against the U87MG cells. (C) 2013 Elsevier Ltd. All rights reserved.

A new stable nitronyl nitroxyl radical NIT2011 was synthesized and characterized. The radioprotective effect and pharmacokinetics profiles of NIT2011 were investigated. The results showed that when irradiation exposure dose was 6.5 Gy gama radiation, the survival rate in the irradiation-only group was 20% on 30th day. The survival rate was 70%, 80%, and 90% on 30th day when mice were pretreated with 0.25, 0.5 and 1.0 mmol/kg NIT2011, respectively. The pretreatment of NIT2011 increased number of spleen colonies, the numbers of bone marrow cells and protein level in bone marrow cells. Pretreatment with NIT2011 prior to radiation exposure increased the plasma SOD (superoxide dismutase) activity. 24 h after irradiation exposure, level of plasma MDA (malondialdehyde) in irradiation-only mice was 14.8 ± 2.8 nmol/mL, level of plasma MDA in NIT2011 (1 mmol/kg) pretreated mice was 9.8 ± 2.0 nmol/mL. Three days after irradiation exposure, the micronucleus ratio in irradiation-only mice is 40.2 ± 3.6, the micronucleus ratio in NIT2011 (1 mmol/kg) pretreated mice was 11.7 ± 1.2. NIT2011 was easily absorbed in mice after it was oral administrated. Compared with the intraperitoneal injection, the relative oral bioavailability of the NIT2011 was 27.5% in mice. The LD50 of NIT2011 was 1510 mg/kg in mice by oral administration. Thus, NIT2011 has potential in being developed as an oral dosage form, safe and effective radioprotective agent.

Phytochemical investigation of the n-BuOH extract of the rhizomes of Anemone taipaiensis led to the isolation of three new oleanane-type triterpenoid saponins (1-3), together with four known saponins (4-7). Their structures were elucidated on the basis of spectroscopic analysis and chemical derivatization. All the compounds were isolated for the first time from A. taipaiensis. The cytotoxicity of these compounds was evaluated in five human cancer cell lines including A549 (lung carcinoma), HeLa (cervical carcinoma), HepG2 (hepatocellular carcinoma), HL-60 (promyelocytic leukemia), and U87MG (glioblastoma). The monodesmosidic saponin 4 exhibited cytotoxic activity toward all cancer cell lines, with IC50 values ranging from 6.42 to 18.16 μM. In addition, the bisdesmosidic saponins 1 and 7 showed selective cytotoxicity against the U87MG cells.

What is known and Objective: Tenofovir dipivoxil fumarate is a novel ester prodrug of tenofovir, a specific anti-hepatitis B virus (HBV) drug candidate. The pharmacokinetic properties and the effects of food intake on tenofovir dipivoxil have not yet been reported in healthy adults. The aim of this study was to evaluate the pharmacokinetic properties and food interaction of tenofovir dipivoxil in healthy Chinese volunteers.Methods: Pharmacokinetic studies included an ascending single dose of 150, 300, 600 mg and multiple doses of 300 mg. Food interaction was evaluated following a single oral dose of tenofovir dipivoxil fumarate 300 mg administered with a high-fat and high-energy standard breakfast or after a 12-h fast. Pharmacokinetic parameters of tenofovir given in each treatment period were calculated using non-compartmental analysis.Results: After a single dose of 150, 300 and 600 mg, the main pharmacokinetic parameters for tenofovir were as follows: C-max 209.6, 456.7, 989.8 ng/mL; AUC(last) 1744.9, 2663.5, 6010.2 ng h/mL, respectively. After multiple doses of 300 mg, the main pharmacokinetic parameters for tenofovir were C-max 523.4 ng/mL, AUC(last) 4152.4 ng h/mL. After a single dose of 300 mg with a high-fat and high-energy standard breakfast, the main pharmacokinetic parameters for tenofovir were C-max 448.5 ng/mL, AUC(last) 3286.8 ng h/mL. The plasma C-max and AUC of tenofovir showed significance difference between a single dose of 300 mg and the accordingly multiple doses (P < 0.05). A standard high-fat meal enhanced mean AUC(last) values of tenofovir (relative AUC(last) = 125.8%; 90% CI 114.5, 136.2); however, food did not show any significant on C-max (relative C-max = 103.4%; 90% CI 94.6, 112.6).What is new and Conclusions: Oral tenofovir dipivoxil fumarate produced predictable and dose-proportional plasma tenofovir pharmacokinetics. The accumulation ratio was 1.51, suggesting tenofovir dipivoxil fumarate displayed accumulation after repeated administration. The bioavailability of tenofovir dipivoxil fumarate was increased by approximately 25% as measured by AUC(last) after a single dose when taken with food, compared with fasting.

We have developed a series of new C(10) dipeptide stationary phases via a simple and effective synthetic method. The preparation of the new phases involves the synthesis of silanes and the surface modification of silica. Chromatographic evaluations of these columns were performed using the Engelhardt, Tanaka, and Neue test mixtures. The applicability of these new stationary phases was also evaluated using a series of diagnostic probes including acids, bases or neutral compounds and several generic applications. These new C(10) dipeptide stationary phases showed excellent hydrolytic stability over a wide pH range. Like other existing amide-embedded columns, these new stationary phases exhibit higher retention for polar and hydrophilic compounds and different selectivity as compared to conventional C(18) columns. These new phases are compatible with 100% aqueous mobile phases, and also provide high column efficiency and good peak shapes for both acidic and basic compounds.

A new complex [Mn(hfac)(2)NIT(Ph-m-OPh)] has been synthesized and structurally characterized by X-ray diffraction. It crystallizes in the monoclinic space group P2(1)/c. The structure consists of a 1-D chain with Mn(II) bridged by NIT(Ph-m-OPh). The manganese(II) is in a distorted octahedral environment formed by one oxygen from NIT(Ph-m-OPh) and three atoms from hexafluoro acetylacetone (hfac) in the equatorial plane and two oxygens from hfac and the other NIT(Ph-m-OPh) in the axial position. The units of [Mn(hfac)(2)NIT(Ph-m-OPh)] are connected as a 1-D chain by Mn(II) and oxygen of N-O in bridging NIT(Ph-m-OPh) along the b-axis. The 2-D layer in the ab plane is formed via hydrogen interactions to connect neighboring chains. The complex exhibits intramolecular antiferromagnetic interactions between Mn(II) and NIT(Ph-m-OPh).

A sensitive and specific liquid-chromatography tandem mass spectrometry (LC-MS/MS) assay has been developed and validated for the simultaneous quantification of ivabradine and its active metabolite N-desmethylivabradine in human plasma and urine. The assay employed a single liquid–liquid extraction of the analytes from plasma and urine samples, and diazepam was used as internal standard (IS). The chromatographic separation was achieved on a Diamonsil C18 column (150 mm×4.6 mm, 5 μm, Dikma) using a mixture of methanol and aqueous 5 mM ammonium acetate buffer containing 0.2% formic acid (80:20, v/v) as mobile phase. The assay for ivabradine and N-desmethylivabradine in plasma showed good linearity (r≥0.99) over the ranges 0.1013–101.3 ng/mL and 0.085–25.5 ng/mL, respectively. The assay for ivabradine and N-desmethylivabradine in urine showed good linearity (r≥0.99) over the ranges 10.13–6078 ng/mL and 8.5–850 ng/mL, respectively. The intra- and inter-day accuracy and precision values were found to be within the assay variability limits (RSD<15%) in accordance with FDA guidelines. The methods were successfully used for evaluating the pharmacokinetic properties of ivabradine and N-desmethylivabradine in human plasma and urine in Chinese healthy volunteers.

Four novel axially chiral nitronyl nitroxides derived from S- or R-1,l'-bi-2-naphthol were synthesized and their crystal structures discussed. Circular dichroism spectra of these compounds showed significant Cotton effects between 200 and 400 nm, and also confirmed the optical activity of these enantiomers. The magnetic properties of the two pairs of nitronyl nitroxide radicals were characterized by magnetic susceptibility measurements. The results showed that in these four radicals exist antiferromagnetic interactions in all cases at low temperatures.

The generation of reactive oxygen species causes cellular oxidative damage, and has been implicated in the etiology of Alzheimer's disease (AD). L-NNNBP, a new chiral pyrrolyl α-nitronyl nitroxide radical synthesized in our department, shows potential antioxidant effects. The purpose of this study was to investigate the protective effects of L-NNNBP on β-amyloid (Aβ) deposition and memory deficits in an AD model of APP/PS1 mice. In cultured cortical neurons, L-NNNBP acted as an antioxidant by quenching reactive oxygen species, inhibiting lipid peroxidation, nitrosative stress, and stimulating cellular antioxidant defenses. L-NNNBP inhibited cell apoptosis induced by Aβ exposure. In vivo treatment with L-NNNBP for 1 month induced a marked decrease in brain Aβ deposition and tau phosphorylation in the blinded study on APP/PS1 transgenic mice (1 mM in drinking water, initiated when the mice were 6 months old). The L-NNNBP-treated APP/PS1 mice showed decreased astrocyte activation and improved spatial learning and memory compared with the vehicle-treated APP/PS1 mice. These actions were more potent compared with that of curcumin, a natural product, and TEMPO, a nitroxide radical, which are used as free radical scavengers in clinics. These results proved that the newly synthesized L-NNNBP was an effective therapeutic agent for the prevention and treatment of AD.

ChemInformVolume 43, Issue 9 Heterocyclic Compounds ChemInform Abstract: A Simple Synthesis of (S)-α,α-Diaryl-2-pyrrolidinemethanols. Ping-An Wang, Ping-An Wang Dep. Chem., Fourth Mil. Med. Univ., Xian 710032, Peop. Rep. ChinaSearch for more papers by this authorWen-Min Liu, Wen-Min Liu Dep. Chem., Fourth Mil. Med. Univ., Xian 710032, Peop. Rep. ChinaSearch for more papers by this authorXiao-Li Sun, Xiao-Li Sun Dep. Chem., Fourth Mil. Med. Univ., Xian 710032, Peop. Rep. ChinaSearch for more papers by this author Ping-An Wang, Ping-An Wang Dep. Chem., Fourth Mil. Med. Univ., Xian 710032, Peop. Rep. ChinaSearch for more papers by this authorWen-Min Liu, Wen-Min Liu Dep. Chem., Fourth Mil. Med. Univ., Xian 710032, Peop. Rep. ChinaSearch for more papers by this authorXiao-Li Sun, Xiao-Li Sun Dep. Chem., Fourth Mil. Med. Univ., Xian 710032, Peop. Rep. ChinaSearch for more papers by this author First published: 02 February 2012 https://doi.org/10.1002/chin.201209106Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume43, Issue9February 28, 2012 RelatedInformation

[Objective] The aim was to develop a method of RP-HPLC for determination of flavnoid aglycones―quercitin in willow leaf,and to discover its content.[Method] Willow leaves were collected in the middle of April.The flavonoids in the leaves were extracted by successive extraction with methanol.The extracts were acid-hydrolyzed before being tested with RP-HPLC.The condition of RP-HPLC was:Diamonsil C18 column(150 mm×4.6 mm,5 μm);concentration of mobile phase was 0.07%;phosphoric acid-water-free ethanol(50:50,V/V);mobile speed was 1.0 ml/min;tested wave length 260 nm;sampling amount 10 μl;flexibility 0.000 1 AUFS;column temperature was indoor temperature(20 ℃).[Result] The constituent of flavnoid aglycones in willow leaves was mainly quercitin and it consisted of 0.36%-0.74% flavnoid aglycones.[Conclusion] The method of RP-HPLC for determination of quercitin in willow leaf provided reference for the effective use of willow.

In the title compound, C(16)H(21)N(2)O(5), the benzene ring is nearly perpendicular to the imidazole ring, making a torsion angle of 88.6 (8)°·The crystal structure is stabilized by non-classical C-H⋯O and C-H⋯π inter-actions, which build up a three-dimensional network.

Two pairs of new optically active nitronyl nitroxides derived from N-Boc-D-or L-prolinol are described. The synthetic route consist of (1) the synthesis of chiral aryl aldehydes by Mitsunobu reaction, (2) the condensation of the 2,3-bis(hydroxylamino)-2,3-dimethylbutane with chiral aldehydes to give 1,3-dihydroxyimidazolidine, and (3) the final oxidation of 1,3-dihydroxyimidazolidine with aqueous NaIO4 at 0 degrees C. These two pairs have been specifically designed for further assessing the differences in activity of chiral nitronyl nitroxides and for developing chiral molecular magnetic material by the metal-radical complexes approach.