Human AKR1A1 involves in metabolic activation of carcinogenic aristolochic acidⅠ

OBJECTIVE To investigate whether aldo-keto reductases(AKRs)can act as a nitrore⁃ductase(NR)and bioactivate aristolochic acidⅠ(AA-Ⅰ)to produce AA-Ⅰ-DNA adducts.METHODS①Human-induced hepatocytes(hiHeps)and human bladder RT4 cells were used as tool cells and treated with AA-Ⅰ0,0.5,1.0 and 2μmol·L^(-1)for 24 h.Cell viability was detected using the CCK-8 method,and the half maximal inhibition concentration(IC_(50))was calculated using the CCK-8 method and the level of DNA adduct production was calculated.②hiHeps and RT4 cells were treated with AKR inhibitor luteotin(0,5,10 and 25μmol·L^(-1))+AA-Ⅰ0.2 and 1.0μmol·L^(-1)for 24 h,respectively,and the levels of DNA adducts were detected by a liquid chromatography-tandem mass spectrometer(LC-MS/MS).③hiHeps cells were incubated with 80 nmol·L^(-1)small interfering RNAs(si-AKRs)for 48 h and treated with AA-Ⅰ1.0μmol·L^(-1)for 24 h.Real-time qualitative PCR(RT-qPCR)method was used to detect the mRNA expression of AKRs gene and LC-MS/MS technology was used to investigate the effect of specific AKR gene knockdown on DNA adduct levels.④500 nmol·L^(-1)human AKR recombinant proteins AKR1A1 and AA-Ⅰwere incubated in vitro under anaerobic conditions and the formation of AA-Ⅰ-DNA adducts was detected.RESULTS①The IC_(50)of AA-Ⅰto hiHeps and RT4 cells was 1.9 and 0.42μmol·L^(-1),respec⁃tively.The level of DNA adduct production of the two cell lines was significantly different(P<0.01).②Luteolin≥5μmol·L^(-1)significantly inhibited the production of AA-Ⅰ-DNA adducts in both cells(P<0.05),and there was a concentration-dependent effect in hiHeps cells(P<0.01,R=0.84).③In the AKR family,the knockdown of AKR1A1 gene up to 80%inhibited the generation of AA-Ⅰ-DNA adducts by 30%-40%.④The AA-Ⅰ-DNA adducts were detected in the incubation of recombinant protein AKR1A1 and AA-Ⅰunder anaerobic conditions in vitro,approximately 1 adduct per 107 nucleotides.CONCLU⁃SION AKR1A1 is involved in AA-Ⅰbioactivation,providing a reference for elucidation of the carcino⁃genic mechanism of AA-Ⅰ.

抗癌药物新剂型—多相脂质体科研成果鉴定会在沈阳召开

由辽宁省科委和上海市科委联合主持召开,有辽宁省卫生厅、辽宁省医药局、上海市卫生局、上海市长宁区卫生局参加的抗癌药物新剂型—多相脂质体科研成果鉴定会,于1984年9月24日至26日在沈阳召开。抗癌药物新剂型—多相脂质体的研究,是沈阳药学院制剂研究室与上海长宁区中心药院抗癌药物研究室,自1979年以来共同研制的抗癌药物载体,除对其处方、工艺、基础理论、临床前药理开展了系统研究之外,并包封了四个品种,进行了五百余例的临床疗效观察。

抗癌药物新剂型——多相脂质体科研成果鉴定会在沈阳召开

由辽宁省科委和上海市科委联合主持召开,有辽宁省卫生厅、辽宁省医药局、上海市卫生局、上海市长宁区卫生局参加的抗癌药物新剂型——多相脂质体科研成果鉴定会,于1984年9月24~26日在沈阳举行。应邀参加鉴定会的有来自北京、成都、广州、南昌、南京、杭州、上海、大连、锦州、沈阳等地的教学、科研、临床、药检及领导机关的代表共48名。辽宁省科委副主任张百伟和上海市科委副主任陈祥禄出席会议并讲了话。

Highly active binuclear Cu(Ⅱ) catalyst bearing an unsymmetrical bipyridine-pyrazole-amine ligand for the azide-alkyne cycloaddition reaction

Ligands containing NH groups often show special characteristics.In this paper,a well-defined dinuclear Cu（II） complex bearing an unsymmetrical bipyridine-pyrazole-amine ligand was synthesized by the condensation of N–H to release H2O.Using sodium L-ascorbate as a reductant,the binuclear complex showed excellent activity in 1,3-dipolar cycloaddition reactions between alkynes and azides to obtain 1,4-disubstituted triazoles in 95%–99% isolated yields.

Chemical constituents isolated from the aerial parts of Swertia pseudochinensis and their potential neuroprotective effects

Objective:Swertia pseudochinensis,an annual herb of the genus Swertia in the family Gentianaceae.Some constituents and extracts from the Swertia genus have been recently reported to possess neuroprotective effects,suggesting their potential utility in the prevention and treatment of Parkinson disease(PD).The aim of this work is to identify the chemical constituents and evaluate the potential biological activists of Swertia pseudochinensis.Methods:The phytochemicals from the aerial parts of S.pseudochinensis were isolated and purified by silica gel,Sephadex LH-20 gel,semi-preparative high-performance liquid chromatography,and identified by the spectroscopic methods.All compounds were evaluated for their potential neuroprotective effects against 1-methyl-4-phenylpyridinium-induced apoptosis in the SH-SY5Y human neuroblastoma cell line using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay.Then,we performed an enrichment analysis using the Database for Annotation,Visualization,and Integrated Discovery and investigated the mechanisms by which bellidifolin regulates neurodegenerative disease.Results:Two new anthraquinone,1,5,6-trimethoxy-2-hydroxy-3-methy-anthraquinone(1)and 1,5,6,8-tetramethoxy-2-hydroxy-3-methyanthraquinone(2),together with nine known including 7-O-b-d-glucopyranosyl-1,8-dihydroxy-3-methoxyxanthone(3),gentisin(4),swertianolin(5),bellidifolin(6),gentiacaulein(7),norswertianolin(8),5-O-b-d-glucopyranosyl-1,3,8-trihydroxyapatone(9),1-hydroxy-3,5,8-trimethoxyxanthone(10),and aurantio-obtusin(11),were isolated and compounds 6–8 and 10 exhibited neuroprotective effects at a concentration of 50mmol/L.Among them,bellidifolin showed significant protective activity,and might have potential as a neuroprotective agent for the treatment of PD,possibly by acting on oxidative damage and reactive oxygen species.Conclusions:These findings indicate that further research on the genus Swertia and its bioactive constituents toward neurodegenerative disorders could be extremely rewarding.

Chemical constituents and analgesic activity of Aconitum kusnezoffii Reichb.

In the present study,we aimed to investigate the chemical constituents and analgesic activity of Aconitum kusnezoffii Reichb. The isolation and purification of components were achieved by a series of chromatography, including silica gel, Sephadex LH-20 and HPLC. By using spectroscopic analysis, their structures were identified. Using PDE-4A as analgesic target, moleculardocking was conducted between isolated compounds by using Schrodinger software. Neoline is a typical non-ester diterpene alkaloid. It was studied by using the mouse torsion body method and hot plate method. A total of 12 diterpene alkaloids were obtainedand identified as Mesaconitine(1), Bewutine (2), Bewudine (3), Songoramine (4), Songorine (5), Neoline (6), Talasamine (7), isotalatizidine (8), Hokbusine A (9), Mesaconine (10), 8-OEt-14-benzoylmesaconine (11), 8-Methoxy-14-benzoyl-beiwutinine (12).Compounds 9 and 12 were isolated from Aconitum kusnezoffii Reichb. for the first time. Twelve diterpenealkaloids could act on the analgesic target. Neoline is a typical non-ester diterpene alkaloid. It had significant analgesic effect. Diterpene alkaloids were the main components of Aconitum kusnezoffiiReichb., and they had good analgesic activity.

Analysis of the chemical composition of Angelicae Pubescentis Radix by ultra-performance liquid chromatography and quadrupole time-of-flight tandem mass spectrometry

Angelicae Pubescentis Radix (APR, Duhuo) is a commonly used traditional Chinese medicine and usually used for the treatments of rheumatic diseases. To assess the chemical composition of APR extract, a sensitive and reliable UPLC-Q?TOF-MS method was used for qualitative analysis. The separation was achieved on an Agilent SB-Ci8 column (1.8 pm, 2.1 mm><50 mm) with a gradient elution system consisting of acetonitrile and water containing 0.1% formic acid. An electrospray ionization (ESI) was used for mass spectrometer, and the data were collected in the positive ion mode, which was operated in a full-scan mode at m/z 100-800. A total of 49 compounds including 46 coumarins were identified according to the MS and MS/MS data. Among them, two were new compounds, and isoangenomalin, scoparone, 4-methyl-umbelliferyl acetate, suberenol,/raw5-dehydroosthol, and oroselone were first reported in APR.

Ceralasertib合成路线图解

Ceralasertib(AZD-6738,1),中文化学名称为4-{4-[(3R)-3-甲基吗啉-4-基]-6-[1-(R)-S-甲基亚磺酰亚氨基环丙基]嘧啶-2-基}-1H-吡咯并[2,3-b]吡啶,英文化学名称为4-(4-(3R)-3-methylmorpholin-4-yl)-6-(1-(R)-S-methylsulfonimidoyl)(cyclopropyl pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine,分子式为C_(20)H_(24)N_(6)O_(2)S,分子量为412.512,CAS登记号为1352226-88-0。

Quantification of flupirtine and its active metabolite D-13223 in human plasma by LC-MS/MS: application to a clinical trial of flupirtine maleate capsules in healthy male Chinese volunteers

In the present study, we developed a simple, sensitive, precise, and accurate liquid chromatography-tandem mass spectrometric(LC-MS/MS) method and validated such approach for simultaneous determination of flupirtine and its active metabolite D-13223 in human plasma. The flupirtine, D-13223, and stable isotope internal standard(IS) were extracted from plasma samples by liquid-liquid extraction and chromatographed on a C18 column with a mobile phase consisting of acetonitrile–water–ammonia(55:45:0.1, v/v/v) at a flow rate of 0.25 m L/min. Detection was performed on a triple quadrupole tandem mass spectrometer with an electrospray ionization source(ESI) by multiple reaction monitoring(MRM) in positive ion mode. The linear calibration curves were obtained within the concentration range of 10.00–2000.00 ng/m L for flupirtine and 2.00–400.00 ng/m L for D-13223. The intra-and inter-run RSD, calculated from quality control(QC) samples, was less than 9.26% for flupirtine and D-13223. The accuracy was –5.80%–3.31% for flupirtine and D-13223. The extraction recoveries of flupirtine, D-13223, and their IS were all between 88.3%–97.2%. The method was successfully applied to investigate the pharmacokinetic profiles of flupirtine and its active metabolite D-13223 in human plasma following peroral administration of 100 mg flupirtine maleate capsules in healthy male Chinese volunteers.

Design, synthesis and antitumor activity evaluation of novel 2,6-dichloro-3,5-dinitrotoluene derivatives

A series of novel 2,6-dichloro-3,5-dinitrotoluene derivatives were designed, synthesized in the present study, and their antitumor activities against five cell lines（A431, HepG2, A549, HT-29 and HEK-293） were tested. Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines in comparison with cisplatin. Studies on their preliminary structure-activity relationships（SARs） indicated that compounds containing phenyl（piperazin-1-yl） methanone groups, especially chlorine atom at 4-position of the phenyl ring, were more effective. Compound 4g was found to be the most potent derivative with IC_（50） values of 1.04, 3.20, 6.93, 4.10 and 20.15 μmol/L against A431, HepG2, A549, HT-29 and HEK-293 cell lines, respectively, which was better than positive control cisplatin, one of the most clinically used chemotherapeutic drugs.