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Establishment of LC-MS/MS method for the determination of forsklin in rat plasma and its pharmacokinetics

Dianwei SONG ; Decai WANG ; Zhiyun MENG ; Ruolan GU ; Meihui SHI ; Zhuona WU ; Jingze WANG ; Guifang DOU

Journal of International Pharmaceutical Research.2012;(2):149-153. doi:10.3969/j.issn.1674-0440.2012.02.010

Objective To develop a sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the determination of forsklin in rat plasma.Methods After extraction with methyl tert-butyl ether,chromatographic separation was performed on a C18 column with the mobile phase consisting of water ( 0.1％ formic acid)-acetonitrile in a gradient elution mode.A tandem mass spectrometer equipped with electrospray ionization (ESI) source was used as detector in the positive ion mode.Quantification was performed using multiple reaction monitoring (MRM) with the precursor product combination ions of m/z 411→375.3 and 285→193 for forsklin and diazepam.Results Good linearity was obtained in the 0.5-1000 ng/ml range for the analyte and the analytical method was validated in terms of specificity,precision,accuracy,recovery,stability and matrix effect.These assays gave RSD values always lower than 14.4％ and RE values between -3.5 ％ and 3.8％.In addition,the specificity,extraction recovery,stability and matrix effect were satisfactory.Conclusion Due to its high sensitivity,specificity and simplicity,the method could be used for pharmacokinetic studies of forsklin.

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Determination of aconitine in dog tissue homogenates by HPLC-MS/MS and its application to in vitro metabolic stability study

Cuiping YANG ; Sha LIAO ; Tianhong ZHANG ; Jinglai LI ; Xiaoying WANG ; Jinxiu RUAN ; Zhenqing ZHANG

Journal of International Pharmaceutical Research.2012;(3):256-260. doi:10.3969/j.issn.1674-0440.2012.03.015

Objective To develop a HPLC-MS/MS method for the determination of aconitine and study thein vitro metabolic stability of aconitine in dog tissue homogenates.Methods The chromatographic separation was performed on a C18 column.The mobile phase consisted of acetonitrile and water with 0.2％ formic acid and 5 mmol/L ammonium acetate.A triple quadrupole tandem mass spectrometer equipped with an electrospray ionization interface source was used for the quantitative determination in the positive selective reaction monitor mode.Aconitine was incubated with dog tissue homogenates and samples were withdrawn at different time points and precipitated by acetonitrile with internal standards citalopram.Results Aconitine showed good linear relationship over the range from 5 to 500 ng/ml.The recoveries of aconitine were between 85.73％ and 92.12％ at three QC concentration levels.The intra- and inter-day precisions were 5.32％ - 8.95％ and 5.45％ - 8.86％,respectively.After incubation,about 20％ of aconitine were cleared in the liver and small intestine,and t1/2 were 460.6 and 521.3 min,respectively.But none was metabolized in the stomach and kidney.Conclusion These results demonstrated that aconitine was mainly metabolized in the liver and small intestine at a slow rate.

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Drug resistance to target therapy in colorectal cancer:research advances

Ke XU ; Guojiang CHEN ; Hui PENG

Journal of International Pharmaceutical Research.2017;44(5):402-408. doi:10.13220/j.cnki.jipr.2017.05.004

Colorectal cancer(CRC)ranks the third in incidence and mortality rate among human tumors. Tumor relapse,me?tastasis and drug resistance remain the main obstacle to the success of CRC treatments. Compared to traditional chemotherapy ,target therapy seems to treat tumors in more precise and rational fashion with good response and often less toxic side-effect. Although target agents provide hope for more effective therapy,recent clinical studies have shown only modest benefit from target therapy similar to tra?ditional chemotherapy. Primary and secondary resistance to target agents is still observed and contributes to CRC treatment failure. The review summarizes research progress in the mechanism of drug resistance to target therapy in CRC treatment.

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Simultaneous determination of five furostanol saponins in rhizome and fibrous root of Anemarrhena asphodeloides Bge. by HPLC-CAD

Fengxia MA ; Xinguang SUN ; Jie ZHANG ; Zhen LONG ; Yang ZHAO ; Chunni ZHANG ; Fangxu WANG ; Shuchen LIU ; Baiping MA

Journal of International Pharmaceutical Research.2017;44(6):642-646. doi:10.13220/j.cnki.jipr.2017.06.033

Objective To develop a method for the determination of five furostanol saponins(timosaponin N,timosaponin L, timosaponin BⅡ,25R-timosaponin BⅡ,and 25S-officinalisnin-Ⅰ)in rhizome and fibrous root of Anemarrhena asphodeloides Bge. by HPLC with the charged aerosol detector(CAD). Methods The analysis was performed on TechMate C18-ST-II(250 mm×4.6 mm,5μm)with acetonitrile:water(22:78,V/V),the flow rate of 1.0 ml/min and column temperature at 30℃. The Corona parameters were as follows:sampling rate 10 Hz,filter 5 s,and the nebulizer temperature 55℃. Results The approach showed good linearity for five saponins. The correlation coefficients(r2)for calibration curves varied from 0.9992 to 0.9998. The limits of detection(LOD)were 0.28,0.92,0.92,0.92 and 0.92 ng for five steroidal saponins,respectively. The limits of quantitation(LOQ)were found to be 0.92, 2.77,2.77,2.77 and 2.76 ng,respectively. RSD calculated from peak area of precision,repeatability and stability in 48 h were all less than 3.0%. The average recoveries of timosaponin N,timosaponin L,timosaponin BⅡ,25R-timosaponinBⅡ,and 25S-officinalis-nin-Ⅰwere 98.17%,101.37%,98.53%,97.63%,and 98.17%,respectively. Conclusion The developed method is accurate,reli-able,which could be applied to the quality control of multiple components in A. asphodeloides Bge.

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Lignan constituents and activities of Linum usitatissimum L. above ground

Xiang CHEN ; Jingming JIA ; Yu YANG ; Nengjiang YU

Journal of International Pharmaceutical Research.2017;44(6):590-594. doi:10.13220/j.cnki.jipr.2017.06.023

Objective To investigate the chemical constituents and activities of Linum usitatissimum L.aboveground. Meth-ods The chemical constituents were separated through silica gel,ODS,Sephadex LH-20,and semi-preparative RP-HPLC chroma-tography and identified by optical rotation and spectroscopic analysis. All of the isolates were evaluated for their inhibitory activities by the luciferase assay. Results Eight dibenzylbutyrolactone lignans were separated from L. usitatissimum and identified as(-)-hinoki-nin(1),(-)-bursehernin(2),(-)-dimethylmatairesinol(3),(-)-yatein(4),(-)-thujaplicatin trimethyl ether(5),nemerosin (6),(+)-E-7,8-dehydromatairesinol dimethyl ether(7),and E-7,8-dehydrothujaplicatin trimethyl ether(8),respectively. Conclu-sion Compounds 7 and 8 were isolated from L. usitatissimum for the first time,and NMR spectral data of compound 8 were reported for the first time. Compounds 1 and 3 showed moderate inhibitory activities on IL-6/STAT3 signaling pathway with IC50 values of 42.12 and 43.43μmol/L,respectively.

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Hemin-air,an efficient catalytic-oxidation system for disulfide formation in linaclotide synthesis

Weiwei GE ; Jing CHEN ; Ye ZHANG ; Liang ZONG ; Ming ZHANG ; Junjun DONG

Journal of International Pharmaceutical Research.2017;44(6):585-589. doi:10.13220/j.cnki.jipr.2017.06.022

Objective To use hemin as a catalyst in the formation of disulfide bonds in the synthesis of linaclotide. Methods The linaclotide peptide was synthesized by the standard 9-fluorenylmethyl(Fmoc)solid-phase synthetic strategy. Wang resin and Trt-protected cysteine were used in the synthesis. Hemin was used in random oxidation of line linaclotide. The result was compared with those of air,dimethyl sulfoxide(DMSO),and I2 oxidation systems. Results and Conclusion Hemin is a highly effective catalyst for disulfide bond formation in linaclotide synthesis. It overcomes some disadvantages in oxidation reactions with conventional oxidative re-agents,and supplies a convenient way for the synthesis of peptide with concentrated disulfide bonds.

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Synthesis and activity evaluation of novel tyrosine kinase inhibitors

Hongpeng YANG ; Gang WANG ; Tao PENG ; Xiaoxue WEN ; Jianyun YANG ; Yunbo SUN ; Shuchen LIU ; Shouguo ZHANG ; Lin WANG

Journal of International Pharmaceutical Research.2017;44(6):575-579. doi:10.13220/j.cnki.jipr.2017.06.020

Objective To design and synthesize compounds with protein tyrosine kinase(PTK)inhibitory activity with L029 as the lead compound. Methods L029 derivatives were designed and synthesized from L029 by reduction and/or substitution with the 3-dimethylamino-1-propyl,methyl acetate,methyl propionate in its active H and other sites. PTK activity was measured by enzyme-linked immunosorbent assay(ELISA). The inhibitory rate was calculated to screen out the compounds with PTK inhibitory activity. Re-sults Five target compounds were synthesized and their structures were confirmed by 1H NMR and MS. Three compounds T2,T3 and T5 were screened out with strong PTK inhibitory activity. Conclusion The synthetic routes of the target compounds are simple with mild reaction condition,and 3 compounds show strong inhibitory activity by ELISA. These results can provide reference for the further design and synthesis of this kind of molecules.

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Design,synthesis and activity evaluation of novel 2-indolone derivatives as the c-Met kinase inhibitors

Shouguo ZHANG ; Jieying WANG ; Haiyan YAN ; Tao PENG ; Xiaoxue WEN ; Gang WANG ; Yunbo SUN ; Shuchen LIU ; Lin WANG

Journal of International Pharmaceutical Research.2017;44(6):567-574,579. doi:10.13220/j.cnki.jipr.2017.06.019

Objective To design and synthesize novel 2-indolone derivatives as the c-Met kinase inhibitors. Methods With c-Met kinase inhibitor SU11274 as lead compound,a series of 2-indolone derivatives were designed according to the concept of bioiso-sterism. Then the target compounds(10a-10r)were synthesized from 2-indolone through 5-chlorosulfonation with chlorosulfonic acid, sulfonamidation with intermediate 3,condensation with 6a-6h,7a-7h and 4a-4b,respectively. Their inhibitory activity against c-Met and proliferation of MCF-7 cells were evaluated. Results and Conclusion The designed compounds were successfully prepared and their structures were confirmed by 1H NMR and ESI-MS. Some compounds had certain inhibitory activity against c-Met and prolif-eration of MCF-7 cells. An initial structure-activity relationship analysis of these compounds was performed to provide useful informa-tion for further optimization of their structures.

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Screening for selective TGF-βⅠinhibitors and structure-activity relationship analysis

Long LONG ; Feifei LI ; Xingzhou LI ; Wei CHEN ; Wei LI ; Lili WANG

Journal of International Pharmaceutical Research.2017;44(6):544-550. doi:10.13220/j.cnki.jipr.2017.06.015

Objective To screen for selective transforming growth factor β(TGF-β)inhibitors from the compound library, and analyze their structure-activity relationship. Methods The inhibiting activities of 170 compounds to TGF-βpathway were evaluat-ed by the SMAD3 luciferase reporter system;the positive hits were examined for their selectivity towards activin receptor like kinase (ALK)4、ALK5 or ALK7 by a molecule based screening system composed of SMAD3,ATP and the purified kinase domain for ALK4, ALK5 or ALK7;the EGFP-SMAD2 fusion protein redistribution assay was used to confirm the inhibiting effects of positive hits. The structure-activity relationship was analyzed by comparing the docking module of SB431542 with ALK5 kinase domain. Results Fif-teen compounds were found capable of inhibiting luciferase expression downstream of SMAD3 with≥25%inhibitory rate;several of them showed different selectivity towards ALK4,ALK5 and ALK7. Compound 63 selectively inhibited the activity of ALK4 and ALK7 with IC500.234 and 0.370μmol/L,respectively,while compound 64 showed inhibiting activity towards all three kinases with the IC50 values 10,6 and 85 nmol/L for ALK4、ALK5 and ALK7,respectively. In addition,compounds 63 and 64 further inhibited the TGF-β1 induced EGFP-SMAD2 nuclear translocation,with the IC50 values of 0.45 and 6.30μmol/L,respectively. The MTT anti-proliferative assay indicated that compounds 63 and 64 exerted these activities at non-toxic concentrations. The analysis of structure-activity rela-tionship indicated that the compounds sharing a core structure,the 1,2,4-triarylimizazole or 1,3,5-triarylpyrazoline,with the 3,4 methyoenedioxyphenyl,6-methylpyridine and 4-aminocarboxyl substitution groups tended to exhibit better activities. Conclusion The two potent TGF-βpathway inhibitors,63 and 64 are identified through this screening project,of which,63 selectively inhibited the ALK4 and ALK7 activity,while 64 showed inhibiting activity towards all three tested types of ALKs.

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Ameliorative effect of cannabinoid 2 receptor agonist JWH-015 on cognitive impairment of Alzheimer′s disease model mice and its possible mechan ism

Chao LI ; Jingpu SHI ; Likuan WANG ; Huiqun JIA ; Bo WANG ; Jin LI

Journal of International Pharmaceutical Research.2017;44(6):537-543. doi:10.13220/j.cnki.jipr.2017.06.014

Objectives To investigate the ameliorative effect of cannabinoid 2 receptor(CB2R)agonist JWH-015 on the cog-nitive impairment of Alzheimer' s disease(AD)model mice and to assess the correlation with microglial phenotype transformation. Methods Twenty adult male C57BL/6J mice were randomly divided into four groups:C57BL/6J solvent group,JWH-015 control group,AD model group,and AD model treated with JWH-015 group. Amyloidβ1-42 oligomers of 4μg and the same volume of saline were intraventricularly administered to construct the AD mouse model and the solvent groups. CB2R agonist JWH-015 or the corre-sponding vehicle at a dose of 0.5 mg/(kg·d)was administered by intraperitoneal injection for 3 weeks. Non-spatial learning and memo-ry was measured using novel object recognition task. Furthermore,the mRNA expression levels of M1 microglia marker inducible ni-tric oxide synthase(iNOS)and M2 microglia marker chitinase-3 like protein(Ym1/2)in brain samples of cortex and hippocampus were evaluated using real-time quantitative PCR(qPCR). In the meantime,fifteen CB2R knockout(CB2RKO)mice and five CB2R wild-type(CB2RWT)littermates were assigned to identify the specificity of CB2R in the research. Based on the genotype and different treatment,the animals were divided into four groups:CB2RKO solvent group,CB2RKO AD model group,CB2RKO AD model treat-ed with JWH-015 group and CB2RWT solvent group. Results Compared with solvent group,there was a significant decrease in nov-el object recognition index in C57BL/6J AD model group(P<0.01). The mRNA expression levels of M1 phenotype microglia marker iNOS in cortex and hippocampus were significantly up-regulated(both P<0.05)and the mRNA expression levels of M2 phenotype mi-croglia marker Ym1/2 were significantly down-regulated(both P<0.01). Interestingly,administration of JWH-015 could reverse the impairment of novel object recognition index(P<0.05);compared with C57BL/6J AD model group,administration of JWH-015 also decreased the iNOS mRNA expression levels(both P<0.05)and increased the Ym1/2 mRNA expression levels(both P<0.05)in cortex and hippocampus;compared with CB2RKO solvent group,the novel object recognition index of CB2RKO AD model group was decreased(P<0.05);the mRNA expression levels of iNOS in cortex and hippocampus were significantly up-regulated(both P<0.05),the mRNA expression level of Ym1/2 in cortex was significantly down-regulated in cortex(P<0.05);compared with CB2RKO AD model group,administration of JWH-015 had no effect on novel object recognition index and the mRNA expression level of M1/M2 in cortex and hippocampus,respectively. Conclusion JWH-015 improves the cognitive impairment of Aβ-induced AD mice by the specific activation of CB2R,the mechanism of which is related to the direct regulation of CB2R on the M1/M2 microglial phenotype transformation and microglia-mediated neuroinflammation in brain.

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