Hai Qian

China Pharmaceutical University, Nan-ching-hsü, Jiangxi Sheng, China

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Publications (58)105.93 Total impact

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    ABSTRACT: This is the first report on the anti-cancer activity of peptide B1.•A series of B1 analogs were designed and synthesized.•B1 and analogs selectively inhibit the growth of cancer cell lines.•These peptides induce cytochrome C release from mitochondria leading to apoptosis.•The peptides also have drug resistance-reversing effects.
    European Journal of Medicinal Chemistry 01/2015; 89. · 3.43 Impact Factor
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    ABSTRACT: P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7-dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2-[(1-{4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]phenyl}-1H-1,2,3-triazol-4-yl)methoxy]-N-(p-tolyl)benzamide (compound 7 h) was identified as a potent modulator of P-gp-mediated MDR, with high potency (EC50 =127.5±9.1 nM), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR-related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P-gp-mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P-gp-mediated MDR that has good potential for further development. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    ChemMedChem 12/2014; · 2.84 Impact Factor
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    ABSTRACT: A series of novel C-aryl glucosides with various substituents at the distal aryl ring have been synthesized and evaluated for hypoglycemic effect in normal and diabetic mice and in type 2 diabetic rats. The results indicated that introduction of electron donating group at the distal aryl ring could improve glucose tolerance in normal mice, whereas introduction of electron withdrawing group at this position could deteriorate. The urinary glucose excretion was significantly increased after glucose (3 g·kg(-1) ) administration in normal mice with the treatment of 13c. Moreover compound 13c could reduce fed blood glucose levels in a dose-dependent manner in type 2 diabetic rats and showed remarkable anti-hyperglycemic effect with two weeks of treatment in diabetic mice, and might be a promising drug candidate for the treatment of diabetes mellitus. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 12/2014; · 2.47 Impact Factor
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    ABSTRACT: Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic β-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50 = 62.3 nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus.
    Bioorganic & Medicinal Chemistry. 11/2014;
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    ABSTRACT: A novel coumarin-based fluorescence probe has been constructed for the selective and sensitive detection of hydrogen sulfide (H2S). This probe displays high sensitivity and linearity to H2S in degassed PBS buffers and fetal bovine serum. It reacts with H2S with high selectivity over Cys, GSH and other anions. Meanwhile, successful detection of H2S in living cells was also demonstrated.This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 11/2014; · 2.47 Impact Factor
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    ABSTRACT: A novel series of triazol-N-ethyl-tetrahydroisoquinoline based compounds were designed and synthesized via click chemistry. Most of the synthesized compounds showed P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) reversal activities. Among them, compound 7 with little cytotoxicity towards GES-1 cells (IC50 >80 μM) and K562/A02 cells (IC50 >80 μM) exhibited more potency than verapamil (VRP) on increasing anticancer drug accumulation in K562/A02 cells. Moreover, compound 7 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 7 in reversing MDR revealed that it could remarkably increase the intracellular accumulation of both rhodamine-123 (Rh123) and adriamycin (ADM) in K562/A02 cells as well as inhibit their efflux from the cells. These results suggested that compound 7 showed more potency than the classical P-gp inhibitor VRP under the same conditions, which may be a promising P-gp-mediated MDR modulator for further development.
    Bioorganic & Medicinal Chemistry. 10/2014;
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    ABSTRACT: The overexpression of P-glycoprotein (P-gp) in tumors leads to multidrug resistance (MDR), which is a significant obstacle in clinical cancer chemotherapy. The co-administration of anticancer drugs and MDR modulators is a promising strategy for overcoming this problem. Our study aimed to explore the reversal mechanism and safety of the MDR modulator LBM-A5 in vitro, and evaluate its pharmacokinetics and effects on doxorubicin metabolism in vivo. We evaluated an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of anticancer agents mediated by LBM-A5, the effect of LBM-A5 on rhodamine123 intracellular accumulation, and the efflux in K562/DOX cells to investigate the reversal mechanisms of LBM-A5. The results showed that LBM-A5 inhibits rhodamine123 efflux and increases intracellular accumulation by inhibiting the efflux pump function of P-gp. Furthermore, the therapeutic index and CYP3A4 activity analysis in vitro suggested that LBM-A5 is reasonably safe to use. Also, LBM-A5 (10 mg/kg body mass) achieved the required plasma concentration in sufficient time to reverse MDR in vivo. Importantly, the LBM-A5 treatment group shared similar doxorubicin (DOX) pharmacokinetics with the free DOX group. Our results suggest that LBM-A5 effectively reverses MDR (EC50 = 483.6 ± 81.7 nmol·L(-1)) by inhibiting the function of P-gp, with relatively ideal pharmacokinetics and in a safe manner, and so may be a promising candidate for cancer chemotherapy research.
    Canadian Journal of Physiology and Pharmacology 10/2014; · 1.56 Impact Factor
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    ABSTRACT: Overexpression of P-glycoprotein leads to tumor multidrug resistance (MDR). HZ08, a novel tetrahydro-isoquinoline derivate, was discovered to inhibit the MDR in the cancer cell lines of MCF-7/ADM, K562/ADM and KBV in our previous studies. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometric method (UPLC-MS/MS) was developed and validated for determination of HZ08 in rat plasma and tissues after intravenous administration of HZ08 liposome injection at different doses. The analytes were extracted from plasma and tissues using protein precipitation by acetonitrile with clotrimazole as internal standard. The chromatographic separation was performed on a Thermo BDS HYPERSIL C18 column (100mm×4.6mm, 2.4μm) at a flow rate of 0.7ml/min using 0.2% ammonium acetate solution (containing 0.1% formic acid) and methanol as mobile phase. The total run time was 4min. The tandem mass detection was applied with electrospray ionization in positive ion selected reaction monitoring mode. The ion transitions monitored were m/z 523.5 to 342.3 for HZ08 and 277.1 to 165.1 for the internal standard, respectively. The calibration curves obtained were linear in different matrices, and the lower limit of quantification (LLOQ) achieved was 1ng/ml for rat plasma and 0.25ng/ml for rat tissues, respectively. The RSDs for intra- and inter-day precision were less than 15%. Extraction recovery, matrix effect and stability were satisfactory in rat plasma and tissues. The developed method was successfully applied to a pharmacokinetic study of HZ08 liposome injection following intravenous administration of 1, 3, 10mg/kg to Sprague-Dawley rats. The data profiles revealed that HZ08 had linear pharmacokinetic properties at the tested doses, and was rapidly distributed into the systemic circulation with wide distribution throughout the body followed by a rapid elimination phase. The major distribution tissues of HZ08 in rats were lung, spleen and liver. These results provided constructive contribution to support the clinical evaluation.
    Journal of pharmaceutical and biomedical analysis. 09/2014; 102C:246-252.
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    ABSTRACT: To identify the glucose lowering ability and chronic treatment effects of a novel coumarin-glucagon-like peptide-1 (GLP-1) conjugate HJ07.
    Chinese Journal of Natural Medicines 08/2014; 12(8):613-8.
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    ABSTRACT: Aims/hypothesisThe short biological half-time limits the therapeutic use of GLP-1 and the application of chemical modification to improve the interaction of peptide with serum albumin represents an effective strategy to develop long-acting peptide analogues. Coumarin, found naturally in edible plants, is known to bind tightly to plasma proteins and possesses many biological activities. Therefore, we designed and synthesized a series of coumarin modified glucagon-like peptide-1(GLP-1) derivatives, hypothesizing that the conjugation of coumarin would retain the therapeutic effects and improve the long-term acting properties.Methods Firstly, four cysteine modified GLP-1 analogues (1-4) were prepared using Gly8-GLP-1(7-36)-NH2 peptide as a starting point. Then these analogues were further conjugated with two coumarin maleimides (5a, 5b) to yield compounds 6-13. Finally, biological tests were conducted to evaluate in vitro and in vivo effect of these conjugates.ResultsBiological tests demonstrated that most derivatives showed well preserved receptor activation efficacy, enhanced albumin-binding properties and improved in vitro plasma stability and compound 7 was selected to undergoing further assessment. The in vivo pharmacokinetic tests revealed that compound 7 had greater blood circulating t1/2 (∼22.9 h) than exendin-4 (∼2.5 h) and liraglutide (∼14.9 h). Furthermore, the prolonged in vivo anti-diabetic effects of compound 7 was confirmed by multiple oral glucose tolerance test and hypoglycemic efficacies test on db/db mice.Conclusion The results demonstrate that the cysteine-specific coumarin conjugation with GLP-1 offers a useful approach to the development of long-acting incretin-based antidiabetics, and suggest that compound 7 is a promising long term GLP-1 derivative deserving further investigation.
    British Journal of Pharmacology 07/2014; · 5.07 Impact Factor
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    ABSTRACT: Adenosine deaminase (ADA) inhibitors have been found to have antitumor activities. Here, thirteen potential adenosine deaminase inhibitors 5-amino-1H-pyrazole-4-carboxamide derivatives were designed, synthesized and screened for antitumor activities. Compound 8e exhibited strong growth-inhibitory effects which showed selectivity toward the estrogen receptor positive breast cancer cells (MCF-7) compared to other 5-amino-1H-pyrazole-4-carboxamide derivatives. In addition, it also exhibited appropriate (μM) adenosine deaminase inhibitory potency. Preliminary structure-activity relationships indicated that the incorporation of long chain branching on nitrogen atoms at pyrazole moiety was responsible for their activity.
    Historical Journal Of Film Radio and Television 05/2014; 11(6).
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    ABSTRACT: Background: Cholesterol is essential for the growth and maintenance of mammalian cells. However, elevated level of serum cholesterol is among the associated risk factors for the coronary heart disease. Cholesterol is derived from two different sources of endogenous synthesis and diet. Statins can reduce endogenous sterol synthesis by inhibit HMG-CoA reductase, whereas cholesterol absorption inhibitors, such as ezetimibe, can block cholesterol uptake from dietary sources by block Niemann-Pick C1-like 1 (NPC1L1). Objective: The present review focus on the main research progress of cholesterol absorption inhibitors, the structure of NPC1L1 and discovery of novel chemical entities by virtual screening. Conclusion: Studies on the structure-activity relationship reveal that azetidinone is important to keep activity in azetidinone derivatives and the novel heterocyclic compounds with replacement of β-lactam scaffold by oxazolidinone also shows similar activity as ezetimibe. Virtual screening in data bases as computer-aided molecular design tools to propose novel cholesterol absorption inhibitors are kind of complement to design and synthesize structurally novel compounds.
    Medicinal chemistry (Shāriqah (United Arab Emirates)) 04/2014; · 1.64 Impact Factor
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    ABSTRACT: 1, 3, 4-thiadiazole and urea group were hybridized to form new molecular skeleton and 11 compounds were synthesized and evaluated as AChE inhibitors. Most of them showed comparable effects in inhibition of AChE, especially compound 6b which exhibited activity with IC50 value 1.17 μM, as strong as galanthamine. This information offered by our research would be valuable for further investigation of SAR and useful in future research of AChE inhibitors.
    Chemical & pharmaceutical bulletin 04/2014; · 1.70 Impact Factor
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    ABSTRACT: Inflammatory and pain are major areas for drug discovery. Current analgesic drugs often cause a number of side effects. In the present study, we modified carboxylic acid group of ibuprofen, one of non-steroidal anti-inflammatory drugs (NSAIDs), based on the common structure of transient receptor potential vanilloid type 1 (TRPV1) antagonists which are considered as new candidates for analgesic drugs, and synthesized several derivatives of ibuprofen. Comprehensive evaluations of the pharmacological properties of these compounds were investigated. Compound 17 showed weak cyclooxygenase (COX) inhibition and exhibited strong TRPV1 antagonistic activity. It was found to be capable of blocking noxious thermal nociception and capsaicin-induced nociception in mice. Besides, 17 showed less ulcerogenic action than ibuprofen did and had no hyperthermia side effect compared with common TRPV1 antagonists. Therefore, it suggested that 17 could be used as a safe alternative analgesic candidate for pain treatment. This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 03/2014; · 2.47 Impact Factor
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    ABSTRACT: A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors bearing a triazol-phenethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 5 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity (IC50 s > 100 μM). Compared with VRP, compound 5 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 5 persisted longer chemo-sensitizing effect (> 24 h) than VRP (< 6 h) with reversibility. Given the low intrinsic cytotoxicity and the potent reversal activity, compound 5 may represent a promising candidate for developing P-gp-mediated MDR inhibitor. This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 02/2014; · 2.47 Impact Factor
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    ABSTRACT: Two series of peptide MC62 analogues were synthesized, characterized and evaluated for their antihyperglycemic effects. Structure–activity relationship studies of the first series indicated that antihyperglycemic effects were correlated to residues 4, 5, 7 and 8. Peptide I-6 exhibited higher antihyperglycemic activity than the MC62 parent peptide, and was chosen for further modification. Incorporation of Met at position 3 increased potency further and generated II-3, which was screened in vivo and in vitro using exenatide (Ex-4) and GLP-1 as positive controls. The results showed that the antihyperglycemic and antioxidative activities of II-3 were comparable to the positive controls, suggesting II-3 could be a candidate for use as a future diabetic treatment.
    European Journal of Medicinal Chemistry 02/2014; 73:105–111. · 3.43 Impact Factor
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    ABSTRACT: In this study, combination-principle was reported to improve the hepatoprotective activity of andrographolide. Ten andrographolide derivatives were synthesized and evaluated for in vivo hepatoprotective activity in CCl4-induced liver injury mice. The pharmacological results revealed that 6 derivatives exhibited significant hepatoprotective activity. The most promising compound 6b significantly improved liver enzymes (ALT and AST) activity as compared with andrographolide, with high potency to be a new lead.
    Letters in Drug Design &amp Discovery 01/2014; 11(5). · 0.85 Impact Factor
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    ABSTRACT: Twelve novel dicoumarol glucagon like peptide-1 (GLP-1) conjugates were designed, synthesized and tested for biological activity. All derivatives retained receptor activation efficacy, and exhibited improved albumin affinity and in vitro stability in rat plasma. The in vivo elimination half-life of 13c and 13l (22.07 and 18.78 h, respectively) were much longer than those of the GLP-1 receptor agonists exendin-4 (2.82 h) and liraglutide (12.53 h). The prolonged in vivo antidiabetic effects of 13c and 13l on db/db mice were confirmed by the hypoglycemic efficacy test and the multiple intraperitoneal glucose tolerance test. Importantly, a once daily administration of 13c to db/db mice for 7 weeks provided long-term beneficial effects by lowering glycated hemoglobin (HbA1c) levels to 5.05%, which was lower than liraglutide treatment (5.41%). These results suggest 13c is a promising long-lasting GLP-1 mimetic that may be suitable for clinical use following further research.
    Journal of Medicinal Chemistry 12/2013; · 5.61 Impact Factor
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    ABSTRACT: Poor water solubility limits the clinical use of andrographolide and its derivatives. In an attempt to develop potent hepatoprotective drugs, a strategy was proposed to improve the aqueous solubility of andrographolide. Ten andrographolide derivatives were designed, synthesized, evaluated for aqueous solubility and in vivo hepatoprotective activity against CCl4 -induced liver injury in mice. As expected, the aqueous solubility of synthetic derivatives were effectively improved. All compounds demonstrated effect of different degrees in improving the liver enzyme (ALT and AST) activity, especially the most promising compound 9d significantly improved liver enzyme activity, with high potency to be a new lead. This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 10/2013; · 2.47 Impact Factor
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    ABSTRACT: A series of fatty chain conjugates of glucagon-like peptide-1(GLP-1) were designed and synthesized. First, eleven cysteine modified peptides (1-11) were prepared using Gly8-GLP-1(7-36)-NH2 peptide as a starting point. Peptides 1, 6, 9, and 11 which showed comparable GLP-1 receptor activate potency and glucose-lowering effect in vivo with Gly8-GLP-1(7-36)-NH2 were selected for second step modifications to yield conjugates 12-23. All conjugates retained significant GLP-1 receptor activate potency and more importantly exerted enhanced albumin-binding properties and in vitro plasma stability. The protracted antidiabetic effects of the most stable compound 14 were further confirmed by both multiple intraperitoneal glucose tolerance test and hypoglycemic efficacies test in vivo. Furthermore, once daily injection of compound 14 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance. Our results suggest that compound 14 is a promising type 2 antidiabetic agent deserving further investigation.
    Biochemical pharmacology 05/2013; · 4.25 Impact Factor

Publication Stats

87 Citations
105.93 Total Impact Points


  • 2007–2014
    • China Pharmaceutical University
      • • Center of Drug Discovery
      • • School of Pharmacy
      • • Division of Medicinal Chemistry
      Nan-ching-hsü, Jiangxi Sheng, China
  • 2012
    • University of Innsbruck
      • Institut für Pharmazie
      Innsbruck, Tyrol, Austria
  • 2011
    • Nanjing University of Technology
      Nan-ching, Jiangsu Sheng, China