Hai Qian

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

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Publications (65)135.92 Total impact

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    ABSTRACT: Luteinizing hormone-releasing hormone (LHRH) is a decapeptide hormone released from the hypothalamus and shows high affinity binding to the LHRH receptors. It is reported that several cancer cells also express LHRH receptors such as breast, ovarian, prostatic, bladder and others. In this study, we linked B1, an anti-cancer peptide, to LHRH and its analogs to improve the activity against cancer cells with LHRH receptor. Biological evaluation revealed that TB1, the peptide contains triptorelin sequence, present favorable anti-cancer activity as well as plasma stability. Further investigations disclosed that TB1 trigger apoptosis by activating the mitochondria-cytochrome c-caspase apoptotic pathway, it also exhibited the anti-migratory effect on cancer cells.
    Amino Acids 06/2015; DOI:10.1007/s00726-015-2021-2 · 3.65 Impact Factor
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    ABSTRACT: Compared with traditional therapeutics, antimicrobial peptides as novel anti-tumor agents have prominent advantages of higher specificity and circumvention of multi-drug resistance. In previous study, we found B1, an antimicrobial peptide derived from Cathelicidin-BF15, presented specific anti-tumor activity against several tumor cells. Since aliphatic chain-conjugated peptides have shown ameliorative activity and stability, we conjugated the aliphatic acids with different lengths to the amino terminal of B1. All the conjugated peptides exhibited improved anti-tumor activity over B1. Further investigations revealed that the peptides were capable of disrupting the cell membrane, stimulating the cytochrome c release into cytosol which results in apoptosis. The peptides also acted against multidrug resistant cells and had multidrug resistance-reversing effects. Additionally, conjugation of aliphatic acid enhanced peptide stability in plasma. In summary, aliphatic acid-modified peptides might be promising anti-tumor agents in the future.
    Organic & Biomolecular Chemistry 06/2015; DOI:10.1039/C5OB00752F · 3.49 Impact Factor
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    ABSTRACT: Little has been investigated about the intracellular fate of organic nanoparticles (NPs), which is important for the safety and drug delivery efficiency of NPs. In this study, to understand the NP cellular uptake and degradation characteristics, a quantitative method based on fluorescence resonance energy transfer (FRET) was developed and validated to detect the uptake and intracellular degradation of albumin NPs in MCF-7 cells. The effects of ¬the crosslinking density and particle size on the intracellular uptake and degradation kinetics of albumin NPs were then systematically detected. The results indicated that the albumin NPs with higher crosslinking degrees could be internalized more quickly. With increasing NP diameter, the uptake number of NPs decreased, but the uptake NP weight increased due to the compensation of the increased weight of a single particle. The intracellular degradation results showed the NPs with a low crosslinking degree or a small diameter disassociated more quickly in cells, and the half-lives for the albumin NPs disassociation were in the range of 35-79h. These findings will provide fundamental but direct information for the optimal design and biomedical applications of NPs based on their intracellular fates, and the FRET method developed in this study can provide a novel and robust tool to track and monitor the NP intracellular fate.
    RSC Advances 04/2015; 5(44). DOI:10.1039/C5RA01683E · 3.71 Impact Factor
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    ABSTRACT: Three series of Momordica charantia (MC)2 analogues were designed, synthesized and evaluated for their anti-hyperglycaemic effects. Alanine scanning focusing on the peptide MC2 indicated the importance of the residues proline (Pro)3, serine (Ser)6, isoleucine (Ile)7 and Ser10 for anti-hyperglycaemic effects. Among the first series of MC2 analogues, peptide I-4 exhibited a better anti-hyperglycaemic effect and was chosen for further modification. A further two series of conformationally constrained analogues were designed by scanning the residues Pro3, Ser6, Ile7, Ser10 with an i-(i + 2) lactam bridge consisting of a Glutamic acid-Xaa-Lysine (Glu–Xaa–Lys) scaffold and a diproline fragment. Through screening in normal and mice with diabetes mellitus, peptides II-1, II-2 and III-3 showed significant improvement in anti-hyperglycaemic and anti-oxidative activities compared with I-4. These data suggest that II-1, II-2 and III-3 could be candidates for future treatment of diabetes mellitus.
    Organic & Biomolecular Chemistry 03/2015; 13(15). DOI:10.1039/C5OB00333D · 3.49 Impact Factor
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    ABSTRACT: A series of novel C-aryl glucosides with substituents at the 3'- position or cyclization at 3' 4'- positions of the distal aryl ring were designed and synthesized, which might decrease the oxidative metabolism of dapagliflozin. Preliminary evaluation for hypoglycemic effect and the risk of hypoglycemia were carried out both in normal and streptozotocin-induced diabetic mice. Among the synthesized compounds, compound 19a exerted potency-similarity with dapagliflozin and triggered the hypoglycemic effect in a dose-dependent manner. Besides, compound 19a, even at the high dose of 10 mg/kg, revealed a low risk of hypoglycemia. In further studies, 19a exhibited sustained antihyperglycemic effect without particular side effects in 30 days chronic diabetic mice studies. Moreover, histological changes in the pancreas of diabetic mice indicated 19a might protect pancreatic β cell from apoptosis by reducing the damage of glucotoxicity. All of these results demonstrated that compound 19a, with excellent in vivo pharmacological activity and safety profile, was considered to 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 03/2015; DOI:10.1111/cbdd.12547 · 2.51 Impact Factor
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    ABSTRACT: Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated non-selective cation channel that is considered to be an important pain integrator. Tetrahydroisoquinoline, the prototypical antagonist of TRPV1, has a clear therapeutic potential. Here, a series of carbamide derivatives of tetrahydroisoquinoline were designed and synthesized. Preliminary biological tests suggested that the compounds I 1, I 2, and I 9 had favorable TRPV1 antagonism activity. In further studies, I 1 exhibited better antinociceptive activity than the positive control BCTC in diverse pain models. All of these results suggested that I 1 can be considered as the lead candidate for the further development of antinociceptive drugs. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Archiv der Pharmazie 03/2015; 348(5). DOI:10.1002/ardp.201400455 · 1.40 Impact Factor
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    ABSTRACT: Chemotherapy is an important approach used to treat cancer, but severe side effects and emerging drug resistance restrict its clinical application. In this present study, we found that peptide B1 showed specific cytotoxicity to tumor cells. Moreover, a helix-wheel plot predicted that the Ser14 in this peptide is located at the interface of the hydrophobic and hydrophilic faces of B1. Subsequently, we wondered whether replacing Ser14 would alter the activity of B1, and so a series of B1 analogs were synthesized where the Ser14 was replaced by amino acids with distinct physicochemical properties. Amongst them, peptides where Ser14 was substituted by a nonpolar and basic amino acid had improved anti-cancer activity. Further investigations revealed that B1 and its analogs were capable of penetrating into cytoplasm and triggering cytochrome C release from mitochondria, which ultimately resulted in apoptosis. Meanwhile, B1 and its analogs inhibited the migration of cancer cells. The peptides also acted against drug-resistant cells and had drug resistance-reversing effects. In conclusion, these peptides might be promising candidates for oncotherapy.
    European Journal of Medicinal Chemistry 01/2015; 89. DOI:10.1016/j.ejmech.2014.10.072 · 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; 10(2). DOI:10.1002/cmdc.201402463 · 3.05 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; DOI:10.1111/cbdd.12487 · 2.51 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; 23(1). DOI:10.1016/j.bmc.2014.11.016 · 2.95 Impact Factor
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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; DOI:10.1111/cbdd.12483 · 2.51 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; 22(24). DOI:10.1016/j.bmc.2014.10.032 · 2.95 Impact Factor
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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; 93(1):1-6. DOI:10.1139/cjpp-2014-0377 · 1.55 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. DOI:10.1016/j.jpba.2014.09.017 · 2.83 Impact Factor
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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. DOI:10.1016/S1875-5364(14)60093-5
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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; DOI:10.1111/bph.12843 · 4.99 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). DOI:10.2174/1570180811666140115234123
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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; 11(1). DOI:10.2174/1573406410666140428152436 · 1.39 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; DOI:10.1248/cpb.c13-00964 · 1.38 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; 85(5). DOI:10.1111/cbdd.12316 · 2.51 Impact Factor