Hai Qian

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

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Publications (91)163.9 Total impact

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    ABSTRACT: As a NPY-2 receptor agonist, PYY24-36- Leu 31 is reported to suppress appetite and has a potential in obesity treatment, but its short half-life limits the clinical application. The use of chemical modification to improve interactions with human serum albumin (HSA) is an effective strategy for prolonging the half-lives of peptide analogues. So based on the characteristics that phenylbutazone has a good combination with HSA, we selected a proper linker to link with PYY24-36 -Leu31 to create long-acting and highly biologically active PYY24-36 -Leu31 conjugates, and successfully find a novel, long-acting PYY24-36 -Leu31 conjugate 8 that, when dosed every other day in diet induce obese (DIO) mice for two weeks, results in a significant reduction in food intake and body weight and improvement in blood parameter and hepatic steatosis. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Chemical Biology & Drug Design
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    ABSTRACT: Multitarget-directed ligands might offer certain advantages over traditional single-target drugs and/or drug combinations. In the present study, a series of novel analgesic agents targeting both cyclooxygenase and TRPV1 were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazine, ethanediamine cores. These compounds were evaluated for antagonism of hTRPV1 activation by capsaicin and the ability to inhibit Ovine COX-1 and human recombinant COX-2 in vitro. The favorable potentials of these test compounds were further characterized in preliminary analgesic and side-effects tests in vivo. On the basis of comprehensive evaluations, compound 8d which showed strong TRPV1 antagonistic activity, middle COX-2 inhibition, weak ulcerogenic action and had no hyperthermia side-effect was considered as a safe candidate for the further development of analgesic drugs.
    No preview · Article · Jan 2016 · Bioorganic & medicinal chemistry
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    ABSTRACT: The free fatty acid receptor 1 (FFA1) is a novel antidiabetic target for the treatment of type 2 diabetes based on particular mechanism in amplifying glucose-stimulated insulin secretion. We have previously identified a series of phenoxyacetic acid derivatives. Herein, we describe the further chemical modification of this series directed by ligand efficiency and ligand lipophilicity efficiency. All of these efforts lead to the discovery of the promising candidate 16, an excellent FFA1 agonist with robust agonistic activity (43.6 nM), desired LE and LLE values. Moreover, compound 16 revealed a great potential for improving the hyperglycemia levels in both normal and type 2 diabetic mice without the risk of hypoglycemia even at the high dose of 40 mg/kg.
    No preview · Article · Nov 2015 · Bioorganic & Medicinal Chemistry
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    ABSTRACT: Two series of conformationally constrained analogues from Gly3-MC62 were designed by scanning the residues Lys1, Thr2, Met4, Lys5, Met7, and Ala8 with an i-(i + 2) lactam bridge consisting of a Glutamic acid-xaa-lysine (Glu-Xaa-Lys) scaffold and a diproline fragment. They were synthesized and evaluated for their antihyperglycemic effects. Through screening in normal and mice with diabetes mellitus, peptides II-5, III-3, III-4, and III-5 showed significant improvement in antihyperglycemic and antioxidative activities compared with Gly3-MC62, especially the compound III-4. The primary mechanism of the compounds (II-5, III-3, III-4, and III-5) underlying this effect is the islet β-cells against oxidative damage induced by STZ, and III-4-treated mice showed considerable improvement in the preservation of beta cells in the pancreatic islets of DM mice. These data suggested that III-4 could be candidate for the future treatment of diabetes mellitus. Two series of Gly3-MC62 analogues were synthesized and were evaluated for their antihyperglycemic effects. Antihyperglycemic effect of III-4 was more potent than that of parent peptide Gly3-MC62. III-4 merits further screening for antihyperglycemic/antioxidative effects.
    No preview · Article · Nov 2015 · Chemical Biology & Drug Design
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1) is a potential candidate for the treatment of type 2 diabetes. However, native GLP-1 is not suitable for therapy of diabetes due to its short half-life (t1/2=2min). Our recent discovery of the novel long-acting GLP-1 analog, coumaglutide, elicits favorable hypoglycemic effects. The present study was aimed at determining the protection effect of β-cell from apoptosis and in vivo pharmacologic properties of coumaglutide in diabetic mice. To determine the protective effect of coumaglutide on INS-1 cell viability and apoptosis, cells were exposed to 1μM streptozotocin (STZ) and coumaglutide for 24h. Moreover, STZ-induced diabetic mice were treated daily with coumaglutide for 20 days and a range of pharmacologic parameters, including hemoglobin A1c (HbA1C), intraperitoneal glucose tolerance, food intake and body weight were assessed before and after the treatment. As with other glucagon-like peptide-1 receptor agonists, coumaglutide was able to protect β-cell from apoptosis in vitro and induce a durable restoration of glycemic control (normalization of both HbA1C and improvement of intraperitoneal glucose tolerance) in diabetic mice. It can be concluded that coumaglutide retains native GLP-1 activities and thus may serve as a promising hypoglycemic drug candidate.
    No preview · Article · Oct 2015 · European journal of pharmacology
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    ABSTRACT: The free fatty acid receptor 1 (FFA1) has attracted extensive attention as a novel antidiabetic target in the last decade. Several FFA1 agonists reported in the literature have been suffered from relatively high molecular weight and lipophilicity. We have previously reported the FFA1 agonist 1. Based on the common amide structural characteristic of SAR1 and NIH screened compound, we here describe the continued structure-activity exploration to decrease the molecular weight and lipophilicity of the compound 1 series by converting various amide linkers. All of these efforts lead to the discovery of the preferable lead compound 18, a compound with considerable agonistic activity, high LE and LLE values, lower lipophilicity than previously reported agonists, and appreciable efficacy on glucose tolerance in both normal and type 2 diabetic mice.
    No preview · Article · Oct 2015 · Bioorganic & Medicinal Chemistry
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    ABSTRACT: A series of novel pyrrolidinyl-linker TRPV1 antagonists were prepared in an effort to lower hyperthermic side-effects of first-generation antagonist BCTC. These compounds were investigated for antagonism of hTRPV1 activation by capsaicin and acid in vitro. Preliminary results suggested the compounds 10a, 10b, 10c and 10j had favorable TRPV1 antagonism activity. In further studies in vivo, 10b, comparable to BCTC, showed potent analgesic activity in capsaicin-induced and heat-induced pain models. In addition, 10b indicated a reduced risk for body temperature elevation. All of these demonstated that 10b can be considered as a safe candidate for the further development of analgesic drugs.This article is protected by copyright. All rights reserved.
    No preview · Article · Sep 2015 · Chemical Biology & Drug Design
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    ABSTRACT: Antimicrobial peptides have been suggested as promising chemotherapeutics for cancer therapy due to their efficient anti-tumor activity and lower toxicity to benign cells. In previous study, we find the peptide B1 presents specific cytotoxicity to cancer cells. As hydrophobicity plays a pivotal role in the anti-cancer activity of peptide, we introduce cholesterol-like moiety (3β-amino-5-cholestene) to the N-terminus of B1 expect to ameliorate the anti-cancer activity of B1. Biological evaluations revealed that target peptides show improved anti-cancer activity. The peptides can also penetrate into the cytoplasm and activating mitochondria-cytochrome c apoptosis pathway. Besides, the peptides acted on multidrug resistant cells and had multidrug resistance-reversing activity. It is therefore suggested these peptides might be promising candidates for oncotherapy.This article is protected by copyright. All rights reserved.
    No preview · Article · Sep 2015 · Chemical Biology & Drug Design
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    ABSTRACT: We proposed that a pentapeptide, LVKGRamide, GLP-1(32-36) amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), might possess favorable actions against diabetes. Therefore, GLP-1 (32-36) amide was synthesized and the effects of it were examined in INS-1 cell and streptozotocin-induced diabetic mice model. To determine the protective effects of GLP-1(32-36) amide on INS-1 cell viability and apoptosis, cells were exposed to 1μM streptozotocin (STZ) and GLP-1(32-36) amide for 24 h. Results showed that GLP-1(32-36) amide treatment decreased apoptosis rate and significantly retained cell viability compared with saline-treated controls. Then, GLP-1(32-36) amide were administered intraperitoneally to streptozotocin-induced diabetic mice with normal mice used as control. Body weight, energy intake, plasma glucose, and histopathology of the pancreas were assessed. Results showed that GLP-1(32-36) amide protected β-cell viability and apoptosis against STZ-induced toxicity, inhibited weight gain, relieved symptoms of polydipsia. Moreover, GLP-1 pentapeptide-treated mice showed a slight trend toward reduced glucose excursions in intraperitoneal glucose tolerance test at the end of the experiment. GLP-1(32-36) amide exerted favorable protective actions in streptozotocin-induced diabetic mice. The peptide curtailed weight gain and alleviates symptoms of polydipsia. These findings suggested the probable utility of GLP-1(32-36) amide, a peptide mimetic derived there from GLP-1, for adjuvant treatment of diabetes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Chemical Biology & Drug Design
  • Xin Deng · Qianqian Qiu · Ke Ma · Wenlong Huang · Hai Qian
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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.
    No preview · Article · Jun 2015 · Amino Acids
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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.
    No preview · Article · Jun 2015 · Organic & Biomolecular Chemistry
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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.
    No preview · Article · Apr 2015 · RSC Advances
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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.
    Preview · Article · Mar 2015 · Organic & Biomolecular Chemistry
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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.
    No preview · Article · Mar 2015 · Chemical Biology & Drug Design
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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.
    No preview · Article · Mar 2015 · Archiv der Pharmazie
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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.
    No preview · Article · Jan 2015 · European Journal of Medicinal Chemistry
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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.
    No preview · Article · Dec 2014 · ChemMedChem
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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.
    No preview · Article · Dec 2014 · Chemical Biology & Drug Design
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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.
    No preview · Article · Nov 2014 · Bioorganic & Medicinal Chemistry
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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.
    No preview · Article · Nov 2014 · Chemical Biology & Drug Design