Zhangjian Huang

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

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Publications (44)156.8 Total impact

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    ABSTRACT: γ-Lactam is an important structural motif in a large number of biologically active natural products and synthetic small pharmaceutical molecules. However, there is currently no effective approach to construct γ-lactam ring directly from natural rigid polycyclic amides. Herein, we report a facile methodology for synthesis of a new group of olean-28,13β-lactams (10a-j) from their corresponding amides, promoted by an easily available reagent 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), through an intramolecular dehydrogenative C-N coupling reaction via a radical ion mechanism. Biological evaluation indicated that the most active lactam 10h displayed potent anti-proliferative activity against human cancer cells but 13.84~16.92-fold less inhibitory activity on non-cancer cells in vitro. In addition, 10h significantly inhibited the growth of implanted prostate cancer in vivo. Furthermore, 10h induced cell cycle arrest and apoptosis, and down-regulated the AKT/mTOR signaling in DU-145 cells. Finally, 10h was more stable in rat plasma and human liver microsomes than CDDO-Me, and had little hERG channel inhibitory activity. Collectively, 10h may be a potential anti-prostate cancer agent for further investigation.
    Journal of Medicinal Chemistry 05/2015; DOI:10.1021/jm5020023 · 5.48 Impact Factor
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    ABSTRACT: A group of nitric oxide (NO)-releasing derivatives of oleanolic acid (OA) (5–13) were designed, synthesized and biologically evaluated for their anti-colon cancer activity. It was found that the most potent compound 6 preferably released high levels of NO in colon cancer cells but not in normal cells, leading to potent cytotoxicity against colon cancer cells. In addition, 6 was more prone to produce NO catalyzed by GSTπ relative to GSTα. Furthermore, 6 significantly inhibited the tumor growth in a mouse xenograft model. Finally, 6 induced nitration of tyrosine residues in mitochondrial protein, down-regulated Wnt/β-catenin pathway, and inhibited COX-2 centered signaling loop in colon cancer cells. Collectively, our findings suggested that 6 could be a promising candidate for the intervention of colon cancer.
    RSC Advances 02/2015; 5(25). DOI:10.1039/C5RA00270B · 3.71 Impact Factor
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    ABSTRACT: Seventeen CDDO-amino acid-NO donor trihybrids (4a-q) were designed and synthesized. Biological evaluation indicated that the most active compound 4c produced high levels of NO and inhibited the proliferation of drug-sensitive (HCT-8, IC50 = 0.294 μM) and drug-resistant (HCT-8/5-FU, IC50 = 0.232 μM) colon cancer cells, which were attenuated by an NO scavenger or typical substrate of PepT1. Furthermore, 4c triggered HCT-8 and HCT-8/5-FU cell apoptosis more strongly than CDDO-Me, inhibited the HIF-1α, Stat3, AKT, ERK signaling, and induced the nitration of P-gp, MRP1, and BCRP proteins in HCT-8/5-FU cells. Finally, 4c had 4.36~5.53-fold less inhibitory activity against non-tumor colon epithelial-like cells (CCD841, IC50 = 1.282 μM) in vitro, and inhibited the growth of implanted human drug-resistant colon cancers in mice more potently than CDDO-Me. Together, 4c is a novel trihybrid with potent anti-tumor activity and may be a promising candidate for the treatment of drug-resistant colon cancer.
    Journal of Medicinal Chemistry 02/2015; 58(5). DOI:10.1021/jm5019302 · 5.48 Impact Factor
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    ABSTRACT: CDDO-Me, initiated in a phase II clinical trial, is a potential useful therapeutic agent for cancer and inflammatory dysfunctions, whereas the therapeutic efficacy of CDDO-Me on LPS-induced acute lung injury (ALI) has not been reported as yet. The purpose of the present study was to explore the protective effect of CDDO-Me on LPS-induced ALI in mice and to investigate its possible mechanism. BalB/c mice received CDDO-Me (0.5mg/kg, 2mg/kg) or dexamethasone (5mg/kg) intraperitoneally 1h before LPS stimulation and were sacrificed 6h later. W/D ratio, lung MPO activity, number of total cells and neutrophils, pulmonary histopathology, IL-6, IL-1β, and TNF-α in the BALF were assessed. Furthermore, we estimated iNOS, IL-6, IL-1β, and TNF-α mRNA expression and NO production as well as the activation of the three main MAPKs, AkT, IκB-α and p65. Pretreatment with CDDO-Me significantly ameliorated W/D ratio, lung MPO activity, inflammatory cell infiltration, and inflammatory cytokine production in BALF from the in vivo study. Additionally, CDDO-Me had beneficial effects on the intervention for pathogenesis process at molecular, protein and transcriptional levels in vitro. These analytical results provided evidence that CDDO-Me could be a potential therapeutic candidate for treating LPS-induced ALI. Copyright © 2015. Published by Elsevier B.V.
    International Immunopharmacology 01/2015; 25(1). DOI:10.1016/j.intimp.2015.01.011 · 2.71 Impact Factor
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    ABSTRACT: In the present study, a series of hydrogen sulfide (H2S) releasing derivatives ( and ) of 3-n-butylphthalide (NBP) were designed, synthesized and biologically evaluated. The most promising compound significantly inhibited the adenosine diphosphate (ADP) and arachidonic acid (AA)-induced platelet aggregation in vitro, superior to NBP, ticlopidine hydrochloride and aspirin. Furthermore, could slowly produce moderate levels of H2S in vitro, which could be beneficial for improving cardiovascular and cerebral circulation. Most importantly, protected against the collagen and adrenaline induced thrombosis in mice, and exhibited greater antithrombotic activity than NBP and aspirin in rats. Overall, could warrant further investigation for the treatment of thrombosis-related ischemic stroke.
    Organic & Biomolecular Chemistry 07/2014; 12(31). DOI:10.1039/c4ob00830h · 3.49 Impact Factor
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    ABSTRACT: NEDD8-activating enzyme (NAE) is an emerging target for cancer therapy, which regulates the degradation and turnover of a variety of cancer-related proteins by activating the cullin-RING E3 ubiquitin ligase. Among a limited number of known NAE inhibitors, the covalent inhibitors have demonstrated the most potent efficacy through their covalently-linked adducts with NEDD8. Inspired by this unique mechanism, in this study, a novel combined strategy of virtual screening (VS) was adopted with the aim to identify diverse covalent inhibitors of NAE. To be specific, a docking-enabled pharmacophore model was firstly built from the possible active conformations of chosen covalent inhibitors. Meanwhile, a dynamic structure-based phamacophore was also established based on the snapshots derived from molecular dynamic simulation. Subsequent screening of a focused ZINC database using these pharmacophore models combined with covalent docking discovered three novel active compounds. Among them, compound LZ3 exhibited the most potent NAE inhibitory activity with an IC50 value of 1.06 ± 0.18 μM. Furthermore, a cell-based washout experiment proved the proposed covalent binding mechanism for compound LZ3, which confirmed the successful application of our combined VS strategy, indicating it may provide a viable solution to systematically discover novel covalent ligands.
    Journal of Chemical Information and Modeling 05/2014; 54(6). DOI:10.1021/ci5002058 · 4.07 Impact Factor
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    ABSTRACT: A series of hybrids () of farnesylthiosalicylic acid (FTS) and hydroxylcinnamic acid were designed and synthesized. Most of the hybrids displayed potent antiproliferative activity against seven cancer cell lines in vitro, superior to FTS as well as sorafenib. The most potent compound selectively inhibited cancer cells but not non-tumor liver cell proliferation in vitro, and significantly induced SMMC-7721 cell apoptosis. Interestingly, could simultaneously inhibit not only Ras-related signaling but also phosphorylated NF-κB, which may synergetically contribute to the cell growth inhibition and apoptosis induction. Moreover, showed low acute toxicity to mice and significantly inhibited the hepatoma tumor growth.
    Organic & Biomolecular Chemistry 05/2014; 12(25). DOI:10.1039/c4ob00023d · 3.49 Impact Factor
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    ABSTRACT: Twelve dibenzofuran/carbazole derivatives were designed and synthesized as potential multifunctional anti-Alzheimer agents.
    European Journal of Medicinal Chemistry 04/2014; 76:376–386. DOI:10.1016/j.ejmech.2014.02.035 · 3.43 Impact Factor
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    ABSTRACT: Novel compounds 12a-i were synthesized and biologically evaluated. Several ones exhibited stronger inhibitory activity than gefitinib against EGFR L858R/T790M and antiproliferative effects on H1975 and HCC827 cells. The 3-aminopropamide in compounds like 12h could be converted to the active acrylamide in the presence of arginine. Importantly, 12h showed improved stability relative to compound 1 whose structure is same to 12h excepting an acrylamide moiety. Interestingly, 12i, a NO donating compound of 12h, showed more potent and selective inhibition than 12h on H1975 cells. Significantly, 12i produced high levels of NO in H1975 cells but not in non-tumorous 16HBE cells, and its inhibition was diminished by NO scavenger. Furthermore, 12i dose-dependently produced inhibitory effects on EGFR downstream signaling in H1975 cells.
    European Journal of Medicinal Chemistry 02/2014; 77C:75-83. DOI:10.1016/j.ejmech.2014.02.032 · 3.43 Impact Factor
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    ABSTRACT: Compound 12h could be converted to the active compound 1 in the presence of arginine and NO donating compound 12i showed more potent and selective antiproliferative effects than 12h.
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    ABSTRACT: Fourteen hybrids of farnesylthiosalicylic acid (FTS) with various diamines were synthesized and biologically evaluated. It was found that FTS-monoamide molecules (10a-g) displayed strong anti-proliferative activity against seven human cancer cell lines, superior to FTS and FTS-bisamide compounds (11a-g). The mono-amide 10f was the most active, with IC50s of 3.78-7.63μM against all tested cancer cells, even more potent than sorafenib (9.12-22.9μM). In addition, 10f induced SMMC-7721 cell apoptosis, down-regulated the expression of Bcl-2 and up-regulated Bax and caspase-3. Furthermore, 10f had the improved aqueous solubility relative to FTS. Finally, treatment with 10f dose-dependently inhibited the Ras-related signaling pathways in SMMC-7721 cells. Collectively, 10f could be a promising candidate for the intervention of human cancers.
    Bioorganic & medicinal chemistry 11/2013; 22(1). DOI:10.1016/j.bmc.2013.11.013 · 2.95 Impact Factor
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    ABSTRACT: To search for potent nitric oxide (NO) donating epidermal growth factor receptor (EGFR) inhibitors, a series of phenylsulfonylfuroxan-based anilinopyrimidines 10a-h were synthesized and biologically evaluated. Compounds 10f-h exhibited potent inhibitory activity against EGFR L858R/T790M and were as potent as WZ4002 in inhibition of H1975 cells harboring EGFR L858R/T790M. Additionally, 10h produced high levels of NO in H1975 cells but not in normal human cells, and its antiproliferative activity was diminished by hemoglobin, an NO scavenger. Furthermore, 10h inhibited EGFR activation and downstream signaling in H1975 cells. These results suggest that the strong antiproliferative activity of 10h could be attributed to the synergic effects of high levels of NO production and inhibition of EGFR and downstream signaling in the cancer cells.
    European Journal of Medicinal Chemistry 05/2013; 66C:82-90. DOI:10.1016/j.ejmech.2013.05.026 · 3.43 Impact Factor
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    ABSTRACT: A series of hybrids 12a-k from phenylsulfonylfuroxan and anilinopyrimidine were synthesized and biologically evaluated as EGFR inhibitors for intervention of NSCLC. Compound 12k exhibited strong and selective EGFR L858R/T790M inhibitory activity (IC50 = 0.047 μM), and displayed antiproliferative effects on EGFR mutation NSCLC cell lines HCC827 (del E746_A750) and H1975 (L858R/T790M) with IC50s of 0.007 and 0.029 μM, respectively. Additionally, 12k released high levels of NO in H1975 cells but not in normal human cells, and its activity was diminished by pretreatment with a NO scavenger. Furthermore, 12k induced apoptosis of H1975 and HCC827 cells more strongly than WZ4002, inhibited EGFR downstream signaling in H1975 cells, and suppressed the NF-κB activation in H1975 cells while WZ4002 had no significant effects under the same conditions. Finally, 12k substantially inhibited tumor growth in a H1975 xenograft mouse model. Overall, 12k might be a promising candidate for the treatment of NSCLC.
    Journal of Medicinal Chemistry 05/2013; 56(11). DOI:10.1021/jm400463q · 5.48 Impact Factor
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    ABSTRACT: A series of hybrids from O(2)-(2,4-dinitrophenyl)diazeniumdiolate and oleanolic acid (OA) were designed, synthesized, and biologically evaluated as novel nitric oxide (NO) releasing prodrugs which could be activated by glutathione S-transferase π (GSTπ) overexpressed in a number of cancer cells. It was discovered that the most active compound 21 released high levels of NO selectively in HCC cells but not in the normal cells, and exhibited potent antiproliferative activity in vitro as well as remarkable tumor-retarding effects in vivo. Compared with the reported GSTπ-activated prodrugs JS-K and PABA/NO, 21 exhibited remarkably improved stability in the absence of GSTπ. Importantly, the decomposition of 21 occurred in the presence of GSTπ, and was much more effective than in GSTα. Additionally, 21 induced HepG2 cells apoptosis by arresting cell cycle at G2/M phase, activating both the mitochondria-mediated pathway and the MAPKs pathway, as well as enhancing the intracellular production of ROS.
    Journal of Medicinal Chemistry 04/2013; 56(11). DOI:10.1021/jm400393u · 5.48 Impact Factor
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    ABSTRACT: To search for potent anti-Alzheimer's disease (AD) agents with multifunctional effects, 12 NO-donating tacrine-flurbiprofen hybrid compounds (2a-l) were synthesized and biologically evaluated. It was found that all the new target compounds showed selective butyrylcholinesterase (BuChE) inhibitory activity in vitro comparable or higher than tacrine and the tacrine-flurbiprofen hybrid compounds 1a-c, and released moderate amount of NO in vitro. The kinetic study suggests that one of the most active and highest BuChE selective compounds 2d may not only compete with the substrate for the same catalytic active site (CAS) but also interact with a second binding site. Furthermore, 2d and 2l exhibited significant vascular relaxation effect, which is beneficial for the treatment of AD. All the results suggest that 2d and 2l might be promising lead compounds for further research.
    Bioorganic & medicinal chemistry letters 04/2013; 23(11). DOI:10.1016/j.bmcl.2013.04.008 · 2.33 Impact Factor
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    ABSTRACT: In search of novel anti-ischemic stroke agents with higher potency than a known drug 3-n-butylphthalide (NBP), a series of hybrids ((S)- and (R)-5a-f) from optically active ring-opening NBP derivative and isosorbide were synthesized for evaluating their anti-ischemic stroke activity. Compound (S)-5e displayed the strongest activity in inhibiting the adenosine diphosphate (ADP) and arachidonic acid (AA)-induced platelet aggregation in vitro, with 10.0- and 8.4-fold more effectiveness than (S)-NBP, respectively. Furthermore, (S)-5e was stable in artificial gastrointestinal fluids, and could penetrate the blood-brain barrier (BBB) with an appreciate lipid/water partition coefficient relative to (S)-NBP. More importantly, oral treatment with (S)-5e protected from acute thrombosis, and inhibited the ischemia/reperfusion-related brain injury in animals. Our findings suggest that (S)-5e may be promising for further evaluation for the intervention of ischemic stroke.
    Journal of Medicinal Chemistry 03/2013; 56(7). DOI:10.1021/jm4001693 · 5.48 Impact Factor
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    ABSTRACT: To search for multifunctional anti-Alzheimer's disease (AD) agents with good safety, the previously synthesized tacrine-flurbiprofen hybrids 1a and 1b were modified into tacrine-flurbiprofen-nitrate trihybrids 3a-h. These compounds displayed comparable or higher cholinesterase inhibitory activity relative to the bivalent hybrids. Compound 3a was the most potent, which released moderate NO, exerted blood vessel relaxative activity, and showed significant Aβ inhibitory effects whereas tacrine and flurbiprofen did not exhibit any Aβ inhibitory activity at the same dose. In addition, 3a was active in improving memory impairment in vivo. More importantly, the hepatotoxicity study showed that 3a was much safer than tacrine, suggesting it might be a promising anti-AD agent for further investigation.
    Bioorganic & medicinal chemistry 03/2013; 21(9). DOI:10.1016/j.bmc.2013.03.005 · 2.95 Impact Factor
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    ABSTRACT: 1-(7-Azabenzobicyclo[2.2.1]heptane)diazen-1-ium-1,2-diolate (16) was designed with the expectation that it would act as a dual nitric oxide (NO) and nitroxyl (HNO) donor that is not carcinogenic or genotoxic. Compound 16, with a suitable half-life (17.8min) in PBS at pH 7, released NO (19%) and HNO (22%) during a 2h incubation in PBS at pH 7. In addition, compound 16 exhibited a significant in vitro positive inotropic effect, increased the rates of contraction and relaxation, and increased coronary flow rate, but did not induce a chronotropic effect. Furthermore, compound 16 (13.7mgkg(-1), po dose) provided a significant reduction in the blood pressure of mice up to 3h post-drug administration. All these data suggest that compound 16 constitutes an attractive 'lead-compound' that could have potential applications to treat cardiovascular disease(s) such as congestive heart failure.
    Bioorganic & medicinal chemistry letters 02/2013; 23(9). DOI:10.1016/j.bmcl.2013.02.040 · 2.33 Impact Factor
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    ABSTRACT: A series of novel nitric oxide releasing derivatives of 6-amino-3-n-butylphthalide were designed, synthesized and evaluated as potential antiplatelet agents. Compound 10b significantly inhibited the adenosine diphosphate (ADP)-induced platelet aggregation in vitro, superior to 6-amino-3-n-butylphthalide, 3-n-butylphthalide (NBP) and ticlopidine. Meanwhile 10b released moderate levels of NO, which could be beneficial for improving cardiovascular and cerebral circulation. Furthermore, 10b had an enhanced aqueous solubility relative to NBP. These findings may provide new insights into the development of novel antiplatelet agents for the treatment of thrombosis-related ischemic stroke.
    Bioorganic & medicinal chemistry letters 02/2013; 23(7). DOI:10.1016/j.bmcl.2013.02.035 · 2.33 Impact Factor
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    ABSTRACT: Fifteen novel derivatives of glycyrrhetinic acid (GA) were synthesized and evaluated for anti-inflammatory activities. It was found that the introduction of 1-en-3-one and 9(11),12-diene as well as 2,20-dinitrile functionalities into the scaffold of GA led to the discovery of potent compound 19 for inhibition of LPS-induced NO production. Furthermore, 19 effectively inhibited the protein and mRNA expression of inducible NO synthase (iNOS) and the mRNA expression of TNF-α, IL-6 and IL-1β in LPS-stimulated RAW 264.7 macrophages. Mechanistically, 19 exerted inhibitory effects on the activation of the three main MAPKs and phosphorylation and degradation of IκB-α, as well as the ratio of nuclear/cytosolic content of p65. Importantly, 19 significantly decreased the mortality rate in the mice model of LPS-induced sepsis shock. It is noteworthy that inhibitory effect of 19 on NO production was not blocked by the glucocorticoid receptor antagonist mifepristone, indicating that it does not act through the glucocorticoid receptor.
    Journal of Medicinal Chemistry 02/2013; 56(5). DOI:10.1021/jm301652t · 5.48 Impact Factor

Publication Stats

217 Citations
156.80 Total Impact Points

Institutions

  • 2009–2015
    • China Pharmaceutical University
      • Center of Drug Discovery
      Nan-ching-hsü, Jiangxi Sheng, China
  • 2010–2013
    • University of Alberta
      • Faculty of Pharmacy and Pharmaceutical Sciences
      Edmonton, Alberta, Canada