Quan Zhang

Nankai University, T’ien-ching-shih, Tianjin Shi, China

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Publications (22)100.52 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Inspired by the biosynthesis of sesquiterpene lactones (SLs), herein we report the asymmetric total synthesis of germacrane ring (24). The synthetic strategy features a selective aldol reaction between β,γ-unsaturated chiral sulfonylamide 15a and aldehyde 13, as well as the intramolecular α-alkylation of sulfone 21 to construct 10-membered carbocylic ring. The key intermediate 24 can be used to prepare the natural products costunolide and parthenolide (PTL), which are the key precursors for transformation into other SLs. Furthermore, the described synthetic sequences are amenable to the total synthesis of SL analogs, such as trifluoromethylated analogs (32 and 45). Analogs 32 and 45 maintained high activities against a series of cancer cell lines comparing to their parent PTL and costunolide, respectively. In addition, 32 showed enhanced tolerance to acidic media comparing with PTL. To our surprise, PTL and 32 showed comparable half-lives in rat plasma and in the presence of human liver microsomes.
    Journal of Medicinal Chemistry 07/2015; 58(17). DOI:10.1021/acs.jmedchem.5b00915 · 5.45 Impact Factor
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    ABSTRACT: There is no highly effective chemotherapy for malignant gliomas to date. We found that dimethylaminomicheliolide (DMAMCL), a selective inhibitor of acute myeloid leukemia (AML) stem/progenitor cells, inhibited the growth of glioma cells. The distribution of DMAMCL in brain was analyzed by an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS) system. The anti-tumor evaluations of DMAMCL in vitro were performed by MTT, FACS and RT-PCR. In vivo, the mixture of C6 cells and matrigel was injected into caudatum, and the anti-tumor activity of DMAMCL was evaluated by tumor growth and rat survival. The toxicity of DMAMCL was evaluated by body weight, daily food intake, hematological or serum biochemical analyses, and histological appearance of tissues. The IC50 values of DMAMCL against the C6 and U-87MG cell lines in vitro were 27.18 ± 1.89 μM and 20.58 ± 1.61 μM, respectively. DAMMCL down-regulated the anti-apoptosis gene Bcl-2 and increased apoptosis in C6 and U-87MG cells in a dose-dependent manner. In a C6 rat tumor model, daily administration of DMAMCL for 21 days reduced the burden of C6 tumors by 60% to 88% compared to controls, and more than doubled the mean lifespan of tumor-bearing rats. Distribution analysis showed that the DMAMCL concentration was higher in the brain than in plasma. Evaluations for toxicity revealed that oral administration of DMAMCL at 200 or 300 mg/kg once a day for 21 days did not result in toxicity. These results suggest that DMAMCL is highly promising for the treatment of glioma.
    PLoS ONE 02/2015; 10(2):e0116202. DOI:10.1371/journal.pone.0116202 · 3.23 Impact Factor
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    ABSTRACT: Inflammation is a relevant factor in the pathogenesis of diabetes nephropathy (DN). Sesquiterpene lactones (SLs), originally isolated from Tanacetum parthenium, have been reported to exhibit anti-inflammatory effects but few studies have examined their effects on DN. To determine whether advanced oxidation protein products (AOPPs) can induce the expression of chemokine monocyte chemoattractant protein- (MCP-) 1 in cultured mouse podocytes and to explore the mechanisms of the potential renoprotection of SLs, we treated podocytes with AOPPs and SLs (parthenolide and its derivatives micheliolide, compound 1, and compound 2). MCP-1 mRNA and protein expression were tested using quantitative real-time PCR and ELISA, respectively, and the protein levels of IKKβ, phospho-IKKβ, IκBα, NF-κB p65, phospho-NF-κB p65, and tubulin were analyzed by Western blotting. AOPPs activated the expression of MCP-1 mRNA and protein in a dose- and time-dependent manner, activated IKKβ and NF-κB p65, and promoted IκBα degradation. The IKK/NF-κB inhibitor parthenolide decreased AOPP-induced MCP-1 expression. Pretreatment with SLs inhibited MCP-1 mRNA and protein expression and suppressed IKKβ and NF-κB p65 phosphorylation and IκBα degradation. Taken together, these findings provide a novel explanation for the anti-inflammatory effects of SLs that will ultimately benefit DN and potentially other inflammatory and immune renal diseases.
    Oxidative medicine and cellular longevity 01/2015; 2015:1-13. DOI:10.1155/2015/934058 · 3.36 Impact Factor
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    ABSTRACT: Rakicidin A is a cyclic depsipeptide that has exhibited unique growth inhibitory activity against chronic myelogenous leukemia stem cells. Furthermore, rakicidin A has five chiral centers with unknown stereochemical assignment, and thus, can be represented by one of 32 possible stereoisomers. To predict the most probable stereochemistry of rakicidin A, calculations and structural comparison with natural cyclic depsipeptides were applied. A total synthesis of the proposed structure was subsequently completed, and highlighted by the creation of a sterically hindered ester bond (C1-C15) through trans-acylation from an easily established isomer (C1-C13). The analytic data of the synthetic target was consistent with that of natural rakicidin A, and then the absolute configuration of rakicidin A was assigned as 2S, 3S, 14S, 15S, 16R. This work suggests strategies for the determination of unknown chiral centers in other cyclic depsipeptides, such as rakicidin B, C, D, BE-43547 and vinylamycin, and facilitates the investigations of rakicidin A as an anti-cancer stem cell agent.
    Journal of the American Chemical Society 10/2014; 136(44). DOI:10.1021/ja509379j · 12.11 Impact Factor
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    ABSTRACT: The first total synthesis of parthenolide (1) is described. The key feature of this synthesis is the formation of a 10-membered carbocylic ring by a macrocyclic stereocontrolled Barbier reaction, followed by a photo-induced Z/E isomerization. The biological evaluation of a small library of parthenolide analogs (19, 33 and 34) disclosed a preliminary structure-activity relationship (SAR). The results revealed that the C1, C10 double bond configuration of parthenolide has little or no effect on the activity; and the C6 and C7 configurations of the lactone ring have a moderate impact on the activities against some cancer cell lines.
    Journal of Medicinal Chemistry 08/2014; 57(16). DOI:10.1021/jm5009456 · 5.45 Impact Factor
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    ABSTRACT: Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal (GI) tract associated with an increased risk of colorectal cancer (CRC). Current treatments for both IBD and colitis-associated CRC suffer from numerous side effects. Parthenolide (PTL) is a sesquiterpene lactone with anti-inflammatory activity, and previous studies have demonstrated that PTL is a potent inhibitor of the NF-κB pathway. Micheliolide (MCL), substantially more stable than PTL in vivo, was recently developed, and this study aimed to decipher its suitability as therapeutic tool for IBD and IBD-associated diseases. Similar to PTL, MCL inhibited NF-κB activation and subsequent pro-inflammatory pathways activation in vitro. Pro-drug forms of both compounds inhibited the DSS-induced colitis when administrated intraperitoneally or encapsulated in a polysaccharide gel designed to release drugs in the colon. Interestingly, MCL was found to attenuate carcinogenesis in AOM/DSS-induced CRC, thus providing new candidate for the treatment of inflammatory bowel disease and CRC.Laboratory Investigation advance online publication, 28 July 2014; doi:10.1038/labinvest.2014.89.
    Gastroenterology 07/2014; 146(5). DOI:10.1038/labinvest.2014.89 · 16.72 Impact Factor
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    ABSTRACT: Background: Monocyte chemoattractant protein-1 (MCP-1) plays an important role in extracellular matrix accumulation through macrophage recruitment and activation in the development and progression of diabetic nephropathy. Therefore, this study examined whether advanced oxidation protein products (AOPPs) are involved in nuclear factor-κB (NF-κB) activation and MCP-1 mRNA and protein expression in mesangial cells (MCs) and evaluated the effects of derivatives of sesquiterpene lactones (SLs) on AOPP-induced renal damage. Methods: MCP-1 mRNA and protein expression in MCs were determined by quantitative real-time PCR and ELISA, respectively. The level of intracellular reactive oxygen species (ROS) was determined by flow cytometry. The protein expression of tubulin, P47, NF-κB p65, phospho-NF-κB p65, IκB, phospho-IκB, IKKβ and phospho-IKKβ was evaluated by Western blot. Results: AOPPs caused oxidative stress in MCs and activated the NF-κB pathway by inducing IκBα phosphorylation and degradation. Inhibition of ROS by SOD (ROS inhibitor) blocked the AOPP-mediated NF-κB pathway. Moreover, the inhibition of AOPP-induced overproduction of MCP-1 mRNA and protein was associated with inhibition of IκBα degradation by SLs. Conclusion: AOPPs induce MCP-1 expression by activating the ROS/NF-κB pathway and can be inhibited by SLs. These findings may provide a novel approach to treat inflammatory and immune renal diseases, including diabetic nephropathy. © 2014 S. Karger AG, Basel.
    Cellular Physiology and Biochemistry 12/2013; 32(6):1867-1877. DOI:10.1159/000356619 · 2.88 Impact Factor
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    ABSTRACT: Captopril is a New Delhi metallo-β-lactamase-1 (NDM-1) inhibitor with an IC50 value of 7.9μM. It is composed of two units: a 3-mercapto-2-methylpropanoyl fragment and a proline residue. In this study, we synthesized simple amide derivatives of 3-mercapto-2-methylpropanoic acid, and then tested them as NDM-1 inhibitors in order to identify the pharmacophore for NDM-1 inhibition. We found that the lead compound 22 had an IC50 value of 1.0μM. Further structure simplification provided compounds 31 and 32, which had IC50 values of 15 and 10μM, respectively. As compound 32 is a clinically used antidote for metal poisoning, it has great potential to be repurposed to treat bacterial infections.
    Bioorganic & medicinal chemistry letters 11/2013; 24(1). DOI:10.1016/j.bmcl.2013.10.068 · 2.42 Impact Factor
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    ABSTRACT: The procedure is investigated to synthesize rufinamide (III) or triazole analogues of imatinib.
    ChemInform 10/2013; 44(41). DOI:10.1002/chin.201341148
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    ABSTRACT: Diabetic nephropathy (DN) is one of the most common and serious chronic complications of diabetes mellitus, however, no efficient clinical drugs exist for the treatment of DN. We selected and synthesized several sesquiterpene lactones (SLs), and then used the MTT assay to detect rat mesangial cells (MCs) proliferation, ELISA to measure the expression level of monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta (TGF-β1) and fibronectin(FN), real-time fluorescent quantitative PCR analysis to measure the MCP-1 and TGF-β1 gene expression, western blot to detect the level of IκBα protein and EMSA to measure the activation of nuclear factor kappa B (NF-κB). We discovered that SLs, including parthenolide (PTL), micheliolide (MCL), arglabin, and isoalantolactone (IAL), as well as several synthetic analogs of these molecules, could effectively attenuate the high glucose-stimulated activation of NF-κB, the degradation of IκBα, and the expression of MCP-1, TGF-β1 and FN in rat mesangial cells (MCs). These findings suggest that SLs and their derivatives have potential as candidate drugs for the treatment of DN.
    Molecules 10/2013; 18(10):13061-77. DOI:10.3390/molecules181013061 · 2.42 Impact Factor
  • Jing Long · Ya-Hui Ding · Pan-Pan Wang · Quan Zhang · Yue Chen
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    ABSTRACT: Parthenolide showed extensive bioactivities including selective eradication of AML stem cells. Herein we report protection-free semisyntheses of parthenolide and its cyclopropyl analog (compound 10) from the abundant natural product costunolide with an overall yield of 55% and 60%, respectively. Compound 10 was more stable than parthenolide, and it maintained comparable activities against AML cell lines and AML stem cells. Therefore, compound 10 might be a superior small molecule than parthenolide as a tool for investigation of cancer stem cell biology.
    The Journal of Organic Chemistry 09/2013; 78(20). DOI:10.1021/jo401606q · 4.72 Impact Factor
  • Ya-Hui Ding · Hong-Xia Fan · Jing Long · Quan Zhang · Yue Chen
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    ABSTRACT: A series of guaianolide-type sesquiterpene lactones derivatives with arylation of α-methylene-γ-lactone moiety was synthesized using Heck reactions, and was evaluated for their activities against acute myelogenous leukemia (AML) cell line HL-60 and doxorubicin-resistant cell line HL-60/A. Although all compounds were significantly less active against HL-60 than the parent molecules, surprisingly, compounds 3a, 4c-4e, 5e, and 8d exhibited high potency against doxorubicin-resistant cell line HL-60/A (IC50=6.2-19μM), and their activities against HL-60/A were comparable to that of their parent molecules. In view of their novel activities against HL-60/A, compound 5e with inhibitory activity against HL-60/A (IC50=6.2±0.5μM) was selected for study its preliminary mechanism. The result reveals that compound 5e can obviously induce apoptosis.
    Bioorganic & medicinal chemistry letters 09/2013; 23(13). DOI:10.1016/j.bmcl.2013.09.028 · 2.42 Impact Factor
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    ABSTRACT: Epothilone D (Epo D) and its 9-Methyl conformational analogues were synthesized through a highly efficient combinatorial approach. The fragment E was synthesized in 11 total steps with 6 longest linear steps, and each aldehyde B was prepared via a 3-step sequence. Starting from the common precursor E and a suitable aldehydes B, each target molecule were obtained in only 4 steps. The 9-(S)-epo D and 9-(R)-epo D demonstrated significant difference in inhibition activities against cancer cell lines and in conformational analysis.
    European Journal of Medicinal Chemistry 08/2013; 68C:321-332. DOI:10.1016/j.ejmech.2013.08.003 · 3.45 Impact Factor
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    ABSTRACT: Triazole moiety is frequently employed in drug discovery and optimization. However, most syntheses of triazole drugs involve isolation of highly explosive azides. Herein we report safe and high efficient syntheses of triazole drugs in aqueous/organic solvent systems with Cu2O nanoparticle (Cu2O-NP) as the catalyst of azide–alkyne cycloaddition (CuAAC). Since Cu2O-NP can be efficiently dispensed in aqueous and some organic solvents, the azide solutions from the previous preparation could be used directly in the next CuAAC stage without isolation. Therefore, this synthetic strategy is safe, convenient, and high yielding for the syntheses of triazole drugs.
    Tetrahedron Letters 06/2013; 54(26):3406–3409. DOI:10.1016/j.tetlet.2013.04.067 · 2.38 Impact Factor
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    ABSTRACT: A tubulysin V analogue with triazole/Me modified Tuv fragment was synthesized in 14 linear steps. The triazoltubulysin analogue maintains significant biological activities against several cancer cell lines, and then provides a new insight into the biological conformation of tubulysins.
    Tetrahedron Letters 06/2013; 54(23):2986–2988. DOI:10.1016/j.tetlet.2013.03.127 · 2.38 Impact Factor
  • Quan Zhang · Yuhuan Jing · David C. Myles · Yong Li · Yue Chen
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    ABSTRACT: Allylalumination of alkynes (i.e. forming Negishi's (Z)-alkenyl dialkylalane) followed by alkenylation of epoxides provides 1,4-disubstituted (Z)-3,6-alkadienols. The alkenylation can be facilitated by the presence of a neighbouring coordinating group in the epoxides. This "one-pot" approach has been successfully applied in the large-scale production of C10-C15 fragment of 9,10-didehydroepothilone D (a synthetic epothilone analog as an anti-cancer agent in phase 2 clinical trials). Copyright © 2013 SIOC, CAS, Shanghai & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Chinese Journal of Chemistry 06/2013; 31(6). DOI:10.1002/cjoc.201300235 · 1.58 Impact Factor
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    ABSTRACT: The Tup fragments of tubulysins were synthesized with a tandem reaction as the key step, and unexpected diastereoselectivity was observed in the first Grignard addition stage. The coupling of the enolate of a thiazolyl ketone with chiral sulfinimines furnished the backbone of the Tuv fragment with over 100:1 d.r. and high yield. Thus, tubulysin U and C-4 epi-tubulysin U were prepared in a highly selective and efficient manner. The results of the MTT assay furthermore indicated that C-4 epi-tubulysin U maintained significant growth inhibition activities against several cancer cell lines.
    Chemistry - An Asian Journal 06/2013; 8(6). DOI:10.1002/asia.201300051 · 4.59 Impact Factor
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    ABSTRACT: Micheliolide (MCL) derivatives with etherification or esterification of the hydroxyl group at the C4 position were synthesized and evaluated for their activities against different acute myelogenous leukemia (AML) cell lines. These derivatives demonstrated comparable activities against AML cell lines HL-60 and doxorubicin resistant cell line HL-60/A. As to multi-drug resistant AML progenitor cells KG-1a, MCL and some of its derivatives maintained significant activities, and only 1.1-2.7 fold activity reductions were observed when compared with the activities against HL-60, while doxorubicin showed 20-fold activity reduction. Our study demonstrated that the C4 hydroxyl group of MCL might not only be a suitable position for structural modifications, but also be a starting point for the design of appropriate molecular probes to explore the specific targets in the progenitor cell line KG-1a.
    Molecules 05/2013; 18(5):5980-5992. DOI:10.3390/molecules18055980 · 2.42 Impact Factor
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    ABSTRACT: Small molecules that can selectively target cancer stem cells (CSCs) remain rare currently and exhibit no common structural features. Here we report a series of guaianolide sesquiterpene lactones (GSLs) and their derivatives that can selectively eradicate acute myelogenous leukemia (AML) stem or progenitor cells. Natural GSL compounds arglabin, an anticancer clinical drug, and micheliolide (MCL), are able to reduce the proportion of AML stem cells (CD34(+)CD38(-)) in primary AML cells. Targeting of AML stem cells is further confirmed by a sharp reduction of colony-forming units of primary AML cells upon MCL treatment. Moreover, DMAMCL, the dimethylamino Michael adduct of MCL, slowly releases MCL in plasma and in vivo and demonstrates remarkable therapeutic efficacy in the nonobese diabetic/severe combined immunodeficiency AML models. These findings indicate that GSL is an ample source for chemical agents against AML stem or progenitor cells and that GSL is potentially highly useful to explore anti-CSC approaches.
    Journal of Medicinal Chemistry 09/2012; 55(20):8757-69. DOI:10.1021/jm301064b · 5.45 Impact Factor
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    ABSTRACT: The semisynthesis of arglabin, an anticancer drug in clinical application, is developed from abundant natural product parthenolide via three steps. Each step in this sequence is highly stereoselective, and the substrate-dependent stereoselectivity in the epoxidation step can be explained by computational calculations. The success of chemical semisynthesis of arglabin suggests that the biosynthesis of arglabin might proceed in a similar pathway.
    The Journal of Organic Chemistry 07/2012; 77(16):7103-7. DOI:10.1021/jo300888s · 4.72 Impact Factor

Publication Stats

71 Citations
100.52 Total Impact Points


  • 2012–2015
    • Nankai University
      • • State Key Laboratory of Elemento-Organic Chemistry
      • • State Key Laboratory of Medicinal Chemical Biology
      T’ien-ching-shih, Tianjin Shi, China