Chia-Lin Lee

China Medical University Hospital, 臺中市, Taiwan, Taiwan

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Publications (22)72.61 Total impact

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    ABSTRACT: CalDAG-GEFI is a guanine nucleotide exchange factor, which actives small GTPase Rap1 and plays an important role in platelet aggregation. Our previous study has shown that CalDAG-GEFI contains redox-sensitive thiols, and its function can be inhibited by thiol modification. In the present study, the effect of CLL2-1, a 1,4-phenanthrenequinone, on CalDAG-GEFI and platelet functions was investigated. In human platelets, CLL2-1 prevented platelet aggregation caused by various stimulators. Flow cytometric analysis revealed that CLL2-1 inhibited GPIIb/IIIa activation and P-selectin secretion. Moreover, CLL2-1 prevented Rap1 activation caused by thrombin, the Ca(2+) ionophore A23187, and the diacylglycerol mimetic phorbol 12-myristate 13-acetate, while only slightly inhibited thrombin-induced increases in [Ca(2+)]i and did not inhibit protein kinase C activation. Western blots after reducing SDS-PAGE showed that treatment of either platelets or platelet lysates with CLL2-1 led to a decrease of monomeric CalDAG-GEFI and appearance of cross-linked oligomers of CalDAG-GEFI, and these effects were inhibited by pretreatment of platelets or lysates with thiol reducing agents prior to the addition of CLL2-1, indicating thiol modification of CalDAG-GEFI by CLL2-1. Furthermore, the thiol reducing agents also prevented the inhibitory effect of CLL2-1 on Rap1 activation, GPIIb/IIIa activation, and platelet aggregation. In CalDAG-GEFI-overexpressing human embryonic kidney 293T cells, CLL2-1 also inhibited CalDAG-GEFI-mediated Rap1 activation. Taken together, our results suggest that the antiplatelet effect of CLL2-1 is due to, at least in part, inhibition of CalDAG-GEFI-mediated Rap1 activation, and provide the basis for development of novel antiplatelet drugs. Copyright © 2014 Elsevier Inc. All rights reserved.
    Free Radical Biology and Medicine 10/2014; 78C:101-110. · 5.71 Impact Factor
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    ABSTRACT: Eight new spirostanol saponins, macaosides A-H (1-8), and 10 new furostanol saponins, macaosides I-R (9-18), together with six known spirostanol compounds (19-24) were isolated from Solanum macaonense. The structures of the new compounds were determined from their spectroscopic data, and the compounds were tested for in vitro antineutrophilic inflammatory activity. It was found that both immediate inflammation responses including superoxide anion generation and elastase release were significantly inhibited by treatment with compounds 20, 21, and 24 (superoxide anion generation: IC50 7.0, 7.6, 4.0 μM; elastase release: IC50 3.7, 4.4, 1.0 μM, respectively). However, compounds 1 and 4 exhibited effects on the inhibition of elastase release only, with IC50 values of 3.2 and 4.2 μM, respectively, while 19 was active against superoxide anion generation only, with an IC50 value of 6.1 μM. Accordingly, spirostanols may be promising lead compounds for further neutrophilic inflammatory disease studies.
    Journal of Natural Products 07/2014; · 3.95 Impact Factor
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    ABSTRACT: Three phenanthrenes (1-3), four indole alkaloids (4-7) and one steroid (8) were isolated from the leaves of Calanthe arisanensis for the first time. In the antiplatelet aggregation assay, phenanthrenes 1 and 2 showed potential antiplatelet activity. We have reported and discussed here the antiplatelet aggregation properties of the eleven naturally-occurring phenanthrenes (1-2 and 9-17) isolated from the underground part of the plant and eighteen chemically synthesized phenanthrenes (18-35). Overall, our data demonstrated that 1,4-phenanthrenequinones 20, 21 and 22 (collagen, IC50 0.2, 0.2, 0.1 microg/mL; thrombin, IC50 0.8, 1.0, 1.1 microg/mL, respectively) could be promising lead candidates for further cardiovascular disease studies.
    Natural product communications 01/2014; 9(1):83-4. · 0.92 Impact Factor
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    ABSTRACT: Torvpregnanosides A and B, two pregnane glycosides, and torvoside Q, a 23-keto-spirostanol glycoside, along with twelve known steroidal saponins were isolated from aerial parts of Solanum torvum. Of the latter, four of the 23-hydroxy-spirostanol glycosides, and, a yamogenin glycoside, were in this plant discovered. All structures were identified from spectroscopic data, and all the compounds were tested for in vitro anti-neutrophilic inflammatory activity. Two compounds showed selective inhibition against elastase release and superoxide anion generation, respectively, by human neutrophils with IC50 values of 5.66 and 3.59μM, while two others inhibited both inflammatory mediators with IC50 values of 0.66-3.49μM. Structure-activity relationships are discussed.
    Phytochemistry 07/2013; · 3.35 Impact Factor
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    ABSTRACT: Through bioassay-guided fractionation, thirteen compounds (1-13) were isolated from the dry root of Semiaquilegia adoxoides, known as Tiankuizi in traditional Chinese medicine (TCM). Among these, four benzoic acid derivatives (1, 2, 4, 5), one 4,6-dimethoxy-5-methyl-2H-pyran-2-one (10) and one 1,2,3-propanetriol (13) were found for the first time in S. adoxoides. This is the first record of compound 10 from a natural source. 4-Hydroxybenzoic acid (1) and 3,4-dihyroxybenzoic acid (2) showed selective inhibition against elastase release and superoxide anion generation, with IC50 values of 3.20 and 6.21 microg/mL, respectively. Compound 1 had 7-fold better activity than the positive control against elastase release induced by human neutrophils. Overall, our studies demonstrated Tiankuizi (S. adoxoides) as a potential TCM and isolates 1 and 2 as promising lead compounds for neutrophilic inflammatory diseases.
    Natural product communications 12/2012; 7(12):1623-6. · 0.92 Impact Factor
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    ABSTRACT: In a structure-activity relationship (SAR) study, 3-methoxy-1,4-phenanthrenequinones, calanquinone A (6a), denbinobin (6b), 5-OAc-calanquinone A (7a) and 5-OAc-denbinobin (7b), have significantly promising cytotoxicity against various human cancer cell lines (IC(50) 0.08-1.66 µg/mL). Moreover, we also established a superior pharmacophore model for cytotoxicity (r = 0.931) containing three hydrogen bond acceptors (HBA1, HBA2 and HBA3) and one hydrophobic feature (HYD) against MCF-7 breast cancer cell line. The pharmacophore model indicates that HBA3 is an essential feature for the oxygen atom of 5-OH in 6a-b and for the carbonyl group of 5-OCOCH(3) in 7a-b, important for their cytotoxic properties. The SAR for moderately active 5a-b (5-OCH(3)), and highly active 6a-b and 7a-b, are also elaborated in a spatial aspect model. Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model. Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a-b as topoisomerase II inhibitors.
    PLoS ONE 05/2012; 7(5):e37897. · 3.53 Impact Factor
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    ABSTRACT: In a search for natural phytoestrogens, 130 traditional Chinese medicinal extracts related to gynecological disorders were investigated by the Arabidopsis pER8:GUS reporter assay system. The EtOH extract of Cuscuta chinensis showed estrogenic activity (100 μg/mL) and affored three new lignans, cuscutaresinols A-C (1-3), and 16 known compounds. Cuscutaresinols A-C (1-3), (+)-sesamin (4), (+)-xanthoxylol (5), 9-hydroxysesamin (6), (+)-pinoresinol (7), kaempferol (8), and isorhamnetin (9) showed estrogenic activity, with 8 and 9 exhibiting the most potent activity. Kaempferol (8) and isorhamnetin (9) are the major components of C. chinenesis EtOH extract and the key contributors to its estrogenic activity in the Arabidopsis pER8:GUS reporter assay system.
    Journal of Natural Products 05/2012; 75(7):1424. · 3.95 Impact Factor
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    ABSTRACT: Five new steroidal glycosides (1-5) and nine known compounds were isolated from Solanum violaceum. Indiosides G (1) and H (2) are spirostene saponins with an iso-type F ring, indioside I (3) is a spirostane saponin, and indiosides J (4) and K (5) are unusual furostanol saponins with a deformed F ring. These structures represent rare naturally occurring steroidal skeletons. The structures of the new compounds were elucidated using 1D and 2D spectroscopic techniques and acid hydrolysis. Compounds 2, 3, and 7-9 exhibited cytotoxic activity against six human cancer cell lines (HepG2, Hep3B, A549, Ca9-22, MDA-MB-231, and MCF-7) with IC(50) values of 1.83-8.04 μg/mL. Steroidal saponins 3, 8, and 9 showed inhibitory effects on superoxide anion generation with IC(50) values of 2.84 ± 0.18, 0.62 ± 0.03, and 1.62 ± 0.59 μg/mL, respectively. Saponins 8 and 9 also inhibited elastase release with IC(50) values of 111.05 ± 7.37 and 4.04 ± 0.51 μg/mL, respectively. Structure-activity relationship correlations of these compounds with respect to cytotoxic and anti-inflammatory effects are discussed.
    Journal of Natural Products 03/2012; 75(4):636-43. · 3.95 Impact Factor
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    ABSTRACT: Protoapigenone, a natural flavonoid possessing an unusual p-quinol moiety on its B-ring, is a novel prospective anticancer agent with low toxicity that is currently in development. The first economical, one-step synthesis of protoapigenone from apigenin is described on up to gram scale. 13 new 1'-O-alkylflavone analogs were also synthesized, either from apigenin or β-naphthoflavone. The in vitro cytotoxic activity of each compound was tested on six human cancer cell lines (HepG2, Hep3B, Ca9-22, A549, MCF-7 and MDA-MB-231). In the case of 1'-O-alkyl-protoapigenone derivatives, structure-activity relationships were found depending on the side-chain, and protoapigenone 1'-O-butyl ether was found to exert significantly stronger activity against three of the cell lines (Hep3B, MCF-7 and MDA-MB-231) than its non-substituted analog, protoapigenone itself. In contrast to this, all β-naphthoflavone derivatives bearing the same pharmacophore on their B-ring showed decreased cytotoxic activities when substituted with an O-alkyl side-chain at position 1', comparing to that of the non-substituted compound.
    PLoS ONE 08/2011; 6(8):e23922. · 3.53 Impact Factor
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    ABSTRACT: Recycling agricultural resources has become an important issue worldwide promoting the economical value of agricultural production processes. Desugared sugar cane extract (DSE) from Saccharum officinarum is a byproduct obtained during sugar production. Two new neolignan glucosides, saccharnan A (1) and saccharnan B (2), together with 10 known phenolics (3-12) were isolated from DSE, and their structures were elucidated on the basis of NMR spectral analysis. Compounds 3, 4, 8, and 9 showed good activity against DPPH radical (IC(50) ≤ 51.20 μM) and compounds 3-8 and 12 exhibited strong ABTS(+) free radical scavenging activity (IC(50) ≤ 51.57 μM) compared to those of the positive controls, ascorbic acid and Trolox. Moreover, compounds 7 and 12 acted as potent tyrosinase inhibitors (IC(50) ≤ 42.59 μM) compared to the positive control arbutin. Our results highlighted the economical value of recycling DSE for the future development of natural antioxidants and/or tyrosinase inhibitors.
    Journal of Agricultural and Food Chemistry 08/2011; 59(17):9219-25. · 3.11 Impact Factor
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    ABSTRACT: Five new benzofurans, pterolinuses A-E (1-5), six new neoflavonoids, pterolinuses F-J (8-13), and five known compounds (6, 7, 14-16) were isolated from an extract of Pterocarpus santalinus heartwood. All new structures were elucidated by spectroscopic methods, and configurations were confirmed by CD spectral data and optical rotation values. The isolates were evaluated for anti-inflammatory and cytotoxic activities. Six compounds (1, 2, 4, 6, 7, and 15) showed significant inhibition in at least one anti-inflammatory assay. Compound 2 showed the best selective effect against superoxide anion generation in human neutrophils with, an IC50 value of 0.19 μg/mL, and was 6.2-fold more potent than the positive control LY294002. Compound 14 showed the highest cytotoxicity against Ca9-22 cancer cells, with an IC50 value of 0.46 μg/mL.
    Journal of Natural Products 05/2011; 74(5):989-96. · 3.95 Impact Factor
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    ABSTRACT: Defects in apoptotic pathways confer resistance to tubulin-binding agents via downregulation of caspases or overexpression of antiapoptotic factors, urging the need for novel agents acting on an alternative pathway. The purpose of this study was to investigate whether induction of ROS can induce caspase-independent cell death in breast cancer cells and thereby enhance the activity of paclitaxel. Here, we report that gelomulide K acts as a caspase-independent cell death-inducing agent that synergizes with paclitaxel in breast cancer cells and has low toxicity in normal cells. Treatment with gelomulide K induced PARP-1 hyperactivation, AIF nuclear translocation, and cytoprotective autophagy. These effects were associated with increased ROS production and a decrease in cellular GSH levels in cancer cells. Furthermore, pretreatment with NAC, a precursor of intracellular GSH, effectively abrogated gelomulide K-induced caspase-independent cell death and autophagy, suggesting that ROS-mediated downstream signaling is essential to the anticancer effects of gelomulide K. Additionally, in a xenograft model, gelomulide K induced PARP-1 activation and reduced tumor growth. In terms of structure-activity relationships, analysis not only showed a correlation between ROS levels and drug activity but also highlighted the importance of the 8,14-epoxy group. Taken together, our results show that enhancement of paclitaxel activity can be achieved with gelomulide K and that the structurally relevant pharmacophore provides important insight into the development of new caspase-independent cell death-inducing agents.
    Free Radical Biology and Medicine 05/2011; 51(3):641-57. · 5.27 Impact Factor
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    ABSTRACT: A novel alkaloid, aristopyridinone A (1) and a new phenanthrene, aristolamide II (2), were isolated from Aristolochia manshuriensis (Guanmutong) together with eight known phenanthrenes (3-10). All structures were elucidated by spectroscopic methods. Compound 2 showed a selective inhibitory effect on elastase release by human neutrophils in response to fMLP with an IC(50) value of 4.11 μg/mL. Compound 7 exhibited significant inhibitory effects on superoxide anion generation and elastase release with IC(50) values of 0.12 and 0.20 μg/mL, respectively.
    Bioorganic & medicinal chemistry letters 03/2011; 21(6):1792-4. · 2.65 Impact Factor
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    ABSTRACT: Two novel derivatized peptides, designated as ixorapeptide I (1) and ixorapeptide II (2), in addition to 28 other known compounds, were isolated from the MeOH extract of Ixora coccinea using bioassay-guided fractionation. The structures of metabolites 1 and 2 were determined by interpretation of the spectroscopic data and Marfey's method. Compound 1 exhibited selective potency against Hep3B liver cancer cell line with an IC(50) value of 3.36 μg/mL, and compound 2 did not show notable cytotoxicity toward cancer cell lines but could inhibit superoxide anion generation and elastase release with IC(50) values of 0.21 and 0.27 μg/mL, respectively. Moreover, kaempferol and luteolin from this plant showed inhibition with IC(50) values of 3.55 and 2.56 μg/mL, respectively on platelet aggregation induced by collagen.
    Bioorganic & medicinal chemistry letters 12/2010; 20(24):7354-7. · 2.65 Impact Factor
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    ABSTRACT: Naturally occurring antrocamphin A (1) is a potent anti-inflammatory compound from the edible fungus Antrodia camphorata (Taiwanofungus camphoratus), whose wild fruiting body is used as a valuable folk medicine in Taiwan. This study is the first total synthesis of antrocamphin A (1) and its analogs. Their inhibition ability on NO release, superoxide anion generation, elastase release and platelet aggregation are reported herein.
    Organic & Biomolecular Chemistry 11/2010; 9(1):70-3. · 3.49 Impact Factor
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    ABSTRACT: Two new sesquiterpene coumarins, designated 5'-acetoxy-8'-hydroxyumbelliprenin (1) and 10'R-acetoxy-11'-hydroxyumbelliprenin (2), and a new diterpene, 15-hydroxy-6-en-dehydroabietic acid (3), along with 27 known compounds, were isolated from a CHCl(3)-soluble extract of Ferula assa-foetida through bioassay-guided fractionation. The structures of the new metabolites 1-3 were identified by spectroscopic data interpretation and by the Mosher ester method. Compounds 4 and 6-13 showed greater potency against influenza A virus (H(1)N(1)) (IC(50) 0.26-0.86 microg/mL) than amantadine (IC(50) 0.92 microg/mL), and 11 exhibited the best potency (IC(50) 0.51, 2.6, and 3.4 microg/mL) of these compounds against the HepG2, Hep3B, and MCF-7 cancer cell lines, respectively.
    Journal of Natural Products 09/2009; 72(9):1568-72. · 3.95 Impact Factor
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    Phytochemistry 07/2009; 70(11):1478-1478. · 3.35 Impact Factor
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    ABSTRACT: Two new phenanthrenequinones, calanquinones B and C (2 and 3) and four new 9,10-dihydrophenanthrenes, calanhydroquinones A-C (4-6) and calanphenanthrene A (7), along with five known compounds (1 and 8-11), were isolated from an EtOAc-soluble extract of Calanthe arisanensis through bioassay-guided fractionation. Their structures were identified from spectroscopic data, and the compounds were tested for in vitro cytotoxic activity against human lung (A549), prostate (PC-3 and DU145), colon (HCT-8), breast (MCF-7), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KBVIN) cancer cell lines. Compound 1 showed the highest potency (EC(50) < 0.5 microg/mL) against all seven cancer cell lines, with the greatest activity against breast cancer MCF-7 cells (EC(50) < 0.02 microg/mL). Generally, except for 7, compounds 2-11 also showed significant cytotoxic activity (EC(50) < 4 microg/mL) against some cell lines (especially PC-3 and MCF-7) in the panel.
    Journal of Natural Products 02/2009; 72(2):210-3. · 3.95 Impact Factor
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    ABSTRACT: The dried seeds of XANTHIUM STRUMARIUM (Asteraceae) are used after thorough stir-frying as an ingredient in traditional Chinese medicines for relieving allergy. Two new compounds, xanthialdehyde ( 2) and (-)-xanthienopyran ( 7), as well as 26 known compounds were isolated in the present study. The structures of the isolates were elucidated by spectroscopic methods. Among them, compound 7 exhibited significant selective inhibition of superoxide anion generation by human neutrophils induced by formyl- L-methionyl- L-leucyl- L-phenylalanine, with an IC50 value of 1.72 microg/mL.
    Planta Medica 08/2008; 74(10):1276-9. · 2.34 Impact Factor
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    ABSTRACT: Calanquinone A (1) was isolated from an EtOAc-soluble extract of Calanthe arisanensis through bioassay-guided fractionation. Its structure was identified by spectroscopic methods. Compound 1 showed potent cytotoxicity (EC(50)<0.5microg/mL) against lung (A549), prostate (PC-3 and DU145), colon (HCT-8), breast (MCF7), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KB-VIN) cancer cell lines, and interestingly, showed an improved drug resistance profile compared to paclitaxel. The total synthesis of 1 was also achieved and is reported herein.
    Bioorganic & medicinal chemistry letters 08/2008; 18(15):4275-7. · 2.65 Impact Factor

Publication Stats

144 Citations
72.61 Total Impact Points

Institutions

  • 2011–2014
    • China Medical University Hospital
      臺中市, Taiwan, Taiwan
    • University of Szeged
      Algyő, Csongrád, Hungary
  • 2008–2011
    • Kaohsiung Medical University
      • College of Pharmacy
      Kaohsiung, Kaohsiung, Taiwan
  • 2008–2009
    • University of North Carolina at Chapel Hill
      • Division of Chemical Biology and Medicinal Chemistry
      Chapel Hill, NC, United States