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European journal of medicinal chemistry 163건

  1. [해외논문]   Synthesis of new 1-benzyl tetrahydropyridinylidene ammonium salts and their antimicrobial and anticellular activities   SCI SCIE

    Mohsin, Noor-ul-Amin (Faculty of Pharmaceutical Sciences, Government College University, Allama Iqbal Road, 38000 Faisalabad, Pakistan ) , Seebacher, Werner (Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, 8010 Graz, Austria ) , Faist, Johanna (Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, 8010 Graz, Austria ) , Hochegger, Patrick (Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, 8010 Graz, Austria ) , Kaiser, Marcel (Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland ) , Mä (Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland ) , ser, Pascal (Institute of Chemistry, University of Graz, Universitätsplatz 1, 8010 Graz, Austria ) , Belaj, Ferdinand (Institute for Chemistry and Technology of Organic Materials (ICTM), Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria ) , Saf, Robert (Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Universitätsplatz 4, 8010 Graz, A) , Kretschmer, Nadine , Alajlani, Muaaz , Turek, Ivana , Brantner, Adelheid , Bauer, Rudolf , Bucar, Franz , Weis, Robert
    European journal of medicinal chemistry v.143 ,pp. 97 - 106 , 2018 , 0223-5234 ,

    초록

    Abstract A series of N-benzyl tetrahydropiperidinylidene pyrrolidinium salts have been synthesized and investigated for their antiplasmodial and antitrypanosomal activities as well as for their cytotoxic effects. The antibacterial, antimycobacterial and anticancer potencies of selected compounds were examined, too. Physicochemical parameters were calculated and structure-activity-relationships are discussed. Highlights New N-benzyl tetrahydropyridinylidene salts were prepared and characterized. Their antiprotozoal, antibacterial and anticancer activities were investigated. Physicochemical parameters and structure-activity relationships are described. Few compounds show antibacterial properties and even in vivo antimalarial activity. Graphical abstract [DISPLAY OMISSION]

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  2. [해외논문]   Synthesis and biological evaluation of a novel β-D-2′-deoxy-2′-α-fluoro-2′-β-C-(fluoromethyl)uridine phosphoramidate prodrug for the treatment of hepatitis C virus infection   SCI SCIE

    Li, Ertong (College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China ) , Wang, Yafeng (School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China ) , Yu, Wenquan (College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China ) , Lv, Zhigang (College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China ) , Peng, Youmei (Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China ) , Liu, Bingjie (School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China ) , Li, Shiliang (Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China ) , Ho, Wenzhe (Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA ) , Wang, Qingduan (Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China ) , Li, Honglin (Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China Univers) , Chang, Junbiao
    European journal of medicinal chemistry v.143 ,pp. 107 - 113 , 2018 , 0223-5234 ,

    초록

    Abstract A novel β-D-2′-deoxy-2′-α-fluoro-2′-β- C -(fluoromethyl)uridine phosphoramidate prodrug ( 1 ) has been synthesized. This compound exhibits submicromolar-level antiviral activity in vitro against HCV genotypes 1b, 1a, 2a, and S282T replicons (EC 50 = 0.18–1.13 μM) with low cytotoxicity (CC 50 > 1000 μM). Administered orally, prodrug 1 is well tolerated at doses of up to 4 g/kg in mice, and produces a high level of the corresponding triphosphate in rat liver. Highlights A novel 2′-α-fluoro-2′-β- C -(fluoromethyl)uridine phosphoramidate was synthesized. This prodrug ( 1 ) exhibits submicromolar-level anti-HCV activity with low cytotoxicity. Compound 1 is well tolerated up to 4 g/kg in mice via oral administration. Prodrug 1 produces a high level of the corresponding triphosphate in rat liver. Graphical abstract A novel β-D-2'-deoxy-2'-α-fluoro-2'-β- C -(fluoromethyl)uridine phosphoramidate prodrug has been discovered with submicromolar-level anti-HCV activity and low toxicity profiles. [DISPLAY OMISSION]

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  3. [해외논문]   Design, syntheses and lipid accumulation inhibitory activities of novel resveratrol mimics   SCI SCIE

    Li, Chanjuan (Corresponding author. ) , Cheng, Bao (Corresponding author.) , Fang, Sai , Zhou, Huihao , Gu, Qiong , Xu, Jun
    European journal of medicinal chemistry v.143 ,pp. 114 - 122 , 2018 , 0223-5234 ,

    초록

    Abstract Hispidine was initially discovered from Ficus Hispida for cardiovascular protection. In this paper, hispidine derivatives, which contain a novel resveratrol-like scaffold, have been designed, synthesized, and assayed as agents against lipid accumulations in 3T3-L1 pre-adipocytes. Six hispidine derivatives have the activity of reducing TG in 3T3-L1 adipocytes in dosage-dependent manner. The most active compound can reduce the lipid accumulation up to 78.4% at 10 μM qPCR and Western blotting results demonstrate that the two most active compounds inhibit both lipodenesis and adipogenesis in 3T3-L1 cells through (1) increasing the phosphorylations of AMPK and ACC, promoting SIRT1 expression. These three proteins are key regulators for lipogenesis and energy metabolism. (2) Decreasing the expressions of PPARγ, sREBP-1c, and FABP4, which are pivotal regulators for adipogenesis. Overall, this work proves that hispidine derivatives diminish the lipid accumulation in 3T3-L1 cell line by downregulating lipogenic and adipogenic pathways. Highlights Hispidine derivatives were designed and synthesized against adipocyte lipid increase. Hispidine derivatives inhibit both lipogenesis and adipogenesis in 3T3-L1 cells. Hispidine derivatives increase AMPK and ACC phosphorylations and SIRT1 expression. Hispidine derivatives downregulate adipogenic factors: PPARγ, sREBP-1c, and FABP4. Graphical abstract [DISPLAY OMISSION]

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  4. [해외논문]   Discovery of novel 2,4-diarylaminopyrimidine analogues as ALK and ROS1 dual inhibitors to overcome crizotinib-resistant mutants including G1202R   SCI SCIE

    Wang, Yu (Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China ) , Chen, Shaowei (Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China ) , Hu, Gang (Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China ) , Wang, Jiao (Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China ) , Gou, Wenfeng (Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China ) , Zuo, Daiying (Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China ) , Gu, Yucheng (Syngenta, Jealott's Hill Interna) , Gong, Ping , Zhai, Xin
    European journal of medicinal chemistry v.143 ,pp. 123 - 136 , 2018 , 0223-5234 ,

    초록

    Abstract Aiming to explore novel anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) dual inhibitors to overcome crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine (DAAP) analogues bearing thiazole or 1,2,3-triazole moieties were designed and synthesized based upon the cocrystal structure of ceritinib with ALK WT (PDB 4MKC) as well as the binding model of ceritinib with ALK G1202R . The cellular and enzymatic assays validated 34c ( WY-135 ) as a promising ALK (IC 50 = 1.4 nM) and ROS1 (IC 50 = 1.1 nM) dual inhibitor superior to crizotinib and ceritinib. 34c showed significantly inhibitory activities on ALK-dependent cell lines KARPAS299 (IC 50 = 21 nM) and H2228 (IC 50 = 95 nM) as well as ROS1-positive cell line HCC78 (IC 50 = 40 nM). In particular, 34c was potent against a variety of frequently observed crizotinib-resistant mutants, particularly the L1196M mutant (IC 50 = 3.1 nM) identified as the “gatekeeper” mutation and the G1202R mutant (IC 50 = 8.7 nM) which conferred resistance to all clinical stage ALK inhibitors. Furthermore, 34c was capable of inducing cell apoptosis and strongly inhibiting cellular ALK and ROS1 activity. In addition, the binding models of 34c with ALK WT , ALK L1196M and ALK G1202R provided structural bases for SARs observations. Highlights Two series of DAAP analogues were designed, synthesized and evaluated for their biological activity. 34c was identified as a potent ALK and ROS1 dual inhibitor. 34c was potent against a variety of frequently observed crizotinib-resistant mutants. 34c was capable of inducing cell apoptosis and strongly inhibiting cellular ALK and ROS1 activity. Graphical abstract Two series of 2,4-diarylaminopyrimidine (DAAP) analogues bearing thiazole or 1,2,3-triazole moieties were designed, synthesized and evaluated for their biological activity. [DISPLAY OMISSION]

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  5. [해외논문]   Design, synthesis, and biological evaluation of new 1,2,3-triazolo-2′-deoxy-2′-fluoro- 4′-azido nucleoside derivatives as potent anti-HBV agents   SCI SCIE

    Liu, Yuan (College of Chemistry and Molecular Engineering, Zhengzhou University, Henan 450001, PR China ) , Peng, Youmei (Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, PR China ) , Lu, Jingjing (College of Chemistry and Molecular Engineering, Zhengzhou University, Henan 450001, PR China ) , Wang, Jingwen (College of Chemistry and Molecular Engineering, Zhengzhou University, Henan 450001, PR China ) , Ma, Haoran (College of Chemistry and Molecular Engineering, Zhengzhou University, Henan 450001, PR China ) , Song, Chuanjun (College of Chemistry and Molecular Engineering, Zhengzhou University, Henan 450001, PR China ) , Liu, Bingjie (College of Chemistry and Molecular Engineering, Zhengzhou University, Henan 450001, PR China ) , Qiao, Yan (School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, PR China ) , Yu, Wenquan (College of Chemistry and Molecular Engineering, Zhengzhou University, Henan 450001, PR China ) , Wu, Jie (College of Chemistry and Molecular Engineering, Zhengzhou University, Henan 450001, PR China ) , Chang, Junbiao (College of Chemistry and Molecular Engineering, Zh)
    European journal of medicinal chemistry v.143 ,pp. 137 - 149 , 2018 , 0223-5234 ,

    초록

    Abstract Novel drugs are urgently needed to combat hepatitis B virus (HBV) infection due to drug-resistant virus. In this paper, a series of novel 4-monosubstituted 2′-deoxy-2′-β-fluoro-4′-azido-β- D -arabinofuranosyl 1,2,3-triazole nucleoside analogues ( 1a-g) were designed, synthesized and screened for in vitro anti-HBV activity. At 5.0 μ M in the cellular model, all the synthetic compounds display activities comparable to that of the positive control, lamivudine at 20 μ M. Of the compounds tested, the amide-substituted analogue ( 1a ) shows the most promising anti-HBV activity and low cytotoxicity in the cell model. In particular, it retains excellent activity against lamivudine-resistant HBV mutants. In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (67.4% and 53.3%, respectively) were reduced markedly by the treatment with 1a . Analysis of the structure of HBV polymer/ 1a -triphosphate (1a-TP) complex shows that 1a-TP is stabilized by specific van der Waals interactions with the enzyme residues arising from 4-amino-1,2,3-triazole and the 4′-azido group. Highlights A series of 1,2,3-triazolo-2′-deoxy-2′-fluoro- 4′-azido nucleosides were prepared. 1a can inhibit the wild-type and lamivudine-resistant HBV DNA replication. 1a can inhibit the replication of DHBV DNA in serum and liver effectively. The interactions between 1a-TP and viral DNA polymerase are revealed. Graphical abstract A series of new 1,2,3-triazolo nucleosides have been designed and synthesized, with 1a being the most potent one against both wild-type and drug-resistant HBV strains. [DISPLAY OMISSION]

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  6. [해외논문]   Microwave-promoted facile access to 4-aminoquinoline-phthalimides: Synthesis and anti-plasmodial evaluation   SCI SCIE

    Rani, Anu (Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India ) , Singh, Amandeep (Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India ) , Gut, Jiri (Department of Medicine, University of California, San Francisco, CA, USA ) , Rosenthal, Philip J. (Department of Medicine, University of California, San Francisco, CA, USA ) , Kumar, Vipan (Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India)
    European journal of medicinal chemistry v.143 ,pp. 150 - 156 , 2018 , 0223-5234 ,

    초록

    Abstract Microwave promoted high yielding synthesis of 4-aminoquinoline-phthalimides was developed with an aim to evaluate their anti-plasmodial potential. The scaffolds with longer spacer length (n = 6, 8) between two pharmacophores and a halogen substituent on the phthalimide ring displayed good antiplasmodial activity. Compound 5w , with an optimum combination of hexyl chain as spacer along with a tetra-bromophthalimide ring proved to be most potent and non-cytotoxic among the series exhibiting an IC 50 value of 0.10 μM. Highlights Microwave-promoted high yielding synthesis of 4-aminoquinoline-phthalimides. Synthesized compounds were assayed for their antiplasmodial activities. The potent compounds exhibited selectivity index in the range of 126–291. Graphical abstract Microwave-promoted high yielding synthesis of 4-aminoquinoline-phthalimides along with their anti-plasmodial evaluation. [DISPLAY OMISSION]

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  7. [해외논문]   Amino acid and peptide prodrugs of diphenylpropanones positive allosteric modulators of α7 nicotinic receptors with analgesic activity   SCI SCIE

    Balsera, Beatriz (Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, 28006 Madrid, Spain ) , Mulet, José (Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, 03050 Sant Joan d'Alacant, Spain ) , (Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, 03050 Sant Joan d'Alacant, Spain ) , Sala, Salvador (Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, 03050 Sant Joan d'Alacant, Spain ) , Sala, Francisco (Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Avenida de la Universidad s/n, 03202 Elche(Alicante), Spain ) , de la Torre-Martí (Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Avenida de la Universidad s/n, 03202 Elche(Alicante), Spain ) , nez, Roberto (Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, 28006 Madrid, Spain ) , Gonzá (Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium ) , lez-Rodrí (Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Avenida de la Universidad s/n) , guez, Sara , Plata, Adriá , n , Naesens, Lieve , Ferná , ndez-Carvajal, Asia , Ferrer-Montiel, Antonio , Criado, Manuel , Pé , rez de Vega, Marí , a Jesú , s , Gonzá , lez-Muñ , iz, Rosario
    European journal of medicinal chemistry v.143 ,pp. 157 - 165 , 2018 , 0223-5234 ,

    초록

    Abstract α7 Nicotinic acetylcholine receptors (nAChRs) are ion channels implicated in a number of CNS pathological processes, including pain and psychiatric, cognitive and inflammatory diseases. Comparing with orthosteric agonism, positive allosteric modulation of these channels constitutes an interesting approach to achieve selectivity versus other nicotinic receptors. We have recently described new chalcones and 1,3-diphenylpropanones as positive allosteric modulators (PAMs) of α7 nAChRs, which proved to have good analgesic activities but poor pharmacokinetic properties. Here we report the preparation of amino acid and peptide derivatives as prodrugs of these modulators with the aim of improving their in vivo biological activity. While the valine derivative showed very short half life in aqueous solutions to be considered a prodrug, Val-Val and Val-Pro-Val are suitable precursors of the parent 1,3-diphenylpropanones, via chemical and enzymatic transformation, respectively. Compounds 19 (Val-Val) and 21 (Val-Pro-Val), prodrugs of the 2′,5′,4-trihydroxy-1,3-diphenylpropan-1-one 3 , showed significant antinociceptive activity in in vivo assays. The best compound, 21 , displayed a better profile in the analgesia test than its parent compound 3 , exhibiting about the same potency but long-lasting effects. Highlights Amino acid/peptide prodrugs of 1,3-diphenylpropanone α7 nAChRPAMs are described. Val-Val and Val-Pro-Val are suitable promoieties. Val-Pro-Val derivative exhibited long-lasting analgesic effect than the parent drug. Graphical abstract [DISPLAY OMISSION]

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  8. [해외논문]   Synthesis and biological evaluation of sulfur-containing shikonin oxime derivatives as potential antineoplastic agents   SCI SCIE

    Huang, Guang (School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China ) , Zhao, Hui-Ran (School of Pharmaceutical Sciences and Chemistry, Dali University, Dali 671000, China ) , Meng, Qing-Qing (School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China ) , Zhang, Qi-Jing (School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China ) , Dong, Jin-Yun (School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China ) , Zhu, Bao-quan (Shanghai Institute of Pharmaceutical Industry, Shanghai 201203, China ) , Li, Shao-Shun (School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China)
    European journal of medicinal chemistry v.143 ,pp. 166 - 181 , 2018 , 0223-5234 ,

    초록

    Abstract As a continuation of our research on developing potent and potentially safe antineoplastic agents, a set of forty five sulfur-containing shikonin oxime derivatives were synthesized and evaluated for their in vitro cytotoxic activity against human colon cancer (HCT-15), gastric carcinoma (MGC-803), liver (Bel7402), breast (MCF-7) cancer cells and human skin fibroblast (HSF) cells. All the synthesized compounds exhibited potent cytotoxic activity selectively towards HCT-15 cells and did not display apparent toxicity to the normal HSF cells, some of which were more or comparatively effective to the parent compound against HCT-15, MGC-803 and Bel7402 cells. The most active agent 9m displayed high potency against human cancer cells with IC 50 ranging from 0.27 ± 0.02 to 9.23 ± 0.12 μM. The structure-activity relationships (SARs) studies suggested that the nature of substituent group in the side chain is important for antitumor potency in vitro . Additionally, nitric oxide release studies revealed that the amount of nitric oxide generated from these oxime derivatives was relatively low. Furthermore, cellular mechanism investigations indicated that compound 9m could arrest cell cycle at G1 phase and induce a strong apoptotic response in HCT-15 cells. Moreover, western blot studies revealed that compound 9m induced apoptosis through the down-regulation of Bcl-2 and up-regulation of Bax, caspase 3 and 9. For all these reasons, compound 9m hold promising potential as antineoplastic agent. Highlights 45 sulfur-containing shikonin oxime derivatives were prepared. The structure-activity relationships were discussed. All synthesized compounds displayed excellent cellular selectivity. 9m exhibited the strongest inhibitory activity against HCT-15 cells with IC 50 values of 0.27 ± 0.02 μM. 9m could arrest cell cycle at G1 phase and induce a strong apoptotic response in HCT-15 cells. Graphical abstract [DISPLAY OMISSION]

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  9. [해외논문]   Design, synthesis, biological evaluation and molecular modeling of novel 2-amino-4-(1-phenylethoxy) pyridine derivatives as potential ROS1 inhibitors   SCI SCIE

    Tian, Yuanxin (Corresponding author. ) , Zhang, Tingting (Corresponding author.) , Long, Lifan , Li, Zhonghuang , Wan, Shanhe , Wang, Guangfa , Yu, Yonghuan , Hou, Ju , Wu, Xiaoyun , Zhang, Jiajie
    European journal of medicinal chemistry v.143 ,pp. 182 - 199 , 2018 , 0223-5234 ,

    초록

    Abstract With the aim of discovering potential and selective inhibitors targeting ROS1 kinase, we rationally designed, synthesized and evaluated two series of novel 2-amino-pyridine derivatives with 1-phenylethoxy at C-3 and C-4 position. The enzymic assays results indicated that six of the new compounds 13b - 13d and 14a - 14c showed remarkably higher inhibitory activities against ROS1 kinase. The most promising compounds, 13d and 14c displayed the most desired ROS1 inhibitory activity with IC 50 values of 440 nM and 370 nM respectively. Furthermore, 13d and 14c displayed ROS1 inhibitory selectivity of about 7-fold and 12-fold, relative to that of ALK sharing about 49% amino acid sequence homology in the kinase domains. They also showed good anti-proliferative effects against ROS1-addicted HCC78 cell lines with the IC 50 values of 8.1 μM and 65.3 μM, respectively. Moreover, molecular docking and molecular dynamics simulation studies disclosed that compound 14c and 13d shared similar binding poses with Crizotinib except the selective binding site of ROS1. It also gave a probable molecular explanation for their activity and selectivity, which the methoxyl group in benzene ring was the crucial to the selectivity to ROS1 versus ALK. Highlights Two novel series of 2-amino-pyridine derivatives with 1-phenylethoxy at C-3 and C-4 position were rationally designed and synthesized for ROS1 inhibitors. The compounds 14c and 13d exhibited potential inhibitory activities against ROS1 and HCC78 cell line. Molecular modeling disclosed that the binding mode and also gave a probable explanation for their activity and selectivity. The structures of compounds are novel and expand the chemical diversity of selective ROS1 inhibitors. Graphical abstract [DISPLAY OMISSION]

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  10. [해외논문]   Design, synthesis, and biological evaluation of 1,3-diarylisoquinolines as novel topoisomerase I catalytic inhibitors   SCI SCIE

    Khadka, Daulat Bikram (College of Pharmacy, Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea ) , Park, Seojeong (College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea ) , Jin, Yifeng (College of Pharmacy, Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea ) , Han, Jinhe (College of Pharmacy, Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea ) , Kwon, Youngjoo (College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea ) , Cho, Won-Jea (College of Pharmacy, Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea)
    European journal of medicinal chemistry v.143 ,pp. 200 - 215 , 2018 , 0223-5234 ,

    초록

    Abstract With a goal of identifying potent topoisomerase (topo) inhibitor, the C4-aromatic ring of the anticancer agent, 3,4-diarylisoquinolone, was strategically shifted to design 1,3-diarylisoquinoline. Twenty-two target compounds were synthesized in three simple and efficient steps. The 1,3-diarylisoquinolines exhibited potent anti-proliferative effects on cancer cells but few compounds spared non-cancerous cells. Inhibition of topo I/IIα-mediated DNA relaxation by several derivatives was greater than that by camptothecin (CPT)/etoposide even at low concentration (20 μM). In addition, these compounds had little or no effect on polymerization of tubulin. A series of biological evaluations performed with the most potent derivative 4cc revealed that the compound is a non-intercalative topo I catalytic inhibitor interacting with free topo I. Collectively, the potent cytotoxic effect on cancer cells including the drug resistance ones, absence of lethal effect on normal cells, and different mechanism of action than topo I poisons suggest that the 1,3-diarylisoquinolines might be a promising class of anticancer agents worthy of further pursuit. Highlights 1,3-Diarylisoquinoline was designed based on structure of 3,4-diarylisoquinoline. 1,3-Diarylisoquinolines were cytotoxic against cancer cells. Several derivatives inhibited topo I/IIα activity even at low concentration. 1,3-Diarylisoquinolines had weak or no antitubulin activity. 1,3-Diarylisoquinoline 4 cc is a non-intercalative topo I catalytic inhibitor. Graphical abstract [DISPLAY OMISSION]

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