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European journal of medicinal chemistry 163건

  1. [해외논문]   Synthesis and biological characterization of ubenimex-fluorouracil conjugates for anti-cancer therapy   SCI SCIE

    Jiang, Yuqi (Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China ) , Li, Xiaoyang (Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China ) , Hou, Jinning (Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China ) , Huang, Yongxue (Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong, 261061, PR China ) , Wang, Xuejian (College of Pharmacy, Weifang Medical University, 261053 Wei'fang, Shandong, PR China ) , Jia, Yuping (Shandong Academy of Pharmaceutical Sciences, Ji'nan, Shandong, 250101, PR China ) , Wang, Qingwei (Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shanxi, 710038, PR China ) , Xu, Wenfang (Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China ) , Zhang, Jian (College of Pharmacy, Weifang Medical University, 261053 Wei'fang, Shandong, PR China ) , Zhang, Yingjie (Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'n)
    European journal of medicinal chemistry v.143 ,pp. 334 - 347 , 2018 , 0223-5234 ,

    초록

    Abstract Previously a novel ubenimex-fluorouracil (5-FU) conjugate, BC-01 was identified and validated as a potent CD13 inhibitor with marked in vitro and in vivo antitumor potency. Herein, further structural modifications of the linker part of BC-01 was carried out to get more potent and stable ubenimex–fluorouracil conjugates. It was striking that most of these conjugates showed even more potent CD13 inhibitory activities than BC-01 and the approved CD13 inhibitor ubenimex. One representative compound 12a displayed significant in vitro anti-proliferation, pro-apoptosis, anti-metastasis, anti-angiogenesis and CD13 + cell elimination effects. In vitro stability and in vivo pharmacokinetic study revealed that compound 12a could release ubenimex and 5-FU slowly, which could act as a mutual prodrug of ubenimex and 5-FU. Compared with 5-FU or 5-FU plus ubenimex, 12a exhibited superior in vivo antitumor growth efficiency, even in our mice model of 5-FU-resistant liver cancer. Moreover, 12a exhibited more potent in vivo anti-metastasis and lifespan extension effects compared to the approved 5-FU prodrug capecitabine. Collectively, these results suggest that further optimization and evaluation of 12a as a promising anticancer candidate are warranted to develop effective therapeutic agents for human liver cancer. Highlights A novel series of BC-01 derivates 12a - 12e was synthesized. Most of these conjugates showed even more potent CD13 inhibitory activities than BC-01. In vivo pharmacokinetic study revealed that compound 12a could release ubenimex and 5-FU slowly in two steps. 12a exhibited more potent in vivo anti-metastasis and lifespan extension effects compared to capecitabine. Graphical abstract [DISPLAY OMISSION]

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  2. [해외논문]   Urokinase receptor derived peptides as potent inhibitors of the formyl peptide receptor type 1-triggered cell migration   SCI SCIE

    Yousif, Ali Munaim (Department of Pharmacy, University of Naples 'Federico II', Naples 80131, Italy ) , Ingangi, Vincenzo (Department of Experimental Oncology IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale” I-80131 Naples, Italy ) , Merlino, Francesco (Department of Pharmacy, University of Naples 'Federico II', Naples 80131, Italy ) , Brancaccio, Diego (Department of Pharmacy, University of Naples 'Federico II', Naples 80131, Italy ) , Minopoli, Michele (Department of Experimental Oncology IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale” I-80131 Naples, Italy ) , Bellavita, Rosa (Department of Pharmacy, University of Naples 'Federico II', Naples 80131, Italy ) , Novellino, Ettore (Department of Pharmacy, University of Naples 'Federico II', Naples 80131, Italy ) , Carriero, Maria Vincenza (Department of Experimental Oncology IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale” I-80131 Naples, Italy ) , Carotenuto, Alfonso (Department of Pharmacy, University of Naples 'Federico II', Naples 80131, Italy ) , Grieco, Paolo (Department of Pharmacy, University of Naples 'Federico II', Naples 80131, Italy)
    European journal of medicinal chemistry v.143 ,pp. 348 - 360 , 2018 , 0223-5234 ,

    초록

    Abstract The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration. We and others have previously documented that the uPAR(84–95) sequence, interacts with the formyl peptide receptors (FPR)s, henceforth inducing cell migration of several cell lines, including leukocytes, and the synthetic shorter peptide (Ser 88 -Arg-Ser-Arg-Tyr 92 , SRSRY) retains chemotactic activity in vitro and in vivo . Recently, we have developed the head-to-tail cyclic analog [SRSRY], a new potent and stable inhibitor of monocyte trafficking. This prompted us to develop novel cyclic and linear analogs of [SRSRY] with the aim to broaden the knowledge about structure-activity relationships of peptide [SRSRY]. Herein we report their synthesis, effects on cell migration, conformational and docking analyses which served to envisage a new pharmacophore model for inhibitors of FPR1-triggered cell migration. Highlights Novel peptide analogs of urokinase receptor-derived SRSRY peptide. SAR study supported by the effect of the new generated pentapeptides on FPR1 internalization. Inhibitors of Formyl Peptide Receptor type 1-mediated cell Migration. Conformational studies: CD and NMR spectroscopy analyses. Docking and MD simulations studies. Graphical abstract [DISPLAY OMISSION]

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  3. [해외논문]   Discovery of caffeic acid phenethyl ester derivatives as novel myeloid differentiation protein 2 inhibitors for treatment of acute lung injury   SCI SCIE

    Chen, Lingfeng (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China ) , Jin, Yiyi (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China ) , Chen, Hongjin (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China ) , Sun, Chuchu (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China ) , Fu, Weitao (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China ) , Zheng, Lulu (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China ) , Lu, Min (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China ) , Chen, Pengqin (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou) , Chen, Gaozhi , Zhang, Yali , Liu, Zhiguo , Wang, Yi , Song, Zengqiang , Liang, Guang
    European journal of medicinal chemistry v.143 ,pp. 361 - 375 , 2018 , 0223-5234 ,

    초록

    Abstract Myeloid differentiation protein 2 (MD2) is an essential molecule which recognizes lipopolysaccharide (LPS), leading to initiation of inflammation through the activation of Toll-like receptor 4 (TLR4) signaling. Caffeic acid phenethyl ester (CAPE) from propolis of honeybee hives could interfere interactions between LPS and the TLR4/MD2 complex, and thereby has promising anti-inflammatory properties. In this study, we designed and synthesized 48 CAPE derivatives and evaluated their anti-inflammatory activities in mouse primary peritoneal macrophages (MPMs) activated by LPS. The most active compound, 10s , was found to bind with MD2 with high affinity, which prevented formation of the LPS/MD2/TLR4 complex. The binding mode of 10s revealed that the major interactions with MD2 were established via two key hydrogen bonds and hydrophobic interactions. Furthermore, 10s showed remarkable protective effects against LPS-caused ALI (acute lung injury) in vivo . Taken together, this work provides new lead structures and candidates as MD2 inhibitors for the development of anti-inflammatory drugs. Highlights 48 caffeic acid phenethyl ester derivatives were synthesized and evaluated. Active compounds was found to bind with myeloid differentiation protein 2 with high affinity. 10s exhibited remarkable protective effects against LPS-caused acute lung injury in vivo . Graphical abstract [DISPLAY OMISSION]

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  4. [해외논문]   Synthesis, biological evaluation and structure-activity relationship studies of hederacolchiside E and its derivatives as potential anti-Alzheimer agents   SCI SCIE

    Li, Hui-ning (Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China ) , Liu, Yang (Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China ) , Zhang, Zuo-peng (Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China ) , Wang, Zhi-peng (Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China ) , Hao, Jing-zheng (Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China ) , Li, Feng-ran (Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of E) , Fan, Zhan-fang , Zou, Li-bo , Cheng, Mao-sheng
    European journal of medicinal chemistry v.143 ,pp. 376 - 389 , 2018 , 0223-5234 ,

    초록

    Abstract Inspired by the previously reported neuroprotective activity of hederacolchiside E ( 1 ), we synthesized hederacolchiside E for the first time along with eleven of its derivatives. The neuroprotective effects of these compounds were further evaluated against H 2 O 2 - and A β 1-42 -induced injury using cell-based assays. The derivatives showed obvious differences in activity due to structural variations, and two of them exhibited better neuroprotective effects than 1 in the A β 1-42 -induced injury model. Compound 7 was the most active derivative and had a relatively simple chemical structure. Moreover, 1 and 7 can significantly reduce the release of lactate dehydrogenase (LDH), level of intracellular reactive oxygen species (ROS) and extent of malondialdehyde (MDA) increase resulting from A β 1-42 treatment, which demonstrated that these kinds of compounds show neuroprotective effects in Alzheimer's disease (AD) models via modulating oxidative stress. Compound 7 could be used as promising lead for the development of a new type of neuroprotective agent against AD. Highlights Natural saponin hederacolchiside E and eleven of its derivatives were synthesized for the first time. This series of compounds showed obvious differences in activity in AD-like models due to structural variations. Compound 7 with a relatively simple chemical structure showed the best activity against A β 1-42 -induced cell damage. Compound 7 reduced the levels of LDH, ROS andMDA resulting from A β 1-42 treatment in a concentration-depended manner. Graphical abstract [DISPLAY OMISSION]

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  5. [해외논문]   Design, synthesis, and biological evaluation of a series of resorcinol-based N-benzyl benzamide derivatives as potent Hsp90 inhibitors   SCI SCIE

    Park, Sun You (College of Pharmacy, Keimyung University, Daegu 704-701, South Korea ) , Oh, Yong Jin (College of Pharmacy, Keimyung University, Daegu 704-701, South Korea ) , Lho, Yunmee (Department of Biochemistry, School of Medicine, Keimyung University, Daegu 704-701, South Korea ) , Jeong, Ju Hui (College of Pharmacy, Keimyung University, Daegu 704-701, South Korea ) , Liu, Kwang-Hyeon (BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, South Korea ) , Song, Jaeyoung (New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, South Korea ) , Kim, Soong-Hyun (New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, South Korea ) , Ha, Eunyoung (Department of Biochemistry, School of Medicine, Keimyung University, Daegu 704-701, South Korea ) , Seo, Young Ho (College of Pharmacy, Keimyung University, Daegu 704-701, South Korea)
    European journal of medicinal chemistry v.143 ,pp. 390 - 401 , 2018 , 0223-5234 ,

    초록

    Abstract Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. Therefore, Hsp90 has emerged as an attractive target in the field of cancer chemotherapy. In this study, we report the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors. In particular, compound 30f shows a significant Hsp90 α inhibitory activity with IC 50 value of 5.3 nM and an excellent growth inhibition with GI 50 value of 0.42 μM against non-small cell lung cancer cells, H1975. Compound 30f effectively reduces the expression levels of Hsp90 client proteins including Her2, EGFR, Met, Akt, and c-Raf. Consequently, compound 30f promotes substantial cleavages of PARP, Caspase 3, and Caspase 8, indicating that 30f induces cancer cell death via apoptotic pathway. Moreover, cytochrome P450 assay indicates that compound 30f has weak inhibitory effect on the activities of five major P450 isoforms (IC 50 > 5 μM for 1A2, 2C9, 2C19, 2D6, and 3A), suggesting that clinical interactions between 30f and the substrate drugs of the five major P450 isoforms are not expected. Compound 30f also inhibits the tumor growth in a mouse xenograft model bearing subcutaneous H1975 without noticeable abnormal behavior and body weight changes. The immunostaining and western immunoblot analysis of EGFR, Met, Akt in xenograft tissue sections of tumor further demonstrate a good agreement with the in vitro results. Highlights A series of resorcinol-based N -benzyl benzamide derivatives were synthesized. Compound 30f showed a high Hsp90 binding affinity (IC 50 = 5.3 nM). Compound 30f exerted anticancer activity against H1975 non-small cell lung cancer (GI 50 = 0.42 μM). Compound 30f inhibited the growth of H1975 xenografts in NOD-scid IL2Rgamma null mice through Hsp90 inhibition. Graphical abstract [DISPLAY OMISSION]

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  6. [해외논문]   Design, synthesis and structure-activity relationship of a focused library of β-phenylalanine derivatives as novel eEF2K inhibitors with apoptosis-inducing mechanisms in breast cancer   SCI SCIE

    Guo, Yongzhi (State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu 610041, China ) , Zhao, Yuqian (State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu 610041, China ) , Wang, Guan (State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu 610041, China ) , Chen, Yi (Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, China ) , Jiang, Yingnan (State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu 610041, China ) , Ouyang, Liang (State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu 610041, China ) , Liu, Bo (State Key Laboratory of Biotherapy and Cancer Center, West China)
    European journal of medicinal chemistry v.143 ,pp. 402 - 418 , 2018 , 0223-5234 ,

    초록

    Abstract Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca 2+ /calmudulin-dependent protein kinase, belonging to a small family of an atypical Ser/Thr-protein kinase. eEF2K has been recently reported to be highly activated or overexpressed in many types of cancer; therefore, eEF2K would be regarded as a promising therapeutic target. In this study, we discovered a β-phenylalanine scaffold by virtual high-throughput screening, as well as designed and synthesized 46 derivatives with assessment of inhibition activity against eEF2K and cytotoxicity. After several rounds of kinase and anti-proliferative activity screening, we discovered an eEF2K inhibitor ( 21l ) with best eEF2K enzymatic activity (IC 50 of 5.5 μM) and anti-proliferative activity (MDA-MB-231 cells, IC 50 of 12.6 μM, MDA-MB-436 cells, IC 50 of 19.8 μM). Moreover, we found that 21l could induce cell death via the apoptotic pathways in MDA-MB-231 and MDA-MB-436 cells. Subsequently, we evaluated its anti-tumor activity and apoptosis-inducing mechanisms in vivo . These results suggested that 21l inhibited tumor growth by apoptosis in the xenograft mouse model of breast cancer (MDA-MB-231 and MDA-MB-436). Collectively, our results demonstrate a novel small-molecule inhibitor targeting eEF2K with mechanism of apoptosis and a therapeutic potential in breast cancer. Highlights A focused library of 46 β-phenylalanine derivatives was designed, synthesized. 21l induces significant apoptosis through classical apoptotic pathways in MDA-MB-231 and MDA-MB-436 cells. 21l inhibits tumor growth by apoptosis in the xenograft mouse model of TNBC in MDA-MB-231 and MDA-MB-436 cells. Graphical abstract [DISPLAY OMISSION]

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  7. [해외논문]   Discovery of a novel series of α-terpineol derivatives as promising anti-asthmatic agents: Their design, synthesis, and biological evaluation   SCI SCIE

    Zhu, Wanping (Zhejiang Academy of Traditional Chinese Medicine, Hangzhou 310007, China ) , Liu, Xia (Zhejiang Academy of Traditional Chinese Medicine, Hangzhou 310007, China ) , Wang, Yuji (Zhejiang Academy of Traditional Chinese Medicine, Hangzhou 310007, China ) , Tong, Yeling (Zhejiang Academy of Traditional Chinese Medicine, Hangzhou 310007, China ) , Hu, Yongzhou (ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, Hangzhou 310058, China)
    European journal of medicinal chemistry v.143 ,pp. 419 - 425 , 2018 , 0223-5234 ,

    초록

    Abstract A series of novel α-terpineol derivatives were designed and synthesized through structural derivatization of the tertiary hydroxyl moiety or reduction of the double bond. Of the resulting compounds, eight compounds enhanced relaxation of airway smooth muscle (ASM) compared to the α-terpineol precursor, and four compounds ( 4a , 4d , 4e, and 4i )were superior or comparable to aminophylline at a concentration of 0.75 mmol/L. Assays for 3′-5′-Cyclic adenosine monophpsphate (cAMP) activation revealed that some representative α-terpineol derivatives in this series were capable of upregulating the level of cAMP in ASM cells. Further in vivo investigation using the asthmatic rat model, illustrated that treatment with the compounds 4a and 4e resulted in significantly lowered lung resistance (RL) and enhanced dynamic lung compliance (Cldyn), two important parameters for lung fuction. Moreover, treatment with 4e downregulated the levels of both IL-4 and IL-17. Due to its several favorable physiological functions, including ASM relaxation activity, cAMP activation capability, and in vivo anti-asthmatic efficacy, 4e is a promising remedy for bronchial asthma, meriting extensive development. Highlights A novel series of α-terpineol derivatives were designed and syntheized. Eight α-terpineol (α-T) derivatives demonstrated enhanced airway smooth muscle (ASM) relaxation activity. Some representative α-T derivatives were capable of upregulating the level of cAMP in ASM cells. Derivatives improved rat model lung function. 4e merits extensive development as a promising remedy for bronchial asthma. Graphical abstract [DISPLAY OMISSION]

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  8. [해외논문]   Potent aromatase inhibitors and molecular mechanism of inhibitory action   SCI SCIE

    Kang, Hongjun (Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China ) , Xiao, Xingqing (Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695-7905, USA ) , Huang, Chao (Engineering Research Center of Biopolymer Functional Materials of Yunnan, Yunnan Minzu University, Kunming 650504, PR China ) , Yuan, Yan (Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission, Ministry of Education, Yunnan Minzu University, Kunming 650504, PR China ) , Tang, Dongyan (Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China ) , Dai, Xiaochang (Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China ) , Zeng, Xianghui (Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Edu)
    European journal of medicinal chemistry v.143 ,pp. 426 - 437 , 2018 , 0223-5234 ,

    초록

    Abstract Estrogen is a significant factor in the maintenance and progression of hormone-dependent breast cancer. As well known, aromatase mediates the production of estrogen. Thus, inhibition of aromatase with chemical molecules has been considered to be an effective treatment for estrogen receptor-positive (ER+) breast cancer. In this work, we designed and synthesized a series of novel non-steroidal molecules containing 2-phenylindole scaffold and moiety of either imidazole or 1,2,4-triazole to enhance their binding capacity with the aromatase. Among these molecules, a compound named as 8o was confirmed experimentally to have the highest inhibitory activity to aromatase. Further cell activity assay proved that compound 8o has low cytotoxicity and is a promising lead for developing novel aromatase inhibitors. Molecular modeling and simulation techniques were performed to identify the binding modes of letrozole and 8o with the aromatase. Analysis of energy of the two compound-aromatase complexes revealed that the 8o has low binding energy (strong binding affinity) to the aromatase as compared to letrozole, which was in accordance with the experimental results. As concluded, a combination of experimental and computational approaches facilitates us to understand the molecular mechanism of inhibitory action and discover more potent non-steroidal AIs against aromatase, thereby opening up a novel therapeutic strategy for hormone-dependent breast cancer. Highlights Discovery of novel non-steroidal inhibitors against aromatase. Novel compounds demonstrate higher potencies in aromatase inhibitory than letrozole. Computational models of aromatase with different substrates are built. Binding mode of substrates to aromatase has significant impact on pharmacological effect. Graphical abstract [DISPLAY OMISSION]

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

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  9. [해외논문]   Pyrano[3,2-a]carbazole alkaloids as effective agents against ischemic stroke in vitro and in vivo   SCI SCIE

    Zang, Yingda (Corresponding author. ) , Song, Xiuyun (Corresponding author.) , Li, Chuangjun , Ma, Jie , Chu, Shifeng , Liu, Dandan , Ren, Qian , Li, Yan , Chen, Naihong , Zhang, Dongming
    European journal of medicinal chemistry v.143 ,pp. 438 - 448 , 2018 , 0223-5234 ,

    초록

    Abstract A series of pyrano[3,2- a ]carbazole alkaloids were designed and synthesized as analogues of Claulansine F (Clau F, 10a ) isolated from Clausena lansium . Some of compounds showed strong neuroprotective effects and were promising agents against ischemic stroke. Among these compounds, 7c was the most active in inhibiting the programmed death of PC12 cells and primary cortical neurons. This compound induced neuroprotection following ischemic reperfusion and decreased neurological deficit scores in treated animals. Furthermore, 7c could penetrate the blood-brain barrier (BBB) in rats, and its exposure in the brain was 4.3-fold higher than that in plasma. More importantly, compared to edaravone, 7c exhibited stronger free radical scavenging activity. Our findings suggest that 7c may be promising for further evaluation as an intervention for ischemic stroke. Highlights A series of pyrano[3,2- a ]carbazole alkaloids were designed and synthesized as analogues of Claulansine F. 7c was the most active in inhibiting the programmed death of PC12 cells and primary cortical neurons. 7c induced neuroprotection following ischemic reperfusion and decreased neurological deficit scores in treated animals. 7c could penetrate the blood-brain barrier (BBB) in rats. 7c exhibited stronger free radical scavenging activity compared to Edaravone. Graphical abstract [DISPLAY OMISSION]

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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  10. [해외논문]   Exploiting polypharmacology for improving therapeutic outcome of kinase inhibitors (KIs): An update of recent medicinal chemistry efforts   SCI SCIE

    Ma, Xiaodong (Department of Medicinal Chemistry, School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China ) , Lv, Xiaoqing (College of Medicine, Jiaxing University, Jiaxing 314001, China ) , Zhang, Jiankang (Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, China)
    European journal of medicinal chemistry v.143 ,pp. 449 - 463 , 2018 , 0223-5234 ,

    초록

    Abstract Polypharmacology has been increasingly advocated for the therapeutic intervention in complex pathological conditions, exemplified by cancer. Although kinase inhibitors (KIs) have revolutionized the treatment for certain types of malignancies, some major medical needs remain unmet due to the relentless advance of drug resistance and insufficient efficacy of mono-target KIs. Hence, “multiple targets, multi-dimensional activities” represents an emerging paradigm for innovative anti-cancer drug discovery. Over recent years, considerable leaps have been made in pursuit of kinase-centric polypharmacological anti-cancer therapeutics, providing avenues to tackling the limitation of mono-target KIs. In the review, we summarize the clinically important mechanisms inducing KI resistance and depict a landscape of recent medicinal chemistry efforts on exploring kinase-centric polypharmacological anti-cancer agents that targeting multiple cancer-related processes. In parallel, some inevitable challenges are emphasized for the sake of more accurate and efficient drug discovery in the field. Highlights Summarize clinically important mechanisms inducing KI resistance. Highlight recent strides in exploring kinase-centric polypharmacological anti-cancer agents. Note some inevitable challenges researchers encounter in this field. Graphical abstract [DISPLAY OMISSION]

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

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