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European journal of medicinal chemistry 163건

  1. [해외논문]   Synthesis and biological evaluation of curcumin inspired imidazo[1,2-a]pyridine analogues as tubulin polymerization inhibitors   SCI SCIE

    Ramya, P.V. Sri (Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India ) , Guntuku, Lalita (Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India ) , Angapelly, Srinivas (Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India ) , Digwal, Chander Singh (Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India ) , Lakshmi, Uppu Jaya (Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India ) , Sigalapalli, Dilep Kumar (Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India ) , Babu, Bathini Nagendra (Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India ) , Naidu, V.G.M. (Department of Pharmacology and Toxicology, National Institute of Pharmaceu) , Kamal, Ahmed
    European journal of medicinal chemistry v.143 ,pp. 216 - 231 , 2018 , 0223-5234 ,

    초록

    Abstract With an aim to develop new curcumin inspired analogues as potent anticancer agents, we synthesized a series of (1 E ,4 E )-1-phenyl-5-(3-phenylimidazo[1,2- a ]pyridin-2-yl)penta-1,4-dien-3-ones ( 12a–t ) as tubulin polymerization inhibitors. An initial screening was carried out to evaluate their cytotoxic potential on a panel of six cancer cell lines namely, cervical (HeLa), gastric (HGC-27), lung (NCI-H460), prostate (DU-145 and PC-3) and breast (4T1), using MTT assay. Among the compounds tested, compounds 12e , 12r and 12t showed potent growth inhibition and 12t {(1 E ,4 E )-1-(3-(3,4-difluorophenyl)imidazo[1,2- a ]pyridin-2-yl)-5-(2,4,6-trimethoxyphenyl)penta-1,4-dien-3-one} being the most active member of the series inhibited the growth of all the tested cell lines with IC 50 values varying from 1.7 – 2.97 μM. Moreover, 12t showed promising cytotoxicity on PC-3, HGC-27 and HeLa cell lines with IC 50 values of 2.11 ± 0.27 μM, 2.21 ± 0.25 μM and 2.53 ± 0.01 μM respectively. The results from aqueous solubility test showed that compounds 12e and 12t have 1.7 and 2.8 times more aqueous solubility than curcumin. Interestingly, the most active compound 12t was found to be nearly 2 times more selective on PC-3 cells as well as safe on normal human prostate (RWPE-1) cells. In addition, compound 12t efficiently inhibited tubulin polymerization with IC 50 value of 8.44 ± 0.13 μM and molecular modelling studies disclosed that 12t binds at the colchicine binding site of the tubulin. Cell cycle analysis revealed that 12t arrests PC-3 cells in G2/M phase in a dose dependant manner. Further, treatment of PC-3 cells with 12t showed typical apoptotic morphology, also led to the impairment of mitochondrial membrane potential (DΨm) and increased levels of reactive oxygen species (ROS). Altogether, the results from acridine orange/ethidium bromide (AO-EB) and DAPI staining studies, annexin V-FITC/propidium iodide staining assay, analysis of mitochondrial membrane potential (DΨm) and reactive oxygen species (ROS) levels undoubtedly demonstrated the induction of apoptosis in PC-3 cells by compound 12t . Highlights New series of curcumin inspired imidazo[1,2- a ]pyridine analogues were synthesized. Anticancer activity was tested on six cancer cell lines and one normal cell line. Compound 12t effectively inhibited polymerization of tubulin in a cell-free assay. 12t induced apoptosis and cell cycle arrest in G2/M phase in PC-3 cells. 12t was almost 2 times more selective on PC-3 cells compared to RWPE-1 cells. Graphical abstract [DISPLAY OMISSION]

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  2. [해외논문]   Recent developments in anti-Trichomonas research: An update review   SCI SCIE

    Bala, Veenu (Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, 313001, India ) , Chhonker, Yashpal S. (College of Pharmacy, Department of Pharmacy Practice, University of Nebraska Medical Centre, Omaha, USA)
    European journal of medicinal chemistry v.143 ,pp. 232 - 243 , 2018 , 0223-5234 ,

    초록

    Abstract Trichomonas vaginalis is a major non-viral sexually-transmitted infection resulted into serious obstetrical and gynecological troubles. The increasing resistance to nitroimidazole therapy and recurrence makes it crucial to develop new drugs against trichomoniasis. Over the past few years, a large number of research articles highlighting the synthetic and natural product research to combat Trichomonas vaginalis have been published. Electronic databases were searched to collect all data from the year 2006 through June 2017 for anti- Trichomonas activity potential of synthetic and natural products. This review article put together the synthetic and natural product research to find out an effective metronidazole alternative to cure trichomoniasis. Highlights Trichomonas vaginalis is a major non-viral sexually-transmitted infection. Resistance towards metronidazole enhances the requirement of alternate therapy for T. vaginalis . This report describes synthetic and natural product anti-Trichomonas research in the past decade. Graphical abstract [DISPLAY OMISSION]

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  3. [해외논문]   Targeting tubulin polymerization by novel 7-aryl-pyrroloquinolinones: Synthesis, biological activity and SARs   SCI SCIE

    Bortolozzi, Roberta (Department of Woman's and Child's Health, University of Padova, Laboratory of Oncohematology, 35128 Padova, Italy ) , Mattiuzzo, Elena (Department of Woman's and Child's Health, University of Padova, Laboratory of Oncohematology, 35128 Padova, Italy ) , Dal Pra, Matteo (Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy ) , Sturlese, Mattia (Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy ) , Moro, Stefano (Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy ) , Hamel, Ernest (Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA ) , Carta, Davide (Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy ) , Viola, Giampietro (Department of Woman's and Child's Health, University of Padova, Laboratory of Oncohematology, 35128 Padova, I) , Ferlin, Maria Grazia
    European journal of medicinal chemistry v.143 ,pp. 244 - 258 , 2018 , 0223-5234 ,

    초록

    Abstract Earlier studies had confirmed that the 7-phenylpyrroloquinolinone (7-PPyQ) nucleus was an important scaffold for new chemotherapeutic drugs targeting microtubules. For wide-ranging SARs, a series of derivatives were synthesized through a robust procedure. For comparison with the reference 3-ethyl-7-PPyQ 31 , the angular geometry and substituents at the 3 and 7 positions were varied to explore interactions inside the colchicine site of tubulin. Of the new compounds synthesized, potent cytotoxicity (low and sub-nanomolar GI 50 values) was observed with 21 and 24 , both more potent than 31, in both leukemic and solid tumor cell lines. Neither compound 21 nor 24 induced significant cell death in normal human lymphocytes, suggesting that the compounds may be selectively active against cancer cells. In particular, 24 was a potent inducer of apoptosis in the A549 and HeLa cell lines. With both compounds, induction of apoptosis was associated with dissipation of the mitochondrial transmembrane potential and production of reactive oxygen species, indicating that cells treated with the compounds followed the intrinsic pathway of apoptosis. Moreover, immunoblot analysis revealed that compound 24 even at 50 nM reduced the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1. Finally, molecular docking studies of the newly synthesized compounds demonstrate that active pyrroloquinolinone derivatives strongly bind in the colchicine site of β-tubulin. Highlights A small library of 7-pyrrolo[3,2- f ]quinolinones was synthesized. One of the most active compound 24 showed GI 50 s ranging from 0.2 to 123 nM. Compound 24 did not induce significant cell death in normal human lymphocytes. Compound 24 overcomes multi-drug resistance. Compounds, 24 strongly inhibited tubulin assembly assay with an IC 50 of 0.84 μM. Graphical abstract [DISPLAY OMISSION]

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  4. [해외논문]   Platanic acid: A new scaffold for the synthesis of cytotoxic agents   SCI SCIE

    Kahnt, Michael (Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany ) , Heller, Lucie (Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany ) , Grabandt, Patricia (Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany ) , Al-Harrasi, Ahmed (University of Nizwa, Chair of Oman's Medicinal Plants and Marine Natural Products, PO Box 33, Birkat Al-Mauz, Nizwa, Oman ) , Csuk, René (Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany)
    European journal of medicinal chemistry v.143 ,pp. 259 - 265 , 2018 , 0223-5234 ,

    초록

    Abstract Thirty-seven different derivatives ( 2 - 38 ) have been prepared from platanic acid, a natural occurring triterpenoid. Main emphasis was the introduction of several N-containing functional groups such as amines, amides and oximes and their screening for cytotoxic activity employing several human tumor cell lines using SRB assays. In these SRB assays, nearly all compounds showed good cytotoxicity for these human tumor cell lines. Two compounds ( 17 and 38 ), however, were submitted to extended biological testing and investigated with respect to their mode of action using fluorescence microscopy and FACS analysis. Compound 17 , a methyl (3β, 20 R ) 3-acetyloxy-20-amino-30-norlupan-28-oate, induced apoptosis in A2780 ovarian carcinoma cells. Highlights Thirty seven derivatives of platanic acid have been prepared. The compounds were tested for cytotoxicity employing human tumor cell lines. SRB assays revealed most these compounds cytotoxic in low μM concentration. Extra screening showed a methyl 3-acetyloxy-20-amino-norlupanoate to act by apoptosis. Graphical abstract [DISPLAY OMISSION]

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  5. [해외논문]   Synthesis and antiproliferative activity of pyrrolo[2,3-b]pyridine derivatives bearing the 1,8-naphthyridin-2-one moiety   SCI SCIE

    Tang, Qidong (Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China ) , Duan, Yongli (Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China ) , Wang, Linxiao (Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China ) , Wang, Min (Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China ) , Ouyang, Yiqiang (Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China ) , Wang, Caolin (Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China ) , Mei, Han (Jiangxi Provincial Key Laboratory) , Tang, Sheng , Xiong, Yinhua , Zheng, Pengwu , Gong, Ping , Zhu, Wufu
    European journal of medicinal chemistry v.143 ,pp. 266 - 275 , 2018 , 0223-5234 ,

    초록

    Abstract A series of pyrrolo[2,3- b ]pyridine derivatives bearing the 1,8-naphthyridin-2-one moiety were synthesized, and evaluated for their antiproliferative activity against four cancer cell lines (HT-29, A549, H460, and U87MG) and six tyrosine kinases (c-Met, Flt-3, PDGFR-β, VEGFR-2, EGFR, and c-Kit) inhibitory activities in vitro . Most compounds showed moderate to excellent potency, with the most promising analogue 32 showing Flt-3/c-Met IC 50 value of 1.16/1.92 nM. Structure-activity relationship studies indicated that the hydrogen atom served as R 1 group was benefited to the potency, and mono-electron-withdrawing groups (mono-EWGs) on the phenyl ring (such as R 3 = 4-F) showed a higher preference for antiproliferative activity. Highlights A series of pyrrolo[2,3- b ]pyridine derivatives were designed and synthesized. The target compounds showed potent antitumor activity. Compound 32 showed an IC 50 value of 1.16/1.92 nM against Flt-3/c-Met kinase. Graphical abstract A series of pyrrolo[2,3- b ]pyridine derivatives bearing 1,8-naphthyridin-2-one moiety ( 23 – 54 ) were designed, synthesized and evaluated for their activity against four cancer cell lines and six tyrosine kinases. The most promising compound 32 showed excellent activity in vitro . [DISPLAY OMISSION]

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  6. [해외논문]   Inhibitory effects and structural insights for a novel series of coumarin-based compounds that selectively target human CA IX and CA XII carbonic anhydrases   SCI SCIE

    De Luca, Laura (Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali (CHIBIOFARAM), Università) , Mancuso, Francesca (degli Studi di Messina, Viale Annunziata, I-98168 Messina, Italy ) , Ferro, Stefania (Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali (CHIBIOFARAM), Università) , Buemi, Maria Rosa (degli Studi di Messina, Viale Annunziata, I-98168 Messina, Italy ) , Angeli, Andrea (Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali (CHIBIOFARAM), Università) , Del Prete, Sonia (degli Studi di Messina, Viale Annunziata, I-98168 Messina, Italy ) , Capasso, Clemente (Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali (CHIBIOFARAM), Università) , Supuran, Claudiu T. (degli Studi di Messina, Viale Annunziata, I-98168 Messina, Italy ) , Gitto, Rosaria (Dipartimento NEUROFARBA, Università)
    European journal of medicinal chemistry v.143 ,pp. 276 - 282 , 2018 , 0223-5234 ,

    초록

    Abstract Coumarin derivatives are a peculiar class of inhibitors of the family of metalloenzymes carbonic anhydrases (CA, EC 4.2.1.1). Several coumarins display higher affinity and selectivity toward most relevant and druggable CA isoforms. By decorating the natural compound umbelliferone ( 1 ) we have identified a new series of coumarin-based compounds demonstrating high CA inhibitory effects with nanomolar affinity for hCA IX and hCA XII isoforms that were considered a target amenable to develop antitumor agents. The most active tested compounds proved to be potent inhibitors with K i values equal to that of the well-known inhibitor acetazolamide (AAZ), that lacks selectivity over ubiquitous hCA I and hCA II. As suggested by docking studies the coumarins, that are lacking of the canonical metal binding groups, do not interact with Zinc ion within the catalytic site as found for classical sulfonamide type inhibitors of CAs. Thus, the studied inhibitors might possess a non-classical inhibitory mode of action preventing the carbon dioxide to entry into catalytic cavity and its conversion into bicarbonate ion. Specifically, the most active inhibitor of hCA XII compound 18i ( K i value of 5.5 nM) and its supposed hydrolytic products could establish a web of H-bond interactions within the enzymatic cavity. Highlights New coumarin-based derivatives as CA inhibitors were designed and synthesized. Several cumarins were effective inhibitors of tumor-associated hCA IX and hCA XII. Developed cumarins were selective inhibitors over ubiquitous hCA I and hCA II. Docking studies suggested the binding mode of active compound ( 18i ) and hCA XII. Graphical abstract [DISPLAY OMISSION]

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  7. [해외논문]   Synthesis and biological evaluation of some novel diastereoselective benzothiazole β-lactam conjugates   SCI SCIE

    Alborz, Maryam (Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71946-84795, Iran ) , Jarrahpour, Aliasghar (Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71946-84795, Iran ) , Pournejati, Roya (Department of Biology, College of Sciences, Shiraz University, PO Box: 71467-13565, Shiraz 71454, Iran ) , Karbalaei-Heidari, Hamid Reza (Department of Biology, College of Sciences, Shiraz University, PO Box: 71467-13565, Shiraz 71454, Iran ) , Sinou, Vé (Aix-Marseille Université, UMR-MD3 Relation Hôte-parasites, Physiopathologie & Pharmacologie, Faculté) , ronique (de Pharmacie, Bd Jean Moulin, F-13385, Marseille, France ) , Latour, Christine (Aix-Marseille Université, UMR-MD3 Relation Hôte-parasites, Physiopathologie & Pharmacologie, Faculté) , Brunel, Jean Michel (de Pharmacie, Bd Jean Moulin, F-13385, Marseille, France ) , Sharghi, Hashem (Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS, UMR7258, Institut Paoli Calmettes, Aix-Marseille Université, UM 105, Inserm, U1068, Faculté) , Aberi, Mahdi (de Pharmacie, Bd Jean Moulin, F-13385, Marseille, France ) , Turos, Edward (Departmen) , Wojtas, Lukasz
    European journal of medicinal chemistry v.143 ,pp. 283 - 291 , 2018 , 0223-5234 ,

    초록

    Abstract Highly diastereoselective synthesis of some novel benzothiazole-substituted β-lactam hybrids was achieved starting from (benzo[ d ]thiazol-2-yl)phenol as an available precursor. This is the first time (benzo[ d ]thiazol-2-yl)phenoxyacetic acid has been used as ketene source in synthesizing monocyclic 2-azetidinones. These compounds were evaluated for their antimicrobial activities against a large panel of Gram-positive and Gram-negative bacterial strains and moderate activities were encountered. Antimalarial data revealed that adding methoxyphenyl or ethoxyphenyl group on the β–lactam ring makes compounds that are more potent. Moreover, hemolytic activity and mammalian cell toxicity survey of the compounds showed their potential as a medicine. Highlights A new series of cis benzothiazole β-lactam conjugates have been synthesized. Good activities against chloroquine resistant P. falciparum K1 strain. Less cytotoxicity effect on hepatocellular carcinoma cell line (HepG2). Red blood cells stability as hemolysis assay exhibited excellent results. A single crystal X-ray structure of 5n has been determined. Graphical abstract [DISPLAY OMISSION]

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  8. [해외논문]   Regio- and stereoselective synthesis of dispirooxindole-pyrrolocarbazole hybrids via 1,3-dipolar cycloaddition reactions: Cytotoxic activity and SAR studies   SCI SCIE

    Murali, Karunanidhi (Department of Chemistry, Bharathiar University, Coimbatore 641046, India ) , Sparkes, Hazel A. (School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, United Kingdom ) , Rajendra Prasad, Karnam Jayarampillai (Department of Chemistry, Bharathiar University, Coimbatore 641046, India)
    European journal of medicinal chemistry v.143 ,pp. 292 - 305 , 2018 , 0223-5234 ,

    초록

    Abstract A library of novel dispiro compounds containing oxindole-pyrrolo-carbazole hybrid frame works has been synthesized in a fully regio- and stereoselective fashion by the three-component 1,3-dipolar cycloaddition of azomethineylides generated in situ from the condensation of isatins and benzylamine with 2-arylidene/heteroarylidene-2,3,4,9-tetrahydro-1 H -carbazole-1-one. The structures of the compounds were established by FT-IR, 1 H NMR, 13 C NMR, X-ray diffraction and elemental analysis. The synthesized dispiro heterocycles have been screened for in vitro cytotoxic activity by MTT assay and displayed enviable growth inhibition on both the cancer cell lines i.e. breast cancer cell line MCF-7 and lung cancer cell line A-549. Morphological changes and apoptosis induction have been studied by inverted light microscopic, fluorescent microscopic techniques and by flow cytometry analyses. The preliminary structure activity relationships were also carried out. Data indicated that among dispiro-carbazole compounds,6-chloro-4'-(thiophen-2-yl)-5′-phenyl-3,4-dihydrodispiro[carbazole-2,3′-pyrrolo-2′,3″-indole]-9( H )-1,2″-dione 7e could be exploited as a significant therapeutic drug against breast cancer as well as lung cancer cell proliferation. Highlights The dispiro hybrid compounds were synthesized in a fully regio- and stereoselective fashion. Compounds showed selective growth inhibition on both MCF-7 cell line and A-549 cell line. Tested cells were visualized using fluorescent microscopic technique. The preliminary structure activity relationships were also established. Chloro substituted dispirooxindole-pyrrolo-carbazole exploited as a significant therapeutic drug. Graphical abstract [DISPLAY OMISSION]

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  9. [해외논문]   Novel triazine dimers with potent antitrypanosomal activity   SCI SCIE

    Venkatraj, Muthusamy (Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium ) , Salado, Irene G. (Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium ) , Heeres, Jan (Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium ) , Joossens, Jurgen (Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium ) , Lewi, Paul J. (Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium ) , Caljon, Guy (Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium ) , Maes, Louis (Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium ) , Van der Veken, Pieter (Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium ) , Augustyns, Koen (Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Be)
    European journal of medicinal chemistry v.143 ,pp. 306 - 319 , 2018 , 0223-5234 ,

    초록

    Abstract Human African trypanosomiasis (HAT), also known as sleeping sickness is a parasitic disease transmitted by the bite of the 'Glossina' insect, commonly known as the tsetse fly. This disease affects mostly poor populations living in remote rural areas of Africa. Untreated, it is usually fatal. Currently, safe and effective treatments against this disease are lacking. Phenotypic screening of triazine non-nucleoside HIV-1 reverse transcriptase inhibitors (monomers) resulted in potent and selective antitrypanosomal compounds. This serendipitous discovery and the presence of dimers in many compounds active against these neglected tropical diseases prompted us to investigate antitrypanosomal activity of triazine dimers. Optimization of the triazine dimers resulted in 3,3'-(((ethane-1,2-diylbis(azanediyl))bis(4-(mesityloxy)-1,3,5-triazine-6,2-diyl))bis(azanediyl))dibenzonitrile (compound 38 ), a compound with very potent in vitro and moderate in vivo antitrypanosomal activity. Highlights Design and synthesis of dimeric compounds against T. brucei obtaining extremely potent compounds in vitro. The two selected compounds were able to improve metabolic stability compared to the monomeric derivatives. In vivo data are not in line with the highly promising in vitro potency and in vitro ADME data. Graphical abstract [DISPLAY OMISSION]

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  10. [해외논문]   Design, synthesis and biological evaluation of novel 2-aminobenzamides containing dithiocarbamate moiety as histone deacetylase inhibitors and potent antitumor agents   SCI SCIE

    Xie, Rui (Corresponding author. ) , Li, Yan (Corresponding author.) , Tang, Pingwah , Yuan, Qipeng
    European journal of medicinal chemistry v.143 ,pp. 320 - 333 , 2018 , 0223-5234 ,

    초록

    Abstract A novel series of 2-aminobenzamides with dithiocarbamate as cap group were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most newly synthesized compounds displayed potent antiproliferative activity against diverse human tumor cell lines. The most potent compounds, M101, M122 and M133 exhibited remarkably enhanced anticancer potency against 6 kinds of cancer cell lines with IC 50 values of as low as 0.54–2.49 μM compared with CS055 (2.28∼ >26 μM) and MS275 (0.47–6.74 μM). HDAC isoform selectivity assay indicated that M101, M122 and M133 are HDAC1 and HDAC2 selective inhibitors. We also rationalize the high potency and selectivity of compound M122 by molecular docking. Further investigation showed that M101, M122 and M133 could inhibit colony formation of human hepatocellular carcinoma cell line SMMC7721. Furthermore, M101, M122 and M133 remarkably induced apoptosis in SMMC7721 cancer cells. M101 and M133 were found to potently induce SMMC7721 cancer cell cycle arrest at G2/M phase. This study demonstrated that introducing dithiocarbamate as the capping group of 2-aminobenzamide is effective for improving both HDAC inhibitory activity and antitumor activity. The most potent compounds, M101, M122 and M133 could be promising candidates for cancer therapy. Highlights A series of 2-aminobenzamides with dithiocarbamate moiety as cap group were synthesized. Few synthesized compounds displayed potent antiproliferative activity. M101, M122 and M133 displayed IC 50 values of as low as 0.54–2.49 μM against 6 kinds of cancer cells Graphical abstract [DISPLAY OMISSION]

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