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European journal of medicinal chemistry 163건

  1. [해외논문]   DNA intercalators based on (1,10-phenanthrolin-2-yl)isoxazolidin-5-yl core with better growth inhibition and selectivity than cisplatin upon head and neck squamous cells carcinoma   SCI SCIE

    Varrica, Maria G. (Dipartimento di Scienze del Farmaco, Università) , Zagni, Chiara (degli Studi di Catania, V.le A. Doria, 95125, Catania, Italy ) , Mineo, Placido G. (Dipartimento di Scienze del Farmaco, Università) , Floresta, Giuseppe (degli Studi di Catania, V.le A. Doria, 95125, Catania, Italy ) , Monciino, Giulia (Dipartimento di Scienze Chimiche, Università) , Pistarà (di Catania, Viale A. Doria, 6, 95125, Catania, Italy ) , , Venerando (Dipartimento di Scienze del Farmaco, Università) , Abbadessa, Antonio (degli Studi di Catania, V.le A. Doria, 95125, Catania, Italy ) , Nicosia, Angelo (Dipartimento di Scienze del Farmaco, Università) , Castilho, Rogerio M. (degli Studi di Catania, V.le A. Doria, 95125, Catania, Italy ) , Amata, Emanuele (Dipartimento di Scienze del Farmaco, Università) , Rescifina, Antonio (degli Studi di Catania, V.le A. Doria, 95125, Catania, Italy )
    European journal of medicinal chemistry v.143 ,pp. 583 - 590 , 2018 , 0223-5234 ,

    초록

    Abstract ((3 RS ,5 SR )- and ((3 RS ,5 RS )-2-(2-methoxybenzyl)-3-(1,10-phenanthrolin-2-yl)isoxazolidin-5-yl)methanol have been synthesized, according to 1,3-dipolar cycloaddition methodology, as DNA intercalating agents and evaluated for their anticancer activity against human cervical carcinoma HeLa and head and neck squamous cells carcinoma cell lines. The synthesized compounds exhibited good cytotoxic activity with IC 50 better than cisplatin, used as the main and effective treatment for HNSCC, and a 24.3–72.0-fold selectivity respect to the 184B5 non-cancerous immortalized breast epithelial cell lines. Unwinding assay, circular dichroism data, and Uv-vis melting experiments confirmed that these compounds act as DNA intercalators with a binding constant in the order of 10 4 M −1 . Docking studies showed that both compounds can interact as intercalating agent with both poly-d(AT) 2 and poly-d(GC) 2 , preferring an entrance by the minor groove of the poly-d(AT) 2 . Highlights New 1,10-phenanthrolin-2-yl-substituted isoxazolidines have been synthetized. The molecules act as DNA intercalators with anticancer activity. The anticancer activity against the cisplatin-resistant HN13 cell lines was of 4.5 μM. Graphical abstract [DISPLAY OMISSION]

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  2. [해외논문]   Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors   SCI SCIE

    Emmerich, Juliette (Pharmaceutical and Medicinal Chemistry, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany ) , van Koppen, Chris J. (Pharmaceutical and Medicinal Chemistry, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany ) , Burkhart, Jens L. (Pharmaceutical and Medicinal Chemistry, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany ) , Engeli, Roger T. (Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland ) , Hu, Qingzhong (Pharmaceutical and Medicinal Chemistry, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany ) , Odermatt, Alex (Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland ) , Hartmann, Rolf W. (Pharmaceutical and Medicinal Chemistry, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany)
    European journal of medicinal chemistry v.143 ,pp. 591 - 597 , 2018 , 0223-5234 ,

    초록

    Abstract Previous studies have shown that inhibition of cortisol biosynthesis in skin leads to accelerated wound healing. Here, pyridylmethyl pyridine type 11β-hydroxylase (CYP11B1) inhibitors were optimized for topical application to avoid systemic side effects. The resulting very potent, non-toxic CYP11B1 inhibitor 14 (IC 50 = 0.8 nM) exhibited good selectivity over 11β-HSD1, CYP17A1 and CYP19A1. The compound showed high stability toward human plasma (t 1/2 = > > 150 min, as a substitute for wound fluid) and low stability toward HLS9 (t 1/2 = 1 19 min) for rapid metabolic clearance after absorption. Compound 14 was able to accelerate wound healing in human skin. Highlights Novel CYP11B1 inhibitors for topical treatment of chronic wounds synthesized. Selectivity over 11β-HSD1 and CYP19A1 obtained. Compounds are metabolically instable to avoid systemic effects. Acceleration of wound healing in human skin ( ex vivo ) demonstrated. Graphical abstract [DISPLAY OMISSION]

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  3. [해외논문]   Development of novel anti-filarial agents using carbamo(dithioperoxo)thioate derivatives   SCI SCIE

    Gucchait, Arin (Bose Institute, Division of Molecular Medicine, P-1/12, C.I.T. Scheme VII-M, Kolkata, 700054, India ) , Joardar, Nikhilesh (Parasitology Laboratory, Department of Zoology (Centre for Advanced Studies), Visva-Bharati University, Santiniketan, 731235, West Bengal, India ) , Parida, Pravat Kumar (Bose Institute, Division of Molecular Medicine, P-1/12, C.I.T. Scheme VII-M, Kolkata, 700054, India ) , Roy, Priya (Parasitology Laboratory, Department of Zoology (Centre for Advanced Studies), Visva-Bharati University, Santiniketan, 731235, West Bengal, India ) , Mukherjee, Niladri (Parasitology Laboratory, Department of Zoology (Centre for Advanced Studies), Visva-Bharati University, Santiniketan, 731235, West Bengal, India ) , Dutta, Ananya (Bose Institute, Division of Molecular Medicine, P-1/12, C.I.T. Scheme VII-M, Kolkata, 700054, India ) , Yesuvadian, Ravichandran (Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur, 603203, Tamil Nadu, India ) , SinhaBabu, Santi P. (Parasitology Laboratory, Department of Zoology (Centre for Advanced Studies), Visva-Bharati University, Santiniketan, 731235, West Bengal,) , Jana, Kuladip , Misra, Anup Kumar
    European journal of medicinal chemistry v.143 ,pp. 598 - 610 , 2018 , 0223-5234 ,

    초록

    Abstract A series of novel carbamo(dithioperoxo)thioate derivatives have been prepared in excellent yield using a significantly fast, one-pot three component reaction and experimented for their potential as anti-filarial agents against model filarial nematode Setaria cervi . Among 23 compounds ( 4a-w ) evaluated for the anti-filarial activities, five compounds ( 4a, 4b, 4c, 4d and 4h ) have shown promising anti-proliferative effects on the juvenile stage microfilariae (mf) as well as in adults in a time and dose dependent manner. Compound 4a was found most active against oocytes, mf and adult nematods as well as non-cytotoxic to the normal cells. It has been established that the anti-filarial activity of the compounds were observed due to the involvement of reactive oxygen species (ROS) and apoptosis. Several biochemical and microscopic experiments have been carried out to establish the fact that both intrinsic and extrinsic pathways of apoptosis contribute to the compound 4a mediated death phenomenon of the filarial nematodes. Highlights Carbamo(dithioperoxo)thioate derivatives were prepared using one-pot reaction. Synthetic compounds were evaluated for their potential as antifilarial agents. Five compounds were found promising anti-filarial agents against Setaria cervi. Biochemical and microscopic experiments were carried out for the best compound. Anti-filarial potential of active compounds rely on ROS and apoptosis pathway. Graphical abstract [DISPLAY OMISSION]

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  4. [해외논문]   Identification of an oxime-containing C-glucosylarene as a potential inhibitor of sodium-dependent glucose co-transporter 2   SCI SCIE

    Yuan, Mao-Chia (Corresponding author.) , Yeh, Teng-Kuang , Chen, Chiung-Tong , Song, Jen-Shin , Huang, Yu-Chen , Hsieh, Tsung-Chih , Huang, Chung-Yu , Huang, Yu-Ling , Wang, Min-Hsien , Wu, Szu-Huei , Yao, Chun-Hsu , Chao, Yu-Sheng , Lee, Jinq-Chyi
    European journal of medicinal chemistry v.143 ,pp. 611 - 620 , 2018 , 0223-5234 ,

    초록

    Abstract Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C -glycosides bearing a C=N/C−N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C -glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin ( 1 ). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC 50 > 50 μM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 μM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor. Highlights A small library of aryl C -glycosides, whose glycone is a 6-amino-/6-imino-6-deoxy-β- D -glucosyl group, was synthesized. All the synthesized derivatives were evaluated for their inhibitory activities against hSGLT2. Potent aryl C -glycoside SGLT2 inhibitors were studied for selectivity over hSGLT1. Five representative aryl C -glycosides were subjected to pharmacokinetic analysis. 2a was identified as a potential SGLT2 inhibitor with promising pharmacokinetic properties and good in vivo performance. Graphical abstract Twenty-seven aryl C -glycosides, whose glycone is a 6-amino-/6-imino-6-deoxy-β- D -glucosyl group, were synthesized. Biological, pharmacokinetic and efficacy studies culminated in the identification of oxime 2a as a potential SGLT2 inhibitor. [DISPLAY OMISSION]

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  5. [해외논문]   Design, synthesis and evaluation of an anthraquinone derivative conjugated to myelin basic protein immunodominant (MBP85-99) epitope: Towards selective immunosuppression   SCI SCIE

    Tapeinou, Anthi (Department of Chemistry, University of Patras, GR-26504, Rion, Greece ) , Giannopoulou, Efstathia (Clinical Oncology Laboratory, University Hospital of Patras, Patras Medical School, GR-26504, Rion, Greece ) , Simal, Carmen (Department of Chemistry, University of Patras, GR-26504, Rion, Greece ) , Hansen, Bjarke E. (Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen, Denmark ) , Kalofonos, Haralabos (Clinical Oncology Laboratory, University Hospital of Patras, Patras Medical School, GR-26504, Rion, Greece ) , Apostolopoulos, Vasso (Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia ) , Vlamis-Gardikas, Alexios (Department of Chemistry, University of Patras, GR-26504, Rion, Greece ) , Tselios, Theodore (Department of Chemistry, University of Patras, GR-26504, Rion, Greece)
    European journal of medicinal chemistry v.143 ,pp. 621 - 631 , 2018 , 0223-5234 ,

    초록

    Abstract Anthraquinone type compounds, especially di-substituted amino alkylamino anthraquinones have been widely studied as immunosuppressants. The anthraquinone ring is part of mitoxandrone that has been used for the treatment of multiple sclerosis (MS) and several types of tumors. A desired approach for the treatment of MS would be the immunosuppression and elimination of specific T cells that are responsible for the induction of the disease. Herein, the development of a peptide compound bearing an anthraquinone derivative with the potential to specifically destroy the encephalitogenic T cells responsible for the onset of MS is described. The compound consists of the myelin basic protein (MBP) 85–99 immunodominant epitope (MBP 85-99 ) coupled to an anthraquinone type molecule (AQ) via a disulfide (S-S) and 6 amino hexanoic acid (Ahx) residues (AQ-S-S-(Ahx) 6 MBP 85-99 ). AQ-S-S-(Ahx) 6 MBP 85-99 could bind to HLA II DRB1*-1501 antigen with reasonable affinity (IC 50 of 56 nM) The compound was localized to the nucleus of Jurkat cells (an immortalized line of human T lymphocytes) 10 min after its addition to the medium and resulted in lowered Bcl-2 levels (apoptosis). Entrance of the compound was abolished when cells were pre-treated with cisplatin, an inhibitor of thioredoxin reductase. Accordingly, levels of free thiols were elevated in the culture supernatants of Jurkat cells exposed to N- succinimidyl 3-(2-pyridyldithio) propionate coupled to (Ahx) 6 MBP 85-99 via a disulphide (SPDP-S-S-(Ahx) 6 MBP 85-99 ) but returned to normal after exposure to cisplatin. These results raise the possibility of AQ-S-S-(Ahx) 6 MBP 85-99 being used as an eliminator of encephalitogenic T cells via implication of the thioredoxin system for the generation of the toxic, thiol-containing moiety (AQ-SH). Future experiments would ideally determine whether SPDP-S-S-(Ahx) 6 MBP 85-99 could incorporate into HLA II DRB1*-1501 tetramers and neutralize encephalitogenic T cell lines sensitized to MBP 85-99 . Highlights Design and synthesis of a molecule with an anthraquinone moiety coupled via a disulfide to an immunodominant myelin epitope. The synthetic molecule may bind to the HLA II DRB1-1501 antigen (IC 50 of 56 nM). Reduction of the disulfide by cell reductases may facilitate entry of the molecule to cells. The synthetic molecule can cause apoptosis via Bcl-2. Graphical abstract [DISPLAY OMISSION]

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  6. [해외논문]   Substituted carbamothioic amine-1-carbothioic thioanhydrides as novel trichomonicidal fungicides: Design, synthesis, and biology   SCI SCIE

    Mandalapu, Dhanaraju (Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India ) , Kushwaha, Bhavana (Endocrinology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India ) , Gupta, Sonal (Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India ) , Krishna, Shagun (Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India ) , Srivastava, Nidhi (Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India ) , Shukla, Mahendra (Pharmacokinetic & Metabolism Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India ) , Singh, Pratiksha (Microbiology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India ) , Chauhan, Bhavana S. (Parasitology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India ) , Goyani, Ravi (Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli 229 010, Ind) , Maikhuri, Jagdamba P. , Sashidhara, Koneni V. , Kumar, Brijesh , Tripathi, Renu , Shukla, Praveen K. , Siddiqi, Mohammad I. , Lal, Jawahar , Gupta, Gopal , Sharma, Vishnu L.
    European journal of medicinal chemistry v.143 ,pp. 632 - 645 , 2018 , 0223-5234 ,

    초록

    Abstract Sexually transmitted diseases like trichomoniasis along with opportunistic fungal infections like candidiasis are major global health burden in female reproductive health. In this context a novel non-nitroimidazole class of substituted carbamothioic amine-1-carbothioic thioanhydride series was designed, synthesized, evaluated for trichomonacidal and fungicidal activities, and was found to be more active than the standard drug Metronidazole (MTZ). Compounds were trichomonicidal in the MIC ranges of 4.77–294.1 μM and 32.46–735.20 μM against MTZ-susceptible and -resistant strains, respectively. Further, compounds inhibited the growth of at least two out of ten fungal strains tested at MIC of 7.50–240.38 μM. The most active compound ( 20 ) of this series was 3.8 and 9.5 fold more active than the MTZ against the two Trichomonas strains tested. Compound 20 also significantly inhibited the sulfhydryl groups present over Trichomonas vaginalis and was found to be more active than the MTZ in vivo . Further, a docking analysis carried out with cysteine proteases supported their thiol inhibiting ability and preliminary pharmacokinetic study has shown good distribution and systemic clearance. Highlights Thirty new compounds comprising different structural variations were synthesized. Evaluated for MTZ-susceptible, –resistant Trichomoniasis , and fungal activities. Several compounds were found more active than MTZ against both the strains tested. Compound 20 showed good in vivo activity and thiol inhibition on Trichomonas. Most active compounds of the series exhibited moderate antimalarial activity. Graphical abstract [DISPLAY OMISSION]

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  7. [해외논문]   Synthesis and antimicrobial activity of amino acid and peptide derivatives of mycophenolic acid   SCI SCIE

    Siebert, Agnieszka (Department of Organic Chemistry, Gdansk University of Technology, ul. G. Narutowicza 11/12, 80-233 Gdansk, Poland ) , Wysocka, Magdalena (Department of Molecular Biotechnology and Microbiology, Gdansk University of Technology, ul. G. Narutowicza 11/12, 80-233 Gdansk, Poland ) , Krawczyk, Beata (Department of Molecular Biotechnology and Microbiology, Gdansk University of Technology, ul. G. Narutowicza 11/12, 80-233 Gdansk, Poland ) , Cholewiń (Department of Organic Chemistry, Gdansk University of Technology, ul. G. Narutowicza 11/12, 80-233 Gdansk, Poland ) , ski, Grzegorz (Department of Organic Chemistry, Gdansk University of Technology, ul. G. Narutowicza 11/12, 80-233 Gdansk, Poland) , Rachoń , , Janusz
    European journal of medicinal chemistry v.143 ,pp. 646 - 655 , 2018 , 0223-5234 ,

    초록

    Abstract The series of 16 novel amino acid and peptide mycophenolic acid (MPA) derivatives was obtained as potential antibacterial agents. Coupling of MPA with respective amines was optimized with condensing reagents such as EDCI/DMAP and T3P/TEA. Amino acid analogs were received both as methyl esters and also with the free carboxylic group. The biological activity of the products was tested on five references bacterial strains: Klebsiella pneumoniae ATCC 700603 (ESBL), Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus MRSA ATCC 43300, Staphylococcus aureus MSSA ATCC 25923. Peptide derivatives proved to be the most versatile ones, their MIC values relative to most strains was lower than MPA alone. It has been noted that the activity of amino acid derivatives depends on the configuration at the chiral center in the amino acid unit and methyl esters indicated better antimicrobial activity than analogs with free carboxylic group. Highlights New derivatives of MPA were obtained as antimicrobial agents. Amino acid analogs were more active as methyl esters. Configuration at chiral center influenced antibacterial properties. Peptide analogs exhibited better activity than parent MPA. Several derivatives gave lower MICs against S. aureus and K. pneumoniae than kanamycin and ampicillin. Graphical abstract [DISPLAY OMISSION]

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  8. [해외논문]   Recent discovery of indoleamine-2,3-dioxygenase 1 inhibitors targeting cancer immunotherapy   SCI SCIE

    Weng, Tianwei (Corresponding author. ) , Qiu, Xiaqiu (Corresponding author.) , Wang, Jubo , Li, Zhiyu , Bian, Jinlei
    European journal of medicinal chemistry v.143 ,pp. 656 - 669 , 2018 , 0223-5234 ,

    초록

    Abstract There has been great attention on indoleamine-2,3-dioxygenase 1 (IDO1) around cancer immunotherapy because of its role in enabling cancers to evade the immune system. The most recent spurt of high potent IDO1 inhibitors has been driven by the solution of the increased crystal structures of inhibitors with IDO1. Though the structural information of the active site of IDO1 obtained from the crystals are quite similar, the structures of reported potent inhibitors are quite different. Besides, while thousands of bioactive small molecule inhibitors of IDO1 exist, to date, only five compounds have entered clinical trials. In an effort to obtain more clinical drugs targeting IDO1, more comprehensive understanding of the active site of IDO1 and the structures of existing potent IDO1 inhibitors are necessary. Thus, this review mainly focus on the key features reported from specific crystal structures of IDO1 and an overview of the most recently developed IDO1 inhibitors under investigation and their other derived applications which may contribute to a better usage in cancer immunotherapy. Highlights Functional roles of IDO1 in immune escape are illuminated. Representative crystal structures of IDO1are listed in turn and compared with each other. Current status of IDO1 inhibitors in clinical trials are covered. Most recently developed IDO1 inhibitors with an emphasis on their chemical structures and their other derived applications are highlighted. Graphical abstract [DISPLAY OMISSION]

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  9. [해외논문]   New estrogen receptor antagonists. 3,20-Dihydroxy-19-norpregna-1,3,5(10)-trienes: Synthesis, molecular modeling, and biological evaluation   SCI SCIE

    Kuznetsov, Yury V. (N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia ) , Levina, Inna S. (N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia ) , Scherbakov, Alexander M. (Institute of Carcinogenesis, N.N. Blokhin Cancer Research Centre, Kashirskoye sh. 24, Moscow 115478, Russia ) , Andreeva, Olga E. (Institute of Carcinogenesis, N.N. Blokhin Cancer Research Centre, Kashirskoye sh. 24, Moscow 115478, Russia ) , Fedyushkina, Irina V. (Orekhovich Institute of Biomedical Chemistry, Pogodinskaya ul. 10, Moscow 119121, Russia ) , Dmitrenok, Andrey S. (N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia ) , Shashkov, Alexander S. (N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia ) , Zavarzin, Igor V. (N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia)
    European journal of medicinal chemistry v.143 ,pp. 670 - 682 , 2018 , 0223-5234 ,

    초록

    Abstract New estrogen receptor α (ERα) antagonists – 3,20-dihydroxy-19-norpregna-1,3,5(10)-trienes containing an additional carbocyclic ring D′ at the 16α,17α positions – were synthesized. The effects of the new compounds on the MCF-7 breast cancer cells and ERα activation were investigated. All the steroids studied were synthesized starting from estrone methyl ether. The scaffold of compounds containing the six-membered ring D′ was constructed via the Diels–Alder reaction of butadiene with 3-methoxy-19-norpregna-1,3,5(10),16-tetraen-20-one 5 . The hydrogenation of primary 16α,17α-cyclohexeno-adduct 7 followed by 3-demethylation (by HBr–AcOH) and reduction of 20-oxo group (by LiAlH 4 ) or in one step by DIBAH gave target mono- and dihydroxy steroids 9 – 11 . The Corey–Chaykovsky reaction of the same 3-methoxy-19-norpregna-1,3,5(10),16-tetraen-20-one 5 gave 16α,17α-methylene-substituted compound. The reaction of the latter with DIBAH immediately yielded 3,20-dihydroxy-16α,17α-methyleno-19-norpregna-1,3,5(10)-triene 13 . The same procedures using 3-methoxy-19-norpregna-1,3,5(10),16-tetraen-20-one 5 produced corresponding 3,20-dihydroxy-16,17-19-norpregna-1,3,5(10)-triene 16 and 3,20-dihydroxy-19-norpregna-1,3,5(10),16-tetraene 17 . All compounds were fully characterized by 1D and 2D NMR, HRMS, and X-ray diffraction. The molecular docking showed that the target compounds can bind to ER, their binding mode being similar to that of natural estradiol. 16α,17α-Methylene- or unsubstituted compounds exhibit the highest cytotoxicity against MCF-7 cells, being simultaneously relatively weak ERα inhibitors. 3,20-Dihydroxy steroids containing the six-membered ring D′ proved to be the most effective ERα inhibitors. These compounds displayed moderate cytotoxicity comparable of that of tamoxifen and showed no toxic effect on MCF-10A normal, nontumorigenic epithelial cells. The new ER antagonists were found to be good candidates for further testing as agents for the treatment and prevention of ERα-positive breast cancers. Highlights Series of 3,20-dihydroxy-19-norpregna-1,3,5(10)-trienes were synthesized. Studied compounds can bind to ERα and their binding mode is similar to that of estradiol. Synthesized 3,20-dihydroxy-19-norpregna-1,3,5(10)-trienes were cytotoxic against MCF-7. Additional ring D′ is responsible for ERα antagonist activity of the compounds synthesized. Graphical abstract [DISPLAY OMISSION]

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  10. [해외논문]   2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition   SCI SCIE

    Romagnoli, Romeo (Dipartimento di Scienze Chimiche e Farmaceutiche, Università) , Kimatrai Salvador, Maria (di Ferrara, 44121 Ferrara, Italy ) , Schiaffino Ortega, Santiago (Departamento de Química Farmaceútica y Orgánica, Facultad de Farmacia, Campus de Cartuja s/n, 18071, Granada, Spain ) , Baraldi, Pier Giovanni (Departamento de Química Farmaceútica y Orgánica, Facultad de Farmacia, Campus de Cartuja s/n, 18071, Granada, Spain ) , Oliva, Paola (Dipartimento di Scienze Chimiche e Farmaceutiche, Università) , Baraldi, Stefania (di Ferrara, 44121 Ferrara, Italy ) , Lopez-Cara, Luisa Carlota (Dipartimento di Scienze Chimiche e Farmaceutiche, Università) , Brancale, Andrea (di Ferrara, 44121 Ferrara, Italy ) , Ferla, Salvatore (Dipartimento di Scienze Chimiche e Farmaceutiche, Università) , Hamel, Ernest (di Ferrara, 44121 Ferrara, Italy ) , Balzarini, Jan (Departamento de Química Farmaceútica y Orgánica, Facultad de Farmacia, Campus de Cartuja s/n, 18071, Granada, Spain ) , Liekens, Sandra (School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK ) , Mattiuzzo, Elena (School of Pharmacy and Pharmaceutical Sciences, Cardiff) , Basso, Giuseppe , Viola, Giampietro
    European journal of medicinal chemistry v.143 ,pp. 683 - 698 , 2018 , 0223-5234 ,

    초록

    Abstract Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3′,4′,5′-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3′,4′,5′-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a , 4c , 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC 50 values ranging from 0.13 to 0.84 μM against four different cancer cell lines. Three agents ( 4a , 4c and 4i ) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c , containing the 2′-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3′,4′,5′-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IC 50 value of 140 nM, inhibited tubulin polymerization with an IC 50 value of 1.2 μM, similar to that of CA-4 (IC 50 : 1.1 μM), and induced apoptosis in HeLa cells. Highlights 2-Methoxycarbonyl-3-anilino-5-aryl/heteroarylthiophene derivatives inhibit the growth of tumor cell lines. Compounds 4a , 4c and 4i inhibited tubulin polymerization with an activity similar to that of CA-4. Compound 4c induced significant production of ROS in good agreement with affecting the mitochondrial depolarization pathway. Compound 4c caused a concentration- and time-dependent PARP clevage, confirming its pro-apoptotic properties. Graphical abstract [DISPLAY OMISSION]

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