- Polyamine ligand-mediated self-assembly of gold and silver nanoparticles into chainlike structures in aqueous solution: Towards new nanostructured chemosensors
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1D Nanochain formation: The binding ability of a polyamine molecular linker (L)2- bearing different functional groups, which favors the self-assembling of silver (AgNPs) and gold nano-particles (AuNPs) into 1D nanochains in aqueous solution was explored. UV/Vis spectrophotometry and TEM were used to determine time-dependent structural changes associated with these 1D structure formations. Sensing of Hg2+ using AgNPs@ (L) 2- and AuNPs@ (L)2- assemblies was also carried out in aqueous solution.
- Fernandez-Lodeiro, Adrian,Fernandez-Lodeiro, Javier,Nunez, Cristina,Bastida, Rufina,Capelo, Jose Luis,Lodeiro, Carlos
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- Selective imaging of damaged bone structure (microcracks) using a targeting supramolecular Eu(III) complex as a lanthanide luminescent contrast agent
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(Chemical Equation Presented) The synthesis and photophysical evaluation of a new supramolecular lanthanide complex is described which was developed as a luminescent contrast agent for bone structure analysis. We show that the Eu(III) emission of this complex is not pH dependent within the physiological pH range and its steady state emission is not significantly modulated by a series of group I and II as well as D-metal ions and that this agent can be successfully employed to image mechanically formed cracks (scratches) in bone samples after 4 or 24 h, using confocal laser-scanning microscopy.
- McMahon, Brian,Mauer, Peter,McCoy, Colin P.,Lee, T. Clive,Gunnlaugsson, Thorfinnur
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- Luminescent sensing of dicarboxylates in water by a bismacrocyclic dinuclear Eu(III) conjugate
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The design, synthesis, and characterization of a novel dinuclear Eu(III) bismacrocyclic conjugate 1·Eu2 as a delayed luminescent lanthanide sensor for dicarboxylates is discussed. The sensor was shown to bind small dicarboxylic acids such as aspartic, malonic, succinic, or glutaric acid in pH 6.5 solutions. However, only malonic acid gave rise to selective Eu(III) luminescent enhancements, as the emission was reduced for all of the other acids.
- Plush, Sally E.,Gunnlaugsson, Thorfinnur
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- Zinc selective chemosensors based on the flexible dipicolylamine and quinoline
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Zinc sensor molecules containing quinoline have been synthesized, which show fluorescence in the presence of Zn2+. The nitrogen in quinoline is critical to fluorescence and fluorescence enhancement is promoted by deprotonating the sensor's amide. One of the sensors is highly selective for Zn2+ over Cd2+ and other cations such as Hg2+, Fe2+, Mn2+ and Ca2+. This selectivity can be attributed to the increased absorption of the sensor in the presence of Zn 2+ and the strong binding of Zn2+. Structural studies, including X-ray and NMR, show the ability of dipicolylamine (DPA) to bind in facial and meridional manners to Zn2+. Crystal structures of different compounds show Zn2+ coordinating to three, four, and five nitrogens from the compounds. They also indicate that the selectivity of DPA containing compounds towards Zn2+ may originate from Zn2+ being stable in different coordination environments.
- Lee, Hong Gyu,Lee, Ju Hoon,Jang, Seung Pyo,Hwang, In Hong,Kim, Sung-Jin,Kim, Youngmee,Kim, Cheal,Harrison, Roger G.
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- Naphthalene appended 2,5-diketopiperazine towards fluorometric response of dihydrogenphosphate
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Naphthalene-based 2,5-diketopiperazine 1 has been synthesized in two steps with moderate yield. The compound shows water templated hydrogen bonded assemblies in the solid state and exhibits unique hydrogen bond mediated emission properties in solution. The monomer emission of 1 in CHCl3 containing 0.1% DMSO is significantly quenched in the presence of large excess of dihydrogenphosphate anion and aliphatic dicarboxylic acids of different chain lengths followed by the appearance of a new peak of moderate intensity at higher wavelength for excimer. The appearance of excimer emission of moderate intensity in presence of H2PO4- distinguishes it from other guests in the present study.
- Ghosh, Kumaresh,Sen, Tanushree
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- Unravelling the anticancer potency of 1,2,4-triazole-N-arylamide hybrids through inhibition of STAT3: synthesis and in silico mechanistic studies
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Abstract: The discovery of potent STAT3 inhibitors has gained noteworthy impetus in the last decade. In line with this trend, considering the proven biological importance of 1,2,4-triazoles, herein, we are reporting the design, synthesis, pharmacokinetic profiles, and in vitro anticancer activity of novel C3-linked 1,2,4-triazole-N-arylamide hybrids and their in silico proposed mechanism of action via inhibition of STAT3. The 1,2,4-triazole scaffold was selected as a privilege ring system that is embedded in core structures of a variety of anticancer drugs which are either in clinical use or still under clinical trials. The designed 1,2,4-triazole derivatives were synthesized by linking the triazole-thione moiety through amide hydrophilic linkers with diverse lipophilic fragments. In silico study to predict cytotoxicity of the new hybrids against different kinds of human cancer cell lines as well as the non-tumor cells was conducted. The multidrug-resistant human breast adenocarcinoma cells (MDA-MB-231) was found most susceptible to the cytotoxic effect of synthesized compounds and hence were selected to evaluate the in vitro anticancer activity. Four of the designed derivatives showed promising cytotoxicity effects against selected cancer cells, among which compound 12 showed the highest potency (IC50 = 3.61?μM), followed by 21 which displayed IC50 value of 3.93?μM. Also, compounds 14 and 23 revealed equipotent activity with the reference cytotoxic agent doxorubicin. To reinforce these observations, the obtained data of in vitro cytotoxicity have been validated in terms of ligand–protein interaction and new compounds were analyzed for ADMET properties to evaluate their potential to build up as good drug candidates. This study led us to identify two novel C3-linked 1,2,4-triazole-N-arylamide hybrids of interesting antiproliferative potentials as probable lead inhibitors of STAT3 with promising pharmacokinetic profiles. Graphic abstract: [Figure not available: see fulltext.]
- Turky, Abdallah,Bayoumi, Ashraf H.,Sherbiny, Farag F.,El-Adl, Khaled,Abulkhair, Hamada S.
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p. 403 - 420
(2020/08/25)
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- Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities
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Aiming to obtain an efficient anti-proliferative activity, structure- and ligand-based drug design approaches were expanded and utilized to design and refine a small compound library. Subsequently, thirty-two 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives were selected for synthesis based on the characteristic pharmacophoric features required for PI3K and B-Raf oncogenes inhibition. All the synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 17 and 22c displayed an acceptable potent activity according to the DTP-NCI and were further evaluated in the NCI five doses assay. To validate our design, compounds with the highest mean growth inhibition percent were screened against the target PI3Kα and B-RafV600E to confirm their multi-kinase activity. The tested compounds showed promising multi-kinase activity. Compounds 17 and 22c anticancer effectiveness and multi-kinase activity against PI3Kα and B-RafV600E were consolidated by the inhibition of B-RafWT, EGFR and VEGFR-2 with IC50 in the sub-micromolar range. Further investigations on the most potent compounds 17 and 22c were carried out by studying their safety on normal cell line, in silico profiling and predicted ADME characteristics.
- Abdel Gawad, Nagwa M.,El Kerdawy, Ahmed M.,George, Riham F.,Georgey, Hanan H.,Mohamed, Abdalla R.
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- Novel selective ido1 inhibitors with isoxazolo[5,4-d]pyrimidin-4(5h)-one scaffold
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Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target in immunomodulation of several pathological conditions, especially cancers. Here we present the synthesis of a series of IDO1 inhibitors with the novel isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold. A focused library was prepared using a 6-or 7-step synthetic procedure to allow a systematic investigation of the structure-activity relationships of the described scaffold. Chemistry-driven modifications lead us to the discovery of our best-in-class inhibitors possessing p-trifluoromethyl (23), p-cyclohexyl (32), or p-methoxycarbonyl (20, 39) substituted aniline moieties with IC50 values in the low micromolar range. In addition to hIDO1, compounds were tested for their inhibition of indoleamine 2,3-dioxygenase 2 and tryptophan dioxygenase, and found to be selective for hIDO1. Our results thus demon-strate a successful study on IDO1-selective isoxazolo[5,4-d]pyrimidin-4(5H)-one inhibitors, defining promising chemical probes with a novel scaffold for further development of potent small-molecule immunomodulators.
- ?vajger, Urban,Bratkovi?, Toma?,Dol?ak, Ana,Gobec, Stanislav,Mlinari?, Larisa,Ogorevc, Eva,Sova, Matej
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- Highly Potent and Selective Butyrylcholinesterase Inhibitors for Cognitive Improvement and Neuroprotection
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Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aβ deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aβ1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.
- Li, Qi,Chen, Ying,Xing, Shuaishuai,Liao, Qinghong,Xiong, Baichen,Wang, Yuanyuan,Lu, Weixuan,He, Siyu,Feng, Feng,Liu, Wenyuan,Chen, Yao,Sun, Haopeng
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p. 6856 - 6876
(2021/05/29)
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- Synthesis of New Thieno[2,3-d]pyrimidines Containing a 1,2,3-Triazole Ring and Their Therapeutic Response in NCI-60 Cell Line Panel
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Abstract: A series of new tetrahydro[1]benzothieno[2,3-d]pyrimidines containing a 1,2,3-triazole fragment linkedthrough an oxymethylene spacer have been synthesized by click reaction of4-(prop-2-yn-1-yloxy)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines with various aryl and alkyl azides inthe presence of copper sulfate and sodium ascorbate as a catalyst. Thestructures of the synthesized compounds were characterized by variousspectroscopic techniques (1H and13C NMR, FT-IR, and mass spectrometry), and theirin vitro anticancer activity against NCI-60 human tumor cell lines wasevaluated. Among the compounds tested, N-(pyridine-3-yl)-acetamide derivative exhibited significantactivity against several cancer cell lines, including SF-539 (CNS cancer),HCT-116 (colon cancer), OVCAR-8 (ovarian cancer), PC-3 (prostate cancer), andCCRF-CEM (leukemia).
- Baluja, S. H.,Bhensdadia, K. A.,Lalavani, N. H.
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p. 1668 - 1677
(2021/12/13)
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- Ultrasonic-Assisted Synthesis of Pyrazolo[3,4-d]pyrimidin-4-ol Tethered with 1,2,3-Triazoles and Their Anticancer Activity
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Abstract: In the presents work synthesis and characterization of new heterocyclic derivatives containing pyrazolo[3,4-d]pyrimidine linkage with 1,4-disubstituted-1,2,3-triazoles via methylene-oxy group. The selected synthesized compounds were tested for their in-vitro anticancer activity against various cancer cell lines. Synthesis of compounds was done under ultrasonic-assisted Huisgen 1,3-dipolar cycloaddition reaction with good yields. Some of the newly synthesized compounds demonstrated good to moderate anticancer activity, most of compounds shows activity against renal cancer cell lines.
- Bhatt, Tejal D.,Gojiya, Dinesh G.,Hadiyal, Sanjay D.,Joshi, Dr. Hitendra S.,Kapupara, Vimal H.,Prakash, L. Kalavadiya
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p. 803 - 813
(2020/10/29)
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- Novel chalcone and flavone derivatives as selective and dual inhibitors of the transport proteins ABCB1 and ABCG2
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During cancer chemotherapy, certain cancers may become cross-resistant to structurally diverse antineoplastic agents. This so-called multidrug resistance (MDR) is highly associated with the overexpression of ATP-binding cassette (ABC) transport proteins. These membrane-bound efflux pumps export a broad range of structurally diverse endo- and xenobiotics, including chemically unrelated anticancer agents. This translocation of drugs from the inside to the outside of cancer cells is mediated at the expense of ATP. In the last 40 years, three ABC transporters – ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP) – have mainly been attributed to the occurrence of MDR in cancer cells. One of the strategies to overcome MDR is to inhibit the efflux transporter function by small-molecule inhibitors. In this work, we investigated new chalcone- and flavone-based compounds for selective as well as broad-spectrum inhibition of the stated transport proteins. These include substituted chalcones with variations at rings A and B, and flavones with acetamido linker at position 3. The synthesized molecules were evaluated for their inhibitory potential against ABCB1, ABCC1, and ABCG2 in calcein AM and pheophorbide A assays. In further investigations with the most promising candidates from each class, we proved that ABCB1- and ABCG2-mediated MDR could be reversed by the compounds. Moreover, their intrinsic toxicity was found to be negligible in most cases. Altogether, our findings contribute to the understanding of ABC transport proteins and reveal new compounds for ongoing evaluation in the field of ABC transporter-mediated MDR.
- Silbermann, Katja,Shah, Chetan P.,Sahu, Niteshkumar U.,Juvale, Kapil,Stefan, Sven Marcel,Kharkar, Prashant S.,Wiese, Michael
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p. 193 - 213
(2019/01/03)
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- Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy
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Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G0/G1 phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells’ ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC50 values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC50 value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC50 of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G0/G1 and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
- Sonawane, Vinay,Mohd Siddique, Mohd Usman,Jadav, Surender Singh,Sinha, Barij Nayan,Jayaprakash, Venkatesan,Chaudhuri, Bhabatosh
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p. 115 - 132
(2019/01/23)
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- Design, synthesis, and biological evaluation of Helicobacter pylori inosine 5′-monophosphate dehydrogenase (HpIMPDH) inhibitors
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Inosine 5′-monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of guanine nucleotides. Being a validated target for immunosuppressive, antiviral, and anticancer drug development, lately it has been exploited as a promising target for antimicrobial therapy. Extending our previous work on Mycobacterium tuberculosis IMPDH, GuaB2, inhibitor development, we screened a set of 23 new chemical entities (NCEs) with substituted flavone (Series 1) and 1,2,3-triazole (Series 2) core structures for their in vitro Helicobacter pylori IMPDH (HpIMPDH) and human IMPDH2 (hIMPDH2) inhibitory activities. All the NCEs possessed acceptable molecular, physicochemical, and toxicity property profiles. The ranges for HpIMPDH and hIMPDH2 inhibition were 9–99.9% and 16–57%, respectively, at 10 μM concentration. The most potent HpIMPDH inhibitor, 25c, exhibited IC50 value of 1.27 μM with no hIMPDH2 inhibitory activity. The moderately potent, structurally novel hit molecule, 25c, may serve as a lead for further design and development of highly potent HpIMPDH inhibitors.
- Sahu, Niteshkumar U.,Purushothaman, Gayathri,Thiruvenkatam, Vijay,Kharkar, Prashant S.
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p. 125 - 132
(2018/11/06)
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- CYP enzymes, expressed within live human suspension cells, are superior to widely-used microsomal enzymes in identifying potent CYP1A1/CYP1B1 inhibitors: Identification of quinazolinones as CYP1A1/CYP1B1 inhibitors that efficiently reverse B[a]P toxicity and cisplatin resistance
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Microsomal cytochrome P450 (CYP) enzymes, isolated from recombinant bacterial/insect/yeast cells, are extensively used for drug metabolism studies. However, they may not always portray how a developmental drug would behave in human cells with intact intracellular transport mechanisms. This study emphasizes the usefulness of human HEK293 kidney cells, grown in ‘suspension’ for expression of CYPs, in finding potent CYP1A1/CYP1B1 inhibitors, as possible anticancer agents. With live cell-based assays, quinazolinones 9i/9b were found to be selective CYP1A1/CYP1B1 inhibitors with IC50 values of 30/21 nM, and > 150-fold selectivity over CYP2/3 enzymes, whereas they were far less active using commercially-available CYP1A1/CYP1B1 microsomal enzymes (IC50, >10/1.3–1.7 μM). Compound 9i prevented CYP1A1-mediated benzo[a]pyrene-toxicity in normal fibroblasts whereas 9b completely reversed cisplatin resistance in PC-3/prostate, COR-L23/lung, MIAPaCa-2/pancreatic and LS174T/colon cancer cells, underlining the human-cell-assays’ potential. Our results indicate that the most potent CYP1A1/CYP1B1 inhibitors would not have been identified if one had relied merely on microsomal enzymes.
- Sonawane, Vinay R.,Siddique, Mohd Usman Mohd,Gatchie, Linda,Williams, Ibidapo S.,Bharate, Sandip B.,Jayaprakash, Venkatesan,Sinha, Barij N.,Chaudhuri, Bhabatosh
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p. 177 - 194
(2019/02/27)
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- Identification and characterization of benzo[d]oxazol-2(3H)-one derivatives as the first potent and selective small-molecule inhibitors of chromodomain protein CDYL
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Chemical probes of epigenetic ‘readers’ of histone post-translational modifications (PTMs) have become powerful tools for mechanistic and functional studies of their target proteins in physiology and pathology. However, only limited ‘reader’ probes have been developed, which restricted our understanding towards these macromolecules and their roles in cells or animals. Here, we reported a structure-guided approach to develop and characterize benzo [d]oxazol-2(3H)-one analogs as the first potent and selective small-molecule inhibitors of chromodomain Y-like (CDYL), a histone methyllysine reader protein. The binding conformation between the chromodomain of CDYL and the modified peptidomimetics was studied via molecular docking and dynamic simulations, facilitating subsequent virtual screening of tens of hits from Specs chemical library validated by SPR technique (KD values: from 271.1 μM to 5.4 μM). Further design and synthesis of 43 compounds helped to interpret the structure-activity relationship (SAR) that lead to the discovery of novel small-molecule inhibitors of CDYL. Compound D03 (KD: 0.5 μM) was discovered and showed excellent selectivity among other chromodomain proteins, including CDYL2 (>140 folds), CDY1 (no observed binding) and CBX7 (>32 folds). Moreover, we demonstrated that D03 engaged with endogenous CDYL in a dose-dependent manner, and perturbed the recruitment of CDYL onto chromatin, resulting in transcriptional derepression of its target genes. Finally, the results showed that D03 promoted the development and branching of neurodendrites by inhibiting CDYL in hippocampal and cortical cultured neurons. This study not only discovers the first selective small-molecule inhibitors of CDYL, but provids a new chemical tool to intervene the dynamic nature of bio-macromolecules involved in epigenetic mechanism.
- Yang, Lixin,Liu, Yongqing,Fan, Minghua,Zhu, Guiwang,Jin, Hongwei,Liang, Jing,Liu, Zhenming,Huang, Zhuo,Zhang, Liangren
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- Synthesis and biological evaluation of novel N-aryl-ω-(benzoazol-2-yl)-sulfanylalkanamides as dual inhibitors of α-glucosidase and protein tyrosine phosphatase 1B
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α-Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B (PTP1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity.
- Wang, Mei-Yan,Cheng, Xian-Chao,Chen, Xiu-Bo,Li, Yu,Zang, Lan-Lan,Duan, Yu-Qing,Chen, Ming-Zhu,Yu, Peng,Sun, Hua,Wang, Run-Ling
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p. 1647 - 1656
(2018/09/10)
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- 1,3-dimethyl-7-substituted-quinazolinyl-2,4-diones, and synthesis method and application thereof
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The invention discloses 1,3-dimethyl-7-substituted-quinazolinyl-2,4-diones. The structural general formula of the compounds is disclosed in the specification, wherein R1 is hydrogen or ethyl; and R2 is a benzene ring, benzene ring derivative, heterocyclic ring or aliphatic hydrocarbon. Part of compounds have favorable inhibiting activities for Candida albicans, Aspergillus flavus, Torula histolytica and Aspergillus fumigatus. The compounds have obvious inhibiting activities for chitin synthetase, have favorable antibacterial effects, and can be used for preparing drugs for anti-pathogenic microorganisms.
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Paragraph 0056; 0057; 0058; 0059; 0060; 0093; 0094
(2017/07/31)
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- Isomeric chiral pyrrole diamides and their efficacy in enantioselective sensing of tartrate in sol–gel medium
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Pyridinium motif-based chiral pyrrole diamide clefts 1 and 2 have been designed and synthesized for chiral recognition of hydroxycarboxylates in sol–gel medium. Of the two isomeric chiral receptors, receptor 1 shows selective sensing of D-tetrabutylammonium tartrate over its mirror image isomer in CH3CN. The isomeric receptor 2 did not show any enantioselectivity in the recognition. Moreover, the receptor 1 validates prompt visual sensing of D-tartrate through gelation. The recognition properties of the receptors have been studied by fluorescence, UV–vis,1H NMR and CD spectroscopic methods.
- Ghosh, Kumaresh,Majumdar, Anupam
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supporting information
p. 3629 - 3634
(2016/07/21)
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- Synthesis and anti-leishmanial evaluation of 1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline derivatives against Leishmania infantum
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In the present study, antileishmanial activity of sixteen novel series of tetrahydro-β-carboline derivatives against transgenic infrared fluorescent Leishmania infantum strain has been reported. Among these reported analogues, most of the compounds exhibited potent inhibition against both promastigote (IC50from 1.99?±?1.40 to 20.69?±?0.95?μM) and amastigote (IC50from 0.67?±?0.05 to 4.16?±?0.008?μM) forms of L.?infantum. Moreover, compound 7l, displayed most potent and selective inhibition of parasite amastigote form with IC500.67?±?0.05?μM, selectivity index >298.5 and was comparable with standard drug amphotericin B. From this study, a new class of tetrahydro-β-carboline derivatives with potent antileishmanial activity was identified and it needs further extensive study to optimize the lead molecules to win the battle against severe and neglected disease leishmaniasis.
- Ashok, Penta,Chander, Subhash,Tejería, Ana,García-Calvo, Laura,Bala?a-Fouce, Rafael,Murugesan, Sankaranarayanan
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p. 814 - 821
(2016/08/23)
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- Chloroquinoline-acetamide hybrids: A promising series of potential antiprotozoal agents
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In an endeavour to develop efficacious antiprotozoal agents 2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]acetamide derivatives were synthesized and screened in vitro against the HM1:IMSS strain of E. histolytica and 3D7 strain of P. falciparum. Among the twenty-seven synthesized compounds, eleven evinced propitious anti-amoebic activity with IC50 values ranging from 0.41 to 1.80 μM) lower than the standard drug metronidazole (IC50 1.80 μM). All the compounds inhibited the in vitro growth of P. falciparum (IC50 range: 0.30-33.52 μM). Compounds A22 and A25 were found to be the most active antimalarial derivatives, and compound A16 the most active in inhibiting β-haematin formation; however compound A25 displayed the more favourable safety profile. The crystal structure for the compounds A7, A8, A12 and A21 was also determined. The molecular docking of crystal resolved inhibitors with PfDHFR allowed identification of stabilizing interactions within enzyme active sites. These compounds affirm the potential for further derivatives to enhance antiprotozoal activity whilst retaining their safety profile.
- Inam, Afreen,Van Zyl, Robyn L.,Van Vuuren, Natasha J.,Chen, Chien-Teng,Avecilla, Fernando,Agarwal, Subhash M.,Azam, Amir
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p. 48368 - 48381
(2015/06/16)
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- Novel aromatic-polyamine conjugates as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase
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Three types of aromatic-polyamine conjugates (6a-6s) were designed, synthesized and evaluated as potential inhibitors for cholinesterases (ChEs). The results showed that anthraquinone-polyamine conjugates (AQPCs) exhibited the most potent acetylcholinesterase (AChE) inhibitory activity with IC 50 values from 1.50 to 11.13 μM. Anthracene-polyamine conjugates (APCs) showed a surprising selectivity (from 76- to 3125-fold) and were most potent at inhibiting butyrylcholinesterase (BChE), with IC50 values from 0.016 to 0.657 μM. A Lineweaver-Burk plot and molecular modeling studies indicated that the representative compounds, 6l and 6k, targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of ChEs. Furthermore, APCs did not affect HepG2 cell viability at the concentration of 100 μM. Consequently, these polyamine conjugates could be thoroughly and systematically studied for the treatment of AD.
- Hong, Chen,Luo, Wen,Yao, Dong,Su, Ya-Bin,Zhang, Xin,Tian, Run-Guo,Wang, Chao-Jie
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p. 3213 - 3219
(2014/06/09)
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- A benzimidazolium-based new flexible cleft built on the piperazine unit: A case of selective fluorometric sensing of ATP
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A benzimidazole-based compound 1 built on the piperazine motif has been designed and synthesized. The chemosensor 1 is highly selective and sensitive towards ATP over ADP and AMP in CH3CN/H2O (1:1, v/v, using 10 mM HEPES buffer, pH 6.4) as evidenced by the significant change in emission. Furthermore, sensor 1 is cell permeable and can detect the presence of ATP in Human cervical cancer cells (HeLa). This journal is
- Ghosh, Kumaresh,Tarafdar, Debojyoti,Samadder, Asmita,Khuda-Bukhsh, Anisur Rahman
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p. 58530 - 58535
(2015/02/19)
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- Homologation of isocyanates with lithium carbenoids: A straightforward access to α-halomethyl- and α,α-dihalomethylamides
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Treatment of widely available isocyanates with monohalolithium and dihalolithium carbenoids provides a valuable protocol for the one-pot preparation of α-halo- and α,α-dihaloacetamide derivatives. While monohalolithium carbenoids can be prepared by a smoo
- Pace, Vittorio,Castoldi, Laura,Mamuye, Ashenafi Damtew,Holzer, Wolfgang
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p. 2897 - 2909
(2015/01/16)
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- Addition of lithium carbenoids to isocyanates: A direct access to synthetically useful N-substituted 2-haloacetamides
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The addition of lithium carbenoids to isocyanates provides a versatile access to N-substituted 2-haloacetamides: the reaction tolerates the presence of variously functionalized substituents on the nitrogen atom, including sterically demanding ones and reactive halogens. No erosion of the enantiopurity was observed in the case of optically active isocyanates. One of the substrates prepared has been employed in Charette's type chemoselective addition of a Grignard reagent to access an α-chloroketone.
- Pace, Vittorio,Castoldi, Laura,Holzer, Wolfgang
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supporting information
p. 8383 - 8385
(2013/09/23)
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- Triazoloamides as potent γ-secretase modulators with reduced hERG liability
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Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Aβ42 IC 50 in cell-based assays and reduced affinity for the hERG channel.
- Fischer, Christian,Zultanski, Susan L.,Zhou, Hua,Methot, Joey L.,Shah, Sanjiv,Nuthall, Hugh,Hughes, Bethany L.,Smotrov, Nadja,Hill, Armetta,Szewczak, Alexander A.,Moxham, Christopher M.,Bays, Nathan,Middleton, Richard E.,Munoz, Benito,Shearman, Mark S.
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scheme or table
p. 3140 - 3146
(2012/06/04)
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- Synthesis and biological evaluation of novel 5-benzylidenethiazolidine-2,4- dione derivatives for the treatment of inflammatory diseases
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Twenty-two compounds based on thiazolidine-2,4-dione moiety were synthesized and evaluated for the inhibitory potency on the production of nitric oxide (NO), inducible nitric oxide synthase (iNOS) activity, and the generation of prostaglandin E2 (PEG2). (Z)-N-(3-Chlorophenyl)-2-(4- ((2,4-dioxothiazolidin-5-ylidene) methyl) phenoxy) acetamide (3I), superior to the commercial anti-inflammatory drug indomethacin, significantly inhibited iNOS activity (IC50 = 8.66 μM), iNOS-mediated NO, and cyclooxygenase (COX)-2-derived PGE2 production (IC50 = 4.16 and 23.55 μM, respectively) on lipopolysaccharide (LPS)-induced RAW 264.7 cells. Docking study revealed that 3I was perfectly docking into the active site of murine iNOS and suppressed the expression of iNOS protein as evidenced by Western blot analysis. At the dose of 50 mg/kg, oral administration of 3I possessed protective properties in both carrageenan-induced paw edema and adjuvant-induced arthritis rat models.
- Ma, Liang,Xie, Caifeng,Ma, Yinghua,Liu, Juan,Xiang, Mingli,Ye, Xia,Zheng, Hao,Chen, Zhizhi,Xu, Qinyuan,Chen, Tao,Chen, Jinying,Yang, Jincheng,Qiu, Neng,Wang, Guangcheng,Liang, Xiaolin,Peng, Aihua,Yang, Shengyong,Wei, Yuquan,Chen, Lijuan
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supporting information; experimental part
p. 2060 - 2068
(2011/06/17)
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- Synthesis and biological activity of novel barbituric and thiobarbituric acid derivatives against non-alcoholic fatty liver disease
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Forty-four barbituric acid or thiobarbituric acid derivatives were synthesized and evaluated for their effects on adipogenesis of 3T3-L1 adipocytes by measuring the expression of adiponectin in vitro. Four compounds (3a, 3o, 3s, 4t) were found to increase the expression of adiponectin and lower the leptin level in 3T3-L1 adipocytes at respective concentration of 10 μM. Among them, 3s showed the most efficacious. Oral administration of 3s effectively reduced body weight, liver weight, and visceral fat and regulated serum levels of biochemical markers in the high-fat/diet-induced Wistar rats. Histopathological evaluation of liver sections by Oil Red O and H&E staining confirmed 3s as a potent, orally active molecule for reducing fat deposition against non-alcoholic fatty liver disease.
- Ma, Liang,Li, Shilin,Zheng, Hao,Chen, Jinying,Lin, Lin,Ye, Xia,Chen, Zhizhi,Xu, Qinyuan,Chen, Tao,Yang, Jincheng,Qiu, Neng,Wang, Guangcheng,Peng, Aihua,Ding, Yi,Wei, Yuquan,Chen, Lijuan
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experimental part
p. 2003 - 2010
(2011/06/25)
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- Synthesis of 2H-1,4-benzoxazin-3(4H)-ones via smiles rearrangement
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An efficient synthetic route for novel 2H-1,4-benzoxazin-3(4H)-ones via smiles rearrangement is developed. Reaction of primary amine and chloroacetyl chloride gave 2-chloroacetamide, which reacted with 2-chlorophenol, followed by Smiles rearrangement to o
- Zhou, Jia-Zhou,Li, Zhu-Bo,Yang, Hao,He, Xiao-Yan,Wang, Li-Ying,Tian, Xiao,Lv, Ting-Ting,Zuo, Hua
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experimental part
p. 2947 - 2950
(2012/01/05)
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- Efficient synthesis of piperazinediones using potassium iodide catalysis in aqueous media
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A simple and efficient synthetic approach to 1,4-disubstituted piperazine-2,5-diones was developed. A series of symmetrical 1,4-disubstituted piperazine-2,5-diones was prepared from chloroacetamides using potassium iodide catalysis in acetone/water. The structures of two products were confirmed by single crystal X-ray diffraction analysis.
- Wen, Yong-Hong,Chen, Xiao-Na,Wen, Hui-Ling,Tang, Xiao-Fang
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body text
p. 732 - 736
(2012/06/01)
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- The effect on the lanthanide luminescence of structurally simple Eu(III) cyclen complexes upon deprotonation of metal bound water molecules and amide based pendant arms
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A series of substituted 1,4,7,10-tetraazacylcododecane ligands 1-4, possessing sensitizing nitrobenzene or naphthalene antennae, as one of the amide pendant arms, and their complexes with europium(iii) were synthesised. The protonation constants and the metal ion stability constants of two of these ligands were determined by potentiometric titration. The pKa of the water molecules coordinated to the complexed metal ion were determined by both luminescent and potentiometric measurements. The luminescence pH dependence of a further three Eu(iii) complexes, 5-7, which lack any antennae, were also studied with the aim of gaining a better understanding of the role of the metal bound water molecules in the luminescence properties of such complexes upon direct excitation of the lanthanide ion. The results from these luminescent measurements demonstrate that the Eu(iii) emission was significantly modulated as a function of pH for all the complexes, which we assigned to changes occurring in the coordination environment of the ion within the cyclen system, caused by deprotonation of metal bound water molecules and/or deprotonation of pendent amide arms.
- Plush, Sally E.,Clear, Naomi A.,Leonard, Joseph P.,Fanning, Ann-Marie,Gunnlaugsson, Thorfinnur
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experimental part
p. 3644 - 3652
(2010/06/18)
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- Synthesis and antibacterial activity of carvacryl ethers
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Structural modifications of phenolic monoterpenoid obtained by reacting carvacrol with various substituted α-chloro acetanilides, to improve biological activities which give the product with better yield and higher purity under mild reaction conditions wi
- Patil, Jagdish U.,Suryawanshi, Kamalakar C.,Patil, Prakash B.,Chaudhary, Sanjay R.,Pawar, Nilesh S.
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scheme or table
p. 129 - 133
(2010/08/22)
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- Solution studies of trimetallic lanthanide luminescent anion sensors: Towards ratiometric sensing using an internal reference channel
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Luminescent europium and terbium complexes and a mixed Eu(iii)-Tb(iii) complex were prepared, each with three macrocycles coordinating to a single lanthanide ion to form a trimetallic system, and can be used for the ratiometric sensing of anions in the case of the mixed complex.
- Plush, Sally E.,Gunnlaugsson, Thorfinnur
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supporting information; experimental part
p. 3801 - 3804
(2009/02/03)
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- Solvent-free synthesis of 2-amino-3-aryl-5-substituted thiophenes as anti-inflammatory agents using KF-Al2O3 under microwave irradiation
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The synthesis of 2-amino-3-aryl-5-substituted thiophenes as anti-inflammatory agents catalyzed by KF-Al2O3 under microwave irradiation is reported. Copyright Taylor & Francis Group, LLC.
- Saeidian, Hamdollah,Sadeghi, Azam,Mirjafary, Zohreh,Moghaddam, Firouz Matloubi
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p. 2043 - 2053
(2008/09/21)
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- A novel synthesis of some 2-imino-4-thiazolidinone derivatives
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(Chemical Equation Presented) An efficient and simple route is presented to the synthesis of some iminothiazolidinone derivatives. α-Chloro amide derivatives undergo coupling reaction with isothiocyanate in the presence of a mild base, followed by nucleophilic substitution of chlorine by the sulfur atom of isothiocyanate.
- Moghaddam, Firouz Matloubi,Hojabri, Leila
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- Synthesis, characterizations and luminescent properties of three novel aryl amide type ligands and their lanthanide complexes
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Three new aryl amide type ligands, N-(phenyl)-2-(quinolin-8-yloxy)acetamide (L1), N-(benzyl)-2-(quinolin-8-yloxy)acetamide (L2) and N-(naphthalene-1-yl)-2-(quinolin-8-yloxy)acetamide (L3) were synthesized. With these ligands, three series of lanthanide(III) complexes were prepared: [Ln(L1)2(NO3)2]NO3, [Ln(L2)2(NO3)2(H2O)2]NO3·H2O and [Ln(L3)2(NO3)2(H2O)2]NO3·H2O (Ln = La, Sm, Eu, Gd). The complexes were characterized by the elemental analyses, molar conductivity, 1H NMR spectra, IR spectra and TG-DTA. The fluorescence properties of complexes in the solid state and the triplet state energies of the ligands were studied in detail, respectively. It was found that the Eu(III) complexes have bright red fluorescence in solid state. The energies of excited triplet state for the three ligands are 20 325 cm-1 (L3), 21 053 cm-1 (L2) and 22 831 cm-1 (L1), respectively. All the three ligands sensitize Eu(III) strongly and the order of the emission intensity for the Eu(III) complexes with the three ligands is L3 > L2 > L1. It can be explained by the relative energy gap between the lowest triplet energy level of the ligand (T) and 5D1 of Eu(III). This means that the triplet energy level of the ligand is the chief factor, which dominates Eu(III) complexes luminescence.
- Wu, Wei-Na,Yuan, Wen-Bing,Tang, Ning,Yang, Ru-Dong,Yan, Lan,Xu, Zi-Hua
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p. 912 - 918
(2007/10/03)
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- SUBSTITUTED HETEROCYCLIC COMPOUNDS
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Disclosed are novel heterocyclic derivatives, useful for the treatment of various disease states, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, and myocardial infarction. The compounds are also useful in the treatment of diabetes.
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- Syntheses of diazadithiacrown ethers containing appended coumarin or 1-aminonaphthalene sidearms
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Six crown ethers containing two coumarin (11, 13, 14, 16, 17 and 19) or two 1-aminonaphthalene (15 and 20) fragments as sidearms and two crown ethers bearing one coumarin (12 and 18) arm were synthesized by a nucleophilic substitution of the secondary macrocyclic amine function on the alkyl halide. The major products of these reactions were the diazadithiacrown ethers containing two sidearms. In some cases, one-armed diazadithiacrown ethers were separated as minor products, although more than 2.5 mmoles of alkyl halide were used for 1.0 mmole of macrocyclic diamine.
- Song, Hua-Can,Chen, Yi-Wen,Yao, Jun-Hua,Xu, Zun-Le,Bradshaw, Jerald S.,Savage, Paul B.,Izatt, Reed M.
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p. 475 - 479
(2007/10/03)
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- Triamine derivatives and their acid-addition salts
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A triamine derivative of the formula (I) ψψ ψwherein Ar1 and Ary are carbocyclic or heterocyclic single ring or fused ring aromatic groups, R1, Ry and R3 are hydrogen, lower alkyl, aryl aryl-alkyl, aryl-alkyloxycarbonyl, alkyloxycarbonyl or acyl, and A1 and Ay are lower alkylene groups optionally substituted by oxo, exhibits a high N-methyl-D-aspartic acid (NMDA) receptor antagonistic effect and are therefore useful as a medicine for nerve degeneration diseases.ψ
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- Synthesis of fluorescent probe - carbohydrate conjugates
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A new type of luminescent label has been synthesized and a range of carbohydrates has been derivatized with various fluorescent probes.Amine-containing labels were readily transformed with chloroacetylchloride into the corresponding fluorescent chloroacet
- Yalpani, Mansur,Hall, Laurence D.
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p. 2934 - 2939
(2007/10/02)
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