- Antitumor agents 187: Synthesis and cytotoxicity of substituted 8,8- dimethyl-2H,8H-pyrano[6,5-h]quinoline-2-one and related compounds
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Several substituted 8,8-dimethyl-2H,8H-pyrano[6,5-h]quinoline-2-ones and related compounds were synthesized and evaluated for their in vitro cytotoxicity against a panel of human tumor cell lines. The most active compound (3) showed significant cytotoxic activity with GI50 values in the micromolar range.
- Yang, Zheng-Yu,Xia, Yi,Xia, Peng,Tachibana, Yoko,Bastow, Kenneth F.,Lee, Kuo-Hsiung
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- Structure-Based Identification of Inhibitory Fragments Targeting the p300/CBP-Associated Factor Bromodomain
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The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors.
- Chaikuad, Apirat,Lang, Steffen,Brennan, Paul E.,Temperini, Claudia,Fedorov, Oleg,Hollander, Johan,Nachane, Ruta,Abell, Chris,Müller, Susanne,Siegal, Gregg,Knapp, Stefan
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- Synthesis and bioactivity of 4,10-dimethyl-pyridino[2,3-h]quinolin-2(1H)-one-9-carboxylic acid and its esters
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4,10-Dimethyl-pyridino[2,3-h]quinolin-2(1H)-one-9-carboxylic acid (1) was synthesized by a new approach via the key intermediate 7-[1-aza-2-(dimethylamino)vinyl]-4-methylquinolin-2(1H)-one (4). Compound 1 and its esters were evaluated in cytotoxicity and anti_HIV assays. The 9-carboxyl (1s)-endo-(-)-borneol ester (9) showed marginal cytotoxic activity in CAK1-1, HOS, KB, and HCT-8 cells.
- Zhang, Qian,Chen, Ying,Zheng, Yun Qing,Xia, Peng,Xia, Yi,Yang, Zheng Yu,Bastow, Kenneth F.,Morris-Natschke, Susan L.,Lee, Kuo-Hsiung
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- In-silico design, synthesis and evaluation of novel DNA-gyrase B inhibitors
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2-Quinolones are an important class of compounds, isomeric to 4-quinolones. They may become promising candidates for exploiting more useful therapeutically active molecules. DNA-gyrase has drawn much attention as a selected target for finding potent anti-bacterial agents against multi-drug resistant strains such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococci pneumonia. The objective of the present study was to study the molecular docking simulations on 2-quinolone analogs as probable candidates for inhibiting DNA gyrase subunit-B of S. aureus. In the present study, docking simulations were carried out on the reported inhibitors of DNA-gyrase subunit A and B using docking software. Based on it, series of 2-quinolone analogs (compound 1-8) were designed, synthesized, characterized, and evaluated for their anti-bacterial activity against S. aureus and E. coli. Out of the eight test compounds, compound-2 showed good anti-bacterial activity against S. aureus and E. coli as compared with the rest of the other compounds. The rational approach to lead discovery has prompted a better insight into developing more specific 2-quinolones as potential antibacterial agents.
- Shiroya, Umesh,Patel, Milan
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- Fluorescent retinoid X receptor ligands for fluorescence polarization assay
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Retinoid X receptor (RXR) agonists are candidate agents for the treatment of metabolic syndrome and type 2 diabetes via activation of peroxisome proliferator-activated receptor (PPAR)/RXR or liver X receptor (LXR)/RXR-heterodimers, which control lipid and glucose metabolism. Reporter gene assays or binding assays with radiolabeled compounds are available for RXR ligand screening, but are unsuitable for high-throughput screening. Therefore, as a first step towards stabilizing a fluorescence polarization (FP) assay system for high-throughput RXR ligand screening, we synthesized fluorescent RXR ligands by modification of the lipophilic domain of RXR ligands with a carbostyril fluorophore, and selected the fluorescent RXR agonist 6-[ethyl(1-isobutyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-7-yl)amino] nicotinic acid 8d for further characterization. Compound 8d showed FP in the presence of RXR and the FP was decreased in the presence of the RXR agonist LGD1069 (2). This compound should be a lead compound for use in high-throughput assay systems for screening RXR ligands.
- Yamada, Shoya,Ohsawa, Fuminori,Fujii, Shuji,Shinozaki, Ryosuke,Makishima, Makoto,Naitou, Hirotaka,Enomoto, Shuichi,Tai, Akihiro,Kakuta, Hiroki
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- Synthesis and biological evaluation of quinolone derivatives as transthyretin amyloidogenesis inhibitors and fluorescence sensors
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Under certain conditions, numerous soluble proteins possess an inherent tendency to convert into insoluble amyloid aggregates, which are associated with several sporadic and genetic human diseases. Transthyretin (TTR) is one of the more than 30 human amyloidogenic proteins involved in conditions such as senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Considerable effort has been focused on identifying the native tetrameric TTR stabilizers to inhibit rate-limiting tetramer dissociation and, consequently, ameliorate TTR amyloidogenesis. Here, we describe the design and synthesis of quinolin-2(1H)-one derivatives that could be structurally complementary to the thyroxine-binding site within tetrameric TTR. Among these quinolin-2(1H)-one derivatives, compound 7a allowed 16.7% of V30M-TTR (3.6 μM) fibril formation at the same concentration and 49.6% at a concentration of 1.8 μM. Compound 7a exhibited much greater potency in complex biological samples like human plasma than that observed with tafamidis, the drug approved for the treatment of TTR amyloid cardiomyopathy for wild-type or hereditary TTR-mediated amyloidosis. Furthermore, the unique spectral properties of compound 7a demonstrated its high potential for TTR quantification, imaging sensors, and fluorescent tools to study the mechanism of TTR amyloidogenesis.
- Reum Han, Ah,Hee Jeon, Eun,Woo Kim, Kun,Ki Lee, Seul,Ohn, Chan-yeong,Jean Park, Sung,Sook Kang, Nam,Koo, Tae-Sung,Bum Hong, Ki,Choi, Sungwook
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- Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease
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A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 μM for eeAChE; IC50 = 0.16 μM for hAChE), and it was also the best inhibitor to AChE-induced Aβ aggregation (29.02% at 100 μM) and an efficient inhibitor to self-induced Aβ aggregation (30.67% at 25 μM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po).
- Fu, Jie,Bao, Fengqi,Gu, Min,Liu, Jing,Zhang, Zhipeng,Ding, Jiaoli,Xie, Sai-Sai,Ding, Jinsong
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p. 118 - 128
(2019/11/16)
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- METAL CHELATORS FOR IMAGING, THERAPEUTICS, AND BIOANALYSIS
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A variety of compounds are provided capable of chelating a metal, in particular a lanthanide such as Eu(III) and Tb(III). Luminescent complexes of the compound and a metal ion are also provided, in particular luminescent metal complexes are provided containing a lanthanide such as Eu(III) or Tb(III) and a compound described herein. In some aspects, the luminescent complexes are capable of exhibiting bright emissions with high quantum yields. Methods of making the compound are provided. Methods of using the compounds and luminescent complexes are also provided, for example for imaging and therapeutic applications.
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Paragraph 0145; 0148
(2018/09/26)
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- Synthesis and anticancer activity evaluation of novel derivatives of 7-amino-4-methylquinolin-2(1H)-one
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In this study, we designed and synthesized sixteen new derivatives of 7-amino-4-methylquinolin- 2(1H)-one with potential anticancer activity. The structures of synthesized compounds were confirmed by 1H and 13C NMR. The activity of novel substances was evaluated by cell viability assay and wound healing assay. In vitro tests for series of sixteen novel compounds were performed. The results showed that examined compounds are selective for a cancer cells, but their activity for various types of cancer is different. Three of the new compounds presented the ability to inhibit cells migration. The novel compounds constitute a good starting point for further studies and optimization of structure for new therapeutically effective anti-cancerous drugs. Seven compounds, which showed the highest rate of cell inhibition, were selected for further studies.
- Kubica, Krzysztof P.,Taciak, Przemyslaw P.,Czajkowska, Agnieszka,Sztokfisz-Ignasiak, Alicja,Wyrebiak, Rafal,Mlynarczuk-Bialy, Izabela,Malejczyk, Jacek,Mazurek, Aleksander P.
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p. 903 - 910
(2018/09/22)
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- Gold-Catalyzed Hydroarylation of N-Aryl Alkynamides for the Synthesis of 2-Quinolinones
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A mild method for the synthesis of 2-quinolinones via hydroarylation of N-aryl alkynamides is reported. While traditional methods have relied on the use of strong Br?nsted or Lewis acids, this report describes the development of mild reaction conditions that yield 2-quinolinones in good to excellent yield using a commercially available gold catalyst. Substrates bearing a variety of functional groups are presented, with N-substitution proving to be key to the reactivity of several substrates.
- Vacala, Taylor,Bejcek, Lauren P.,Williams, Chloé G.,Williamson, Alexandra C.,Vadola, Paul A.
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p. 2558 - 2569
(2017/03/14)
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- Brightly Luminescent and Kinetically Inert Lanthanide Bioprobes Based on Linear and Preorganized Chelators
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The synthesis, photophysical properties, and kinetic stability of a series of water-soluble, highly emissive Tb(III) and Eu(III) complexes featuring triethylenetetraamine hexaacetic acid (TTHA) and cyclohexyl triethylenetetraamine hexaacetic acid (cyTTHA) chelator scaffolds and carbostyril sensitizers are reported. The unique and modular design of the chelators gives rise to striking quantum yields of emission in aqueous solutions (up to 54%) as well as the characteristic lanthanides' photophysical properties (long excited-state lifetimes, large effective Stokes shifts, and narrow emission peaks). Furthermore, the preorganized chelators (L3, L4, and L6) bind metal within minutes at ambient temperature yet exhibit substantial resistance to transchelation in the presence of a challenge solution (EDTA, 1 mM). Moreover, the Eu(III) complex of L4 remains stably luminescent in HeLa cells over hours, demonstrating the suitability of these compounds for live-cell imaging applications. Representative chelators suitable for derivatization and protein bioconjugation were also prepared that were functionalized with clickable azide and alkyne moieties, biotin, and trimethoprim (TMP). With exceptional long-wavelength brightness, enhanced kinetic inertness, and an adaptable synthetic route, the reported lanthanide complexes are promising probes and labels for time-gated bioanalysis, biosensing, and optical microscopy.
- Mohamadi, Ali,Miller, Lawrence W.
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p. 2540 - 2548
(2016/11/02)
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- Synthesis of osthole derivatives with grignard reagents and their larvicidal activities on mosquitoes
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The structure of osthole has been modified to improve its larvicidal activity against mosquitoes. A new efficient synthesis of osthole derivatives with Grignard reagents has been developed, which employs CuI and LiCl as promoters and covers a broad range of substrates to afford the corresponding products in mild to good yields (up to 83%). Bio-activity evaluation showed that several products exhibited better activities than osthole. CuI and LiCl promoted efficient synthesis of osthole derivatives with Grignard reagents has been developed. Bio-activity evaluation showed that several products exhibited far better larvicidal activities against mosquitoes than osthole.
- Liu, Ming,Liu, Yang,Hua, Xuewen,Wu, Changchun,Zhou, Sha,Wang, Baolei,Li, Zhengming
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supporting information
p. 1353 - 1358
(2016/02/18)
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- Novel quinolone substituted thiazolidin-4-ones as anti-inflammatory, anticancer agents: Design, synthesis and biological screening
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Nuclear factor-kappaB (NF-κB) has been reported to regulate various genes involved in cancer and inflammation. Accordingly, drugs suppressing or inhibiting NF-κB may possess both anti-inflammatory and anticancer properties. A library of quinolone substituted thiazolidin-4-ones was docked into the active site of NF-κB and the top-ranked 31 compounds were synthesized and evaluated for anti-inflammatory and anticancer activity. The best-ranked compound 6b showed highest anti-inflammatory activity in carrageenan-induced paw edema model. In vitro anticancer studies revealed 1a and 16a as most active compounds against BT-549, HeLa, COLO-205 and ACHN human cancer cell lines. Compounds 1a and 16a exhibited NF-κB dependent anticancer properties and apoptosis mediated cell death. In vivo Ehrlich ascites carcinoma study further confirmed the antitumor activity of 1a and 16a.
- Suthar, Sharad Kumar,Jaiswal, Varun,Lohan, Sandeep,Bansal, Sumit,Chaudhary, Anil,Tiwari, Amit,Alex, Angel Treasa,Joseph, Alex
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p. 589 - 602
(2013/07/25)
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- Substrate specificity of acetoxy derivatives of coumarins and quinolones towards Calreticulin mediated transacetylation: Investigations on antiplatelet function
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Calreticulin transacetylase (CRTAase) is known to catalyze the transfer of acetyl group from polyphenolic acetates (PA) to certain receptor proteins (RP), thus modulating their activity. Herein, we studied for the first time the substrate specificity of CRTAase towards N-acetylamino derivatives of coumarins and quinolones. This study is endowed with antiplatelet action by virtue of causing CRTAase catalyzed activation of platelet Nitric Oxide Synthase (NOS) by way of acetylation leading to the inhibition of ADP/Arachidonic acid (AA)-dependent platelet aggregation. Among all the N-acetylamino/acetoxy coumarins and quinolones screened, 7-N-acetylamino-4-methylcoumarin (7-AAMC, 17) was found to be the superior substrate to platelet CRTAase and emerged as the most promising antiplatelet agent both in vitro and in vivo. Further it caused the inhibition of cyclooxygenase-1 (Cox-1) resulting in the down regulation of thromboxane A2 (TxA2), modulation of tissue factor and the inhibition of platelet aggregation. It was also found effective in the inhibition of LPS induced pro-thrombotic conditions.
- Kathuria, Abha,Priya, Nivedita,Chand, Karam,Singh, Prabhjot,Gupta, Anjali,Jalal, Sarah,Gupta, Shilpi,Raj, Hanumantharao G.,Sharma, Sunil K.
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experimental part
p. 1624 - 1638
(2012/05/04)
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- Development of a dual functional luminescent sensor for zinc ion based on a peptidic architecture
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A synthetic peptide bearing a lanthanide complex, TbOTZ exhibits a decrease of chromophore fluorescence and a concomitant luminescence enhancement due to sensitized Tb3+ upon Zn2+ binding. Thus, TbOTZ can be a valuable tool for ratiometric sensing of Zn2+ as well as for time-resolved fluorescence detection with a single molecule.
- Hirayama, Tasuku,Taki, Masayasu,Akaoka, Kazushi,Yamamoto, Yukio
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supporting information
p. 7410 - 7413
(2013/02/23)
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- Synthesis, enzymatic evaluation, and docking studies of fluorogenic caspase 8 tetrapeptide substrates
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The synthesis, enzymatic evaluation, and molecular modeling studies of new fluorogenic tetrapeptide-based substrates selective for caspase 8, having the general structure Ac-IETD-AXX, are described. Various fluorescent reporter groups (AXX), i.e., 3- and 4-substituted coumarins and quinolin-2(1H)-ones were synthesized by von Pechmann condensation. They were subsequently coupled with the caspase-8-selective tetrapeptide Ac-IETD-OH under newly developed synthetic conditions to give the desired substrates in good yields and in high enantiomeric purity. Based on KM and Vmax values, the new compounds proved to be excellent substrates for recombinant human caspase 8. In contrast, the KM values for the same compounds as substrates for human caspase 3 were approximately 10-20-fold higher. Molecular modeling studies based on the X-ray crystal structures of both human caspases 3 and 8 revealed that there is sufficient room within both active sites to accommodate substrates with moderately bulky substituents in the 3- and 4-positions of the fluorogenic coumarins and quinolin-2(1H)-ones. Automated docking of the substrates into the active sites of both human caspases 3 and 8 with the program Auto-Dock 3 gave structures similar to the published crystallographic structures for the same tetrapeptide bound to caspase 8 in the form of an irreversible inhibitor. The calculated binding energies for the new substrates to either caspase 3 or 8 showed little difference between the substrates, consistent with the K M data. In addition, the calculated binding energies (ΔG) to caspase 8 were considerably more negative than those to caspase 3, also consistent with the KM data. A possible molecular interaction that might explain the selectivity of the IETD tetrapeptide motif for caspase 8 over caspase 3 is discussed.
- Reszka, Przemyslaw,Schulz, Riad,Methling, Karen,Lalk, Michael,Bednarski, Patrick J.
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experimental part
p. 103 - 117
(2010/11/02)
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- Design and synthesis of 2-quinolones as antioxidants and antimicrobials: A rational approach
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As an important class of compounds, 2-quinolones are isomeric to 4-quinolones and isosteric to coumarins. The compounds that have 2-quinolone moiety are associated with interesting biologic activities such as antibacterial, anticancer, antiviral, cardiotonic, and N-methyl-D-aspartate receptor inhibitor functions, among others. In the current study, based on the rational approach, lead molecules of the 2-quinolone skeleton were designed for binding to the bacterial DNA gyrase subunit A. Docking simulations and quantitative structure activity relationship (QSAR) analysis were performed using the Molegro Virtual Docker and Sarchitech softwares. Based on these studies, the 7-amino-4-methylquinolin-2(1H)-one parent compound and its carboxamides (JST 1-15) were synthesized using Conrad Limpach synthesis. The synthesized test compounds then were characterized by thin-layer chromatography and melting point determination, as well as by ultraviolet, infrared (IR), 1H-NMR, and MS studies. All synthesized and purified compounds were tested for antioxidant and antibacterial activity. Birkhaeuser Boston 2009.
- Jayashree,Thomas, Seeja,Nayak, Yogendra
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experimental part
p. 193 - 209
(2010/12/25)
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- Anticancer and antifungal activity of copper(II) complexes of quinolin-2(1H)-one-derived Schiff bases
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The condensation of substituted aromatic aldehydes with 7-amino-4-methyl-quinolin-2(1H)-one (1) has lead to the isolation of quinolin-2(1H)-one derived Schiff bases (2-14). The copper(II) complexes (2a-14a) of the ligands were also prepared, and together with their corresponding free ligands were fully characterised by elemental analyses, spectral methods (IR, 1H and 13C NMR, AAS, UV-Vis), magnetic and conductance measurements. The bidentate ligands coordinated to the copper(II) ion through the deprotonated phenolic oxygen and the azomethine nitrogen of the ligands in almost all cases. X-ray crystal structures of two of the complexes, 5a and 8a, confirmed the bidentate coordination mode. All of the compounds were investigated for their antimicrobial activities against the fungus, Candida albicans, and against Gram-positive and Gram-negative bacteria. The compounds were found to have excellent anti-Candida activity but were inactive against Staphylococcus aureus and Escherichia coli. Selected compounds (2-8 and 2a-8a) were also screened for their in vitro anticancer potential using the human hepatic carcinoma cell line, Hep-G2. Several derivatives were shown to be active comparable to that of cisplatin.
- Creaven, Bernadette S.,Duff, Brian,Egan, Denise A.,Kavanagh, Kevin,Rosair, Georgina,Thangella, Venkat Reddy,Walsh, Maureen
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experimental part
p. 4048 - 4058
(2011/02/18)
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- Novel angular furoquinolinones bearing flexible chain as antitumor agent: Design, synthesis, cytotoxic evaluation, and DNA-binding studies
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A series of novel N-substituted angular furoquinolinone derivatives were synthesized and evaluated for their antitumor activities against QGY, K562, HeLa, P388, and A549 cell lines in vitro. The derivatives bearing basic amino side chain showed an improved antitumor activity. Compound 5h N-(2-dimethylamino-ethyl)-2-(4,8,9-trimethyl-2-oxo-2H-furo[2,3-h]quinolin-1-yl)-acetamide exhibited the highest activities against P388 and A549 cell lines, which are evidenced by the IC50 values that are four to five fold lower than that for unsubstituted parent compound. DNA-binding experiments suggested that these derivatives bind to DNA through intercalation.
- Xie, Lijuan,Qian, Xuhong,Cui, Jingnan,Xiao, Yi,Wang, Kewei,Wu, Peichun,Cong, Liying
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p. 8713 - 8718
(2009/04/05)
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- Pyrrolo[2,3-h]quinolinones: A new ring system with potent photoantiproliferative activity
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A new class of compounds, the pyrrolo[2,3-h]quinolin-2-ones, nitrogen isosters of the angular furocoumarin Angelicin, was synthesized with the aim of obtaining new photochemotherapeutic agents with increased antiproliferative activity and lower undesired toxic effects than the lead compound. Two synthetic pathways were approached to allow the isolation both of the dihydroderivatives 10-17 and of the aromatic ring system 23. Compounds 10-17 showed a remarkable phototoxicity and a great UVA dose dependence reaching IC50 values at submicromolar level. Intracellular localization of these compounds has been evaluated by means of fluorescence microscopy using tetramethylrhodamine methyl ester and acridine orange, which are specific fluorescent probes for mitochondria and lysosomes, respectively. A weak co-staining was observed with mitochondrial stain, whereas a specific localization in lysosomes was observed. Studies directed to elucidate the mode of action of this series of compounds revealed that they do not intercalate with DNA and do not induce photodamage to the macromolecule. On the contrary, they induce significative photodamage to lipids and proteins.
- Barraja, Paola,Diana, Patrizia,Montalbano, Alessandra,Dattolo, Gaetano,Cirrincione, Girolamo,Viola, Giampietro,Vedaldi, Daniela,Dall'Acqua, Francesco
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p. 8712 - 8728
(2008/02/09)
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- Terbium binding in highly luminescent polymer complexes
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Polymer ligands containing a covalently bonded quinolinone fluorophore and COOH (L1) or COONa (L2) binding sites were synthesized by the reaction of high-molecular-weight poly[styrene-alt-(maleic anhydride)] with 7-amino-4-methylquinolin-2(1H)-one and methanol and subsequent neutralization. The ligand-to-metal energy transfer and ligand binding properties in a series of [Tb(III)-ligand] complexes were investigated by steady-state and time-resolved luminescence spectroscopy in methanol or deuterated methanol. The intensity of the long-lived terbium(III) ion emission at 490, 545, 585 and 620 nm was greatly enhanced upon addition of L1 or L2. Based on the differences in luminescence data obtained for [Tb(III)-L1] and [Tb(III)-L2] complexes, a qualitative model for the interaction of terbium(III) ion with L1 and L2 is put forward. The experimental luminescence decay curves were double-exponential (τ1, τ2) with predominating longer component (rel B1 > 85%) for both [Tb(III)-L1] and [Tb(III)-L2] complexes. About 2.5 or 2 methanol molecules were coordinated to Tb3+ in [Tb(III)-L1] or [Tb(III)-L2] complexes, respectively, whereas ca. 6.5 methanol molecules were coordinated to Tb3+ in methanol.
- Kukla, Stanislav,Cimrova, Vera,Vyprachticky, Drahomir
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p. 1333 - 1349
(2008/09/16)
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- A concise regiospecific synthesis of 8,8-dimethyl-2H, 8H-pyrano [6, 5- h]quinolin-2-one and related compounds
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An efficient method for the regiospecific synthesis of 8,8-dimethyl- 2H,8H-pyrano[6,5-h]quinolin-2-one and related compounds via a Claisen rearrangement is described.
- Yang, Zheng-Yu,Xia, Yi,Xia, Peng,Brossi, Arnold,Lee, Kuo-Hsiung
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p. 4505 - 4506
(2007/10/03)
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- Fluorogenic Substrates Containing 7-Amino-4-methyl-2-quinolinone for Aminopeptidase M, Chymotrypsin, Elastase and Trypsin, Determination of Enzyme Activity
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Several new fluorogenic substrates for four proteases were synthesized by coupling the highly fluorescent 7-amino-4-methyl-2-quinolinone (AMeq) with appropriate amino acids and peptides.Compounds HCl*H-Ala-NH-Meq (1) and HCl*H-Leu-NH-Meq (2) are substrates for aminopeptidase M, Glt-Tyr-NH-Meq (3) and Glt-Leu-Tyr-NH-Meq (4) for chymotrypsin, Boc-(Ala)4-NH-Meq (5) for elastase and Z-Arg-NH-Meq (6) for trypsin.The kinetic parameters for the hydrolysis of the new substrates were determined and showed that each new substrate is suitable for a convenient fluorometric assay of the corresponding enzyme. - Key Words: 2-Quinolinone, 7-amino-4-methyl- / Fluorogenic substrates / Aminopeptidase M / Chymotrypsin / Elastase / Trypsin / Enzymes / Amino acids
- Tzougraki, Chryssa,Noula, Catherine,Geiger, Reinhard,Kokotos, George
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p. 365 - 368
(2007/10/02)
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- NEW FLUOROGENIC SUBSTRATES FOR THE DETERMINATION OF POST-PROLINE ENDOPEPTIDASE ACTIVITY
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A new fluorogenic substrate for determination of the activity of post-proline endopeptidase (EC 3.4.21.26), Z-Cys(Bzl)-Pro-NH-Meq* has been synthesized.Affinity of this substrate to the enzyme was significantly higher than that of the hitherto employed substrates.The Michaelis constant of the post-proline endopeptidase for Z-Cys(Bzl)-Pro-NH-Meq was at the optimum pH (7.0)1.05 . 10-6 moll-1.The concentration of dimethylsulfoxide used for the solubilization of Z-Cys-(Bzl)-Pro-NH-Meq (m = 10.35 10-6 moll-1 at pH 7.0).
- Tzougraki, Chryssa,Kokotos, George,Maskova, Hana P.,Anzenbacherova, Eva,Barth, Tomislav
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p. 1112 - 1118
(2007/10/02)
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- SYNTHESIS AND USE OF AN AMINOQUINOLINONE DERIVATIVE FOR THE FLUOROMETRIC DETERMINATION OF OXYTOCINASE
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A new fluorogenic substrate for the determination of the activity of human serum oxytocinase-cystine aminopeptidase (EC 3.4.11.3), H-Cys(Bzl)-NH-Meq, has been synthesized.The affinity of H-Cys(Bzl)-NH-Meq to oxytocinase was by two orders higher than that of the usuallyemployed chromogenic substrates.The Michaelis constant of oxytocinase for this substrate was within the range of the optimium pH (7.0 - 7.5) 2.3E-6 moll-1, i.e. in the region of the affinity of the natural substrate, oxytocin.The concentration of dimethylsulfoxide used for the enzyme solubilizationof H-Cys(Bzl)-NH-Meq (0.4percent) did not influence adversely the course of the enzyme reaction as in the case of chromogenic substrates, where the concentration of the organic solvent exceeded 3percent
- Maskova, Hana P.,Kokotos, George,Tzougraki, Chryssa,Barth, Tomislav
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p. 2802 - 2808
(2007/10/02)
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- 7-Aminoquinolines. A novel class of agents active against herpesviruses
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A series of 7-aminoquinoline derivatives was synthesized and evaluated for their capacity to produce cytotoxicity in KB cells and to inhibit the replication of herpes simplex virus (HSV) type 1. All compounds tested inhibited the replication of HSV-1 with 50% inhibitory concentrations in the range of 2-50 μg/mL. The antiviral activity of many compounds, however, was separated from cytotoxicity to replicating uninfected cells by only two- to fivefold higher than those required for antiviral activity. Nonetheless, six compounds (10, 28, 29, 32, 34, and 36) were identified in which the separation was greater than fivefold. All compounds examined were more potent inhibitors of viral DNA synthesis than the cellular DNA synthesis.
- Nasr,Drach,Smith,Shipman Jr.,Burckhalter
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p. 1347 - 1351
(2007/10/02)
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