- Mechanism-based inactivation of cytochromes P450 2B1 and P450 2B6 by n- propylxanthate
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n-Propylxanthate (nPX) inactivated the 7-ethoxy-4- (trifluoromethyl)coumarin (7-EFC) O-deethylation activity of purified, reconstituted rat hepatic P450 2B1 or human P450 2B6 in a mechanism-based manner. The inactivation followed pseudo-first-order kinetics and was entirely dependent on both NADPH and nPX. The maximal rate constant for inactivation of P450 2B1 at 30 °C was 0.2 min-1. The apparent K(I) was 44 μM, and the half-time for inactivation was 4.1 min. Purified, reconstituted human P450 2B6 was also inactivated by nPX with a K(I) of 12 μM. The κ(inactivation) for P450 2B6 was 0.06 min-1, and the t(1/2) was 11 min. Incubations of P450 2B1 with nPX and NADPH for 20 min resulted in a 75% loss in enzymatic activity and a concurrent 25% loss of the enzyme's ability to form a reduced CO complex. Little loss in the absolute spectrum of nPX- inactivated P450 2B1 was observed. With P450 2B6, an 83% loss in enzymatic activity and a 12% loss in the CO-reduced spectra were observed. The extrapolated partition ratio for nPX with P450 2B1 was 32. P450 2B1 could be protected from inactivation by nPX by adding an alternate substrate to the reaction mixture. Removal of unbound nPX by dialysis did not reverse the inactivation. The alternate oxidant iodosobenzene was able to partially restore enzymatic activity to nPX-inactivated P450 2B1 samples. A stoichiometry for labeling of 1.2:1 for binding of radiolabeled nPX metabolite to P450 2B1 was seen. These results indicated that nPX inactivated P450 2B1 and P450 2B6 in a mechanism-based manner. P450 2B1 was inactivated primarily by a nPX reactive intermediate that bound to the apoprotein.
- Kent, Ute M.,Yanev, Stanislav,Hollenberg, Paul F.
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- Synthesis of amidoalkyl chromen-2-ones by one pot three component reaction under solvent free conditions
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A mild and efficient method for the functionalization of chromen-2-ones with amidoalkyl derivatives have been developed starting from 4-trifluoromethyl substituted chromen-2-ones, aromatic aldehydes and acetamide promoted by stannous chloride dihydrate in a one pot three component reaction under solvent free condition. Simple reaction conditions, high yields and environmentally benign procedure are the advantage of this protocol. This journal is the Partner Organisations 2014.
- Emmadi, Narender Reddy,Atmakur, Krishnaiah,Chennapuram, Madhu,Nanubolu, Jagadeesh Babu
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- Insight into the Mechanism of the Pechmann Condensation Reaction Using NMR
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The mechanism of the Pechmann condensation is still controversial despite the technological and biochemical importance of coumarins. Here, we present NMR evidence for a mechanism featuring the sequence of initial electrophilic aromatic substitution followed by transesterification and a final dehydration. This mechanism has been convincingly defined and supported by the temporal evolution of two key intermediates which could be purified and identified.
- Tyndall, Stephen,Wong, Koon Fai,Vanalstine-Parris, Melissa A.
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- Delivery of coumarin-containing all-: Trans retinoic acid derivatives via targeted nanoparticles encapsulating indocyanine green for chemo/photothermal/photodynamic therapy of breast cancer
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Development of chemo/photothermal/photodynamic therapy with nanoplatforms offers a promising strategy for effective cancer treatment. Recently, all-trans retinoic acid (ATRA), as a potential antitumor drug, has attracted great attention due to its antitumor activity. In this study, a novel coumarin-containing ATRA (AC) and indocyanine green (ICG) dye-loaded nanoparticles with the targeted ligand cyclic (Arg-Gly-Asp-d-Phe-Lys) (cRGD) peptide were fabricated by self-assembly and used as a new theranostic nanoplatform for chemo/photothermal/photodynamic therapy. The as-formed nanoparticles (AC/ICG-TNPs) had a diameter of around 133 nm with uniform monodispersity. Additionally, AC/ICG-TNPs showed marked stability under normal physiological conditions. However, it could rapidly release drugs in a mild acidic microenvironment. Moreover, confocal microscopic observations confirmed that the uptake of AC/ICG-TNPs increased in the breast cancer cells, particularly in MDA-MB-231 cells, probably mediated by cRGD via specific recognition of the overexpressed integrin αvβ3. Moreover, free AC exhibited stronger cytotoxic effects than free ATRA in the MTT assay, and AC/ICG-TNPs were demonstrated to possess excellent antitumor efficacy when exposed to NIR irradiation through the combination therapy. Hence, the therapeutic method designed in this study is a good candidate for improved bioactivity of ATRA and site-specific combinational therapy against breast cancer.
- Jiao, Jia,Wu, Hongshuai,Chen, Fanghui,Chen, Renjie,Sun, Baiwang,Wang, Mingliang
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- Functional expression and comparative characterization of four feline P450 cytochromes using fluorescent substrates
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1.?Cytochrome P450s (CYP) are a major group of metabolizing enzymes for xenobiotics in humans and other mammals. The properties of CYP isoforms in the domestic cat, an obligate carnivore, are largely unknown at present. In this study, we studied relative expression in tissues and enzymatic properties of nine significant feline CYP isoforms. 2.?CYP2E2 transcript was most abundant in the feline liver, followed by CYP2A13 and 2E1. Transcripts of CYP3A131, 1A2 and 1A1 were also present in the liver, while CYP2D6 and 3A132 were only slightly expressed. CYP3A131 was a major transcript in the small intestine. 3.?Four major CYP isoforms in the feline liver and small intestine (CYP1A2, CYP2A13, CYP2E2 and CYP3A131) were heterologously expressed in Escherichia coli to generate functional monooxygenase systems. We carried out screenings of 17 test compounds known to be inhibitors of CYP isoforms in other mammals as well as two anticancer drugs to assess the activity modulation of feline CYP isoforms using fluorogenic substrates. These CYP isoforms showed similar selectivity to counterparts in other mammals against inhibitors as a whole but with many exceptions. 4.?The present study suggests the usefulness of the feline CYP recombinant system to obtain chemical affinity information and possible drug interactions in CYP metabolism of domestic cats.
- Okamatsu, Gaku,Kawakami, Kei,Komatsu, Tetsuya,Kitazawa, Takio,Uno, Yasuhiro,Teraoka, Hiroki
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- Novel trifluoromethylcoumarinyl urea derivatives: Synthesis, characterization, fluorescence, and bioactivity
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A series of novel trifluoromethylcoumarinyl urea derivatives were designed, synthesized, and characterized by 1H-NMR, 13C-NMR, and HR-ESI-MS. The fluorescence spectra of the target compounds were recorded. The spectra show that most of the title compounds glow green with λmaxem of 500-517 nm, while compounds 5r, 5s, 5u, and 5l (compounds named by authors) glow violet with λmaxem of 381-443 nm. Moreover, the herbicidal and antifungal activities of the synthesized compounds were evaluated for their potential use as pesticides. The results indicate that compound 5f against the caulis of Amaranthus retroflexus and compounds 5j and 5l against the taproot of Digitaria sanguinalis are equivalent to the commercial herbicide Acetochlor. Nine of the title compounds are more antifungal than commercial fungicide Carbendazim against Botrytis cinerea.
- Qiao, Lili,Hao, Shuanghong
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- Metabolism of 7-benzyloxy-4-trifluoromethylcoumarin by human hepatic cytochrome P450 isoforms
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1. The metabolism of 7-benzyloxy-4-trifluoromethylcoumarin (BFC) to 7-hydroxy-4-trifluoromethylcoumarin (HFC) was studied in human liver microsomal preparations and in cDNA-expressed human cytochrome P450 (CYP) isoforms. 2. Kinetic analysis of the NADPH-dependent metabolism of BFC to HFC in four preparations of pooled human liver microsomes revealed mean (± SEM) K(m) and V(max) of 8.3 ± 1.3 μM and 454 ± 98 pmol/min/mg protein respectively. 3. The metabolism of BFC to HFC was determined in a characterized bank of 24 individual human liver microsomal preparations employing BFC substrate concentrations of 20 and 50 μM (i.e. about two and six times K(m) respectively). With 20 μM BFC the highest correlations were observed between BFC metabolism and markers of CYP1A2 (r2 = 0.784-0.797) and then with CYP3A (r2 = 0.434-0.547) isoforms, whereas with 50 μM BFC the highest correlations were observed between BFC metabolism and markers of CYP3A (r2= 0.679-0.837) and then with CYP1A2 (r2 = 0.421-0.427) isoforms. At both BFC substrate concentrations, lower correlations were observed between BFC metabolism and enzymatic markers for CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP4A9/11. 4. Using human β-lymphoblastoid cell microsomes containing cDNA-expressed CYP isoforms, 20 μM BFC was metabolized by CYP1A2 and CYP3A4, with lower rates of metabolism being observed with CYP2C9 and CYP2C19. Kinetic studies with the CYP1A2 and CYP3A4 preparations demonstrated a lower K(m) with the CYP1A2 preparation, but a higher V(max) with the CYP3A4 preparation. 5. The metabolism of 20 μM BFC in human liver microsomes was inhibited to 37-48 % of control by 5-100 μM of the mechanism-based CYP1A2 inhibitor furafylline and to 64-69 % of control by 5-100 μM of the mechanism-based CYP3A4 inhibitor troleandomycin. While some inhibition of BFC metabolism was observed in the presence of 100 and 200 μM diethyldithiocarbamate, the addition of 2-50 μM sulphaphenazole, 50-500 μM S-mephenytoin and 2-50 μM quinidine had little effect. 6. The metabolism of 20 μM BFC to HFC in human liver microsomes was also inhibited by an antibody to CYP3A4, whereas antibodies to CYP2C8/9 and CYP2D6 had no effect. 7. In summary, by correlation analysis, use of cDNA-expressed CYP isoforms, chemical inhibition and inhibitory antibodies, BFC appears metabolized by a number of CYP isoforms in human liver. BFC metabolism appears to be primarily catalysed by CYP1A2 and CYP3A4, with possibly some contribution by CYP2C9, CYP2C19 and perhaps other CYP isoforms. 8. The results also demonstrate the importance of the selection of an appropriate substrate concentration when conducting reaction phenotyping studies with human hepatic CYP isoforms.
- Renwick,Surry,Price,Lake,Evans
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- Development of a human lymphoblastoid cell line constitutively expressing human CYP1B1 cDNA: Substrate specificity with model substrates and promutagens
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An AHH-1 TK(+/-) cell derivative was developed that stably expresses human cytochrome P4501B1 (CYP1B1) cDNA in an extrachromosomal vector which confers resistance to 1-histidinol and co-expresses NADPH cytochrome P450 oxidoreductase (OR). The CYP1B1-expressing cell line was designated h1B1/OR. Microsomes prepared from CYP1B1 cDNA expressing cells exhibit elevated levels of 7-ethoxyresorufin deethylase (EROD), 7-ethoxy-4-trifluoromethylcoumarin deethylase (EFCD), benzo(a)pyrene hydroxylase (BPH), bufuralol 1'-hydroxylase, testosterone hydroxylase activities and spectrally quantifiable cytochrome P450. CYP1B1-containing microsomes did not contain detectable coumarin 7-hydroxylase, p-nitrophenol hydroxylase, lauric acid hydroxylase, (S)-mephenytoin 4'-hydroxylase or diclofenac 4'-hydroxylase activities. Kinetic parameters for selected substrates were compared among CYP1B1 and the two additional members of the CYP1 family, CYP1A1 and CYP1A2. For BPH and EFCD, the rank order of rates of substrate metabolism were CYP1A1 > CYP1B1 > CYP1A2. For EROD, the rank order of substrate metabolism was CYP1A1 > CYP1A2 > CYP1B1. For both EROD and EFCD the apparent K(m) values for CYP1B1 were more similar to CYP1A1 than to CYP1A2. In order to begin to characterize the promutagen activating ability of CYP1B1, the mutagenicity of selected chemicals was examined in h1B1/OR cells; there was increased sensitivity (CYP1B1-expressing relative to control cells) to the mutagenicity of benzo(a)pyrene, cyclopenta(c,d)pyrene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and aflatoxin B1 (AFB). CYP1B1, expressed in this system, appears to be particularly efficient at activating AFB.
- Crespi, Charles L.,Penman, Bruce W.,Steimel, Dorothy T.,Smith, Theresa,Yang, Chung S.,Sutter, Thomas R.
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- Scalable production and application of Pichia pastoris whole cell catalysts expressing human cytochrome P450 2C9
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Background: Currently, the numerous and versatile applications in pharmaceutical and chemical industry make the recombinant production of cytochrome P450 enzymes (CYPs) of great biotechnological interest. Accelerating the drug development process by simple, quick and scalable access of human drug metabolites is key for efficient and targeted drug development in response to new and sometimes unexpected medical challenges and needs. However, due its biochemical complexity, scalable human CYP (hCYP) production and their application in preparative biotransformations was still in its infancy. Results: A scalable bioprocess for fine-tuned co-expression of hCYP2C9 and its essential complementary human cytochrome P450 reductase (hCPR) in the yeast Pichia pastoris (Komagataella phaffii) is presented. High-throughput screening (HTS) of a transformant library employing a set of diverse bidirectional expression systems with different regulation patterns and a fluorimetric assay was used in order to fine-tune hCYP2C9 and hCPR co-expression, and to identify best expressing clonal variants. The bioprocess development for scalable and reliable whole cell biocatalyst production in bioreactors was carried out based on rational optimization criteria. Among the different alternatives studied, a glycerol carbon-limiting strategy at high μ showed highest production rates, while methanol co-addition together with a decrease of μ provided the best results in terms of product to biomass yield and whole cell activity. By implementing the mentioned strategies, up to threefold increases in terms of production rates and/or yield could be achieved in comparison with initial tests. Finally, the performance of the whole cell catalysts was demonstrated successfully in biotransformation using ibuprofen as substrate, demonstrating the expected high selectivity of the human enzyme catalyst for 3′hydroxyibuprofen. Conclusions: For the first time a scalable bioprocess for the production of hCYP2C9 whole cell catalysts was successfully designed and implemented in bioreactor cultures, and as well, further tested in a preparative-scale biotransformation of interest. The catalyst engineering procedure demonstrated the efficiency of the employment of a set of differently regulated bidirectional promoters to identify transformants with most effective membrane-bound hCYP/hCPR co-expression ratios and implies to become a model case for the generation of other P. pastoris based catalysts relying on co-expressed enzymes such as other P450 catalysts or enzymes relying on co-expressed enzymes for co-factor regeneration.
- Garrigós-Martínez, Javier,Weninger, Astrid,Montesinos-Seguí, José Luis,Schmid, Christian,Valero, Francisco,Rinnofner, Claudia,Glieder, Anton,Garcia-Ortega, Xavier
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- Revisiting the photophysical properties and excited singlet-state dipole moments of several coumarin derivatives
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The solvent effects on the electronic absorption and fluorescence emission spectra of several coumarins derivatives, containing amino, N,N-dimethyl-amino, N,N-diethyl-amino, hydroxyl, methyl, carboxyl, or halogen substituents at the positions 7, 4, or 3, were investigated in eight solvents with various polarities. The first excited singlet-state dipole moments of these coumarins were determined by various solvatochromic methods, using the theoretical ground-state dipole moments which were calculated by the AM1 method. The first excited singlet-state dipole moment values were obtained by the Bakhshiev, Kawski-Chamma-Viallet, Lippert-Mataga, and Reichardt-Dimroth equations, and were compared to the ground-state dipole moments. In all cases, the dipole moments were found to be higher in the excited singlet-state than in the ground state because of the different electron densities in both states. The red-shifts of the absorption and fluorescence emission bands, observed for most compounds upon increasing the solvent polarity, indicated that the electronic transitions were of π-π* nature.
- Cisse, Lamine,Djande, Abdoulaye,Capo-Chichi, Martine,Delatre, Franois,Saba, Adama,Tine, Alphonse,Aaron, Jean-Jacques
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- Metabolism of 2,5-bis(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin by human hepatic CYP isoforms: Evidence for selectivity towards CYP3A4
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1. The metabolism of 2,5-bis(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin (BFBFC) to 7-hydroxy-4-trifluoromethylcoumarin (HFC) was studied in human liver microsomes and in cDNA-expressed human liver CYP isoforms. For purposes of comparison, some limited studies were also performed with 7-benzyloxyquinoline (7BQ). 2. Initial interactive docking studies with a homology model of human CYP3A4 indicated that BFBFC was likely to be a selective substrate for CYP3A4 with a relatively high binding affinity, due to the presence of several key hydrogen bonds with active site amino acid residues. 3. Kinetic analysis of NADPH-dependent BFBFC metabolism to HFC in three preparations of pooled human liver microsomes revealed mean (±SEM) Km and Vmax = 4.6 ± 0.3 μM and 20.0 ± 3.8 pmol/min/mg protein, respectively. 4. The metabolism of BFBFC to HFC was determined in a characterized bank of 24 individual human liver microsomal preparations employing a BFBFC substrate concentration of 10 μM (i.e. around twice Km). Good correlations (r2 = 0.736-0.904) were observed between BFBFC metabolism and markers of CYP3A isoforms. 5. While 10 μM BFBFC was metabolized to HFC by cDNA-expressed CYP3A4, little or no metabolism was observed with cDNA-expressed CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. 6. The metabolism of 10 μM BFBFC in human liver microsomes was markedly inhibited by 5-50 μM troleandomycin and 0.2-5 μM ketoconazole, but stimulated by 0.2-10 μM α-naphthoflavone. The metabolism of 10 μM BFBFC in human liver microsomes was also markedly inhibited by an antibody to CYP3A4. 7. Kinetic analysis of NADPH-dependent 7BQ metabolism to 7-hydroxyquinoline (7HQ) in human liver microsomes revealed Km and Vmax = 70 μM and 3.39 nmol/min/mg protein, respectively. 8. While 80 μM 7BQ was metabolized to 7HQ by cDNA-expressed CYP3A4, only low rates of metabolism were observed with cDNA-expressed CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. 9. In summary, by correlation analysis, the use of cDNA-expressed CYP isoforms, chemical inhibition and inhibitory antibodies, BFBFC metabolism in human liver microsomes appears to be primarily catalysed by CYP3A4. BFBFC may be a useful fluorescent probe substrate for human hepatic CYP3A4, but compared with 7BQ has only a low rate of metabolism in human liver microsomes.
- Renwick,Lewis,Fulford,Surry,Williams,Worboys,Cai,Wang,Price,Lake,Evans
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- Computer-aided anticancer drug design: In vitro and in silico studies of new iminocoumarin derivative
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In this study, the aim was computer-aided design of a new anti-cancer drug molecule. For this purpose, 7-hydroxy-8-(((1-hydroxy-3-phenylpropan-2-yl)imino)methyl)-4-(trifluoromethyl)-2H-chromen-2-one (D3) was synthesized by the condensation reaction. Its characterization studies were performed by NMR, FTIR, MS and UV spectral data. Anti-cancer activity of D3 was examined on MCF-7, HeLa and Mat-Lylu cell lines, and it was found that D3 showed cytotoxic activity in all cell lines. Mutagenity of D3 was determined by Ames/Salmonella assay, and it was found that it had no mutagenic effect on S. typhimurium TA98 and TA100 strains. Antioxidant activity of D3 was also revealed. Besides, the interaction of D3 with DNA was investigated by the UV titration method. Experimental results showed D3 binds to DNA by intercalation or groove linking. Moreover, molecular docking approach was used to elucidate the atomic level interaction between the synthesized compound and DNA; thus, the atomic level behavior of the compound in the binding site of DNA was characterized and its binding properties were determined. In addition, the physicochemical and pharmacokinetic properties of the synthesized compound were performed using ADMET and frontier orbital analyses. In conclusion, according to both in vitro and in silico findings, it can be suggested that D3 may be used as a new anti-cancer drug for breast, cervical and prostate cancers.
- Kecel-Gunduz, Serda,Budama-Kilinc, Yasemin,Gok, Bahar,Bicak, Bilge,Akman, Gizem,Arvas, Busra,Aydogan, Feray,Yolacan, Cigdem
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- A double-triggered self-immolative spacer for increased selectivity of molecular release
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A self-immolative spacer based on dissymmetricalN,N′-bis-carbamate aniline is introduced to liberate a substrate from a precursor after dual activation. The proof of principle of its exclusive selectivity for substrate liberation has been conducted on a profluorophore.
- Huvelle, Steve,Le Saux, Thomas,Jullien, Ludovic,Schmidt, Frédéric
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p. 240 - 246
(2021/12/29)
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- Discovery of a Novel Androgen Receptor Antagonist Manifesting Evidence to Disrupt the Dimerization of the Ligand-Binding Domain via Attenuating the Hydrogen-Bonding Network between the Two Monomers
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Androgen receptor (AR) has proved to be a vital drug target for treating prostate cancer. Here, we reported the discovery of a novel AR antagonist 92 targeting the AR ligand-binding pocket, but distinct from the marketed drug enzalutamide (Enz), 92 demonstrated inhibition on the AR ligand-binding domain (LBD) dimerization, which is a novel mechanism reported for the first time. First, a novel hit (26, IC50 = 5.57 μM) was identified through virtual screening based on a theoretical AR LBD dimer bound with the Enz model. Then, guided by molecular modeling, 92 was discovered with 32.7-fold improved AR antagonistic activity (IC50 = 0.17 μM). Besides showing high bioactivity and safety, 92 can inhibit AR nuclear translocation. Furthermore, 92 inhibited the formation of the AR LBD dimer, possibly through attenuating the hydrogen-bonding network between the two monomers. This interesting finding would pave the way for the discovery of a new class of AR antagonists.
- Chai, Xin,Duan, Mojie,Fu, Weitao,Gong, Zhou,Hou, Tingjun,Lei, Yixuan,Li, Dan,Liao, Jianing,Pang, Jinping,Shan, Luhu,Sheng, Rong,Tang, Chun,Tang, Qing,Wang, Xuwen,Xu, Xiaohong,Zhang, Minkui
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p. 17221 - 17238
(2021/12/06)
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- Novel fluorinated 7-hydroxycoumarin derivatives containing an oxime ether moiety: Design, synthesis, crystal structure and biological evaluation
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A series of fluorinated 7-hydroxycoumarin derivatives containing an oxime ether moiety have been designed, synthesized and evaluated for their antifungal activity. All the target compounds were determined by1H-NMR,13C-NMR, FTIR and HR-MS spectra. The single-crystal structures of compounds 4e, 4h, 5h and 6c were further confirmed using X-ray diffraction. The antifungal activities against Botrytis cinerea (B. cinerea), Alternaria solani (A. solani), Gibberella zeae (G. zeae), Rhizoctorzia solani (R. solani), Colletotrichum orbiculare (C. orbiculare) and Alternaria alternata (A. alternata) were evaluated in vitro. The preliminary bioassays showed that some of the designed compounds displayed the promising antifungal activities against the above tested fungi. Strikingly, the target compounds 5f and 6h exhibited outstanding antifungal activity against B. cinerea at 100 μg/mL, with the corresponding inhibition rates reached 90.1 and 85.0%, which were better than the positive control Osthole (83.6%) and Azoxystrobin (46.5%). The compound 5f was identified as the promising fungicide candidate against B. cinerea with the EC50 values of 5.75 μg/mL, which was obviously better than Osthole (33.20 μg/mL) and Azoxystrobin (64.95 μg/mL). Meanwhile, the compound 5f showed remarkable antifungal activities against R. solani with the EC50 values of 28.96 μg/mL, which was better than Osthole (67.18 μg/mL) and equivalent to Azoxystrobin (21.34 μg/mL). The results provide a significant foundation for the search of novel fluorinated 7-hydroxycoumarin derivatives with good antifungal activity.
- Dai, Peng,Jiao, Jian,Wang, Qing-Qing,Zhang, Shu-Guang,Zhang, Wei-Hua
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- Benzopyrone or quinolinone compound and application thereof
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The invention discloses a benzopyrone or quinolinone compound and application thereof in preparation of a medicine for treating prostatic cancer, and belongs to the field of medicines. The benzopyroneand quinolinone compound with the structural formula as shown in the formula (I) has obvious antagonistic activity on androgen receptors and also has inhibitory activity on prostate cancer cells which do not express the androgen receptors. Therefore, the compound can be used as an androgen receptor antagonist to be applied to treatment of diseases related to androgen receptors or treatment of various metastatic prostate cancers, and a new choice is provided for development of drugs for treating prostate cancers.
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Paragraph 0058-0060; 0169-0170
(2020/08/25)
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- Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation
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A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068 μM and 0.0089 μM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 μM for hAChE; 0.101 μM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold.
- He, Qi,Liu, Jing,Lan, Jin-Shuai,Ding, Jiaoli,Sun, Yongbing,Fang, Yuanying,Jiang, Neng,Yang, Zunhua,Sun, Liyuan,Jin, Yi,Xie, Sai-Sai
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supporting information
p. 512 - 528
(2018/09/29)
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- 4-trifluoromethyl-7-hydroxycoumarin derivative as well as preparation method and application thereof
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The invention discloses a 4-trifluoromethyl-7-hydroxycoumarin derivative as well as a preparation method and application thereof. The yield of the preparation method is high. The invention also discloses application of the 4-trifluoromethyl-7-hydroxycoumarin derivative to an agricultural anti-fungal aspect. An inventor detects the toxicity effect on rice sheath blight disease, colletotrichum lagenarium, fusarium graminearum, strawberry botrytis cinerea, apple spot germs and alternaria solani by a growth rate method; certain lateral reactivity is realized on the 4-trifluoromethyl-7-hydroxycoumarin derivative; the activity of individual compounds is superior to that of contrast medicine; the effect of the compound in the aspect of inhibiting the rice sheath blight disease is prominent; or the compound can become a lead compound molecule for developing and creating new pesticide.
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Paragraph 0055-0062
(2018/03/01)
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- Design, synthesis, cytotoxicity and mechanism of novel dihydroartemisinin-coumarin hybrids as potential anti-cancer agents
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To develop novel agents with anticancer activities, thirty-four new dihydroartemisinin-coumarin hybrids were designed and synthesized in this study. Those compounds were identified that had great anticancer activity against two cancer cell lines (MDA-MB-231 and HT-29). The structure-activity relationships of the derivatives were also discussed, and the results of docking analysis had shown that carbonic anhydrases IX (CA IX) was very likely to be one of the drug targets of the hybrids. Meanwhile, to clarify the mechanism of the anticancer activity of the hybrids molecule, we did further exploration in the bioactivity of the hybrids. The results had shown that these derivatives obviously inhibited proliferation of HT-29 cell lines, arrested G0/G1 phase of HT-29 cells, suppressed the migration of tumor cells, and induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells. Interestingly, the hybrids also induced the other cell death pathway-ferroptosis.
- Yu, Haonan,Hou, Zhuang,Tian, Ye,Mou, Yanhua,Guo, Chun
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p. 434 - 449
(2018/04/14)
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- Coumarin-aryloxy carboxylic ester compound and application thereof in pesticide
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The invention provides a coumarin-aryloxy carboxylic ester compound and application thereof in pesticides. A preparation method comprises the following steps of 1, adding resorcinol containing different substituent groups into a reaction bottle containing concentrated sulfuric acid, stirring and dissolving, slowly dripping an acetacetic ester compound while being cooled by an ice-water bath, and reacting for 1h while cooling by the ice-water bath; reacting for 24h at room temperature; pouring into an ice and water mixture under intensely stirring, generating a yellow precipitate, sucking and filtering, and recrystallizing a filter cake by absolute ethyl alcohol, so as to obtain a 7-hydroxycoumarin compound; 2, dissolving 2,4-dichlorphenoxyacetic acid and oxalyl chloride into a CH2Cl2 (methylene chloride) solvent, dripping N,N-dimethylformamide, and reacting for 2h at room temperature, so as to obtain acyl chloride; 3, adding a catalyst into an organic solvent containing the 7-hydroxycoumarin compound and the acyl chloride at certain temperature, reacting for a period of time, and recrystallizing, so as to obtain the coumarin-aryloxy carboxylic ester compound. The coumarin-aryloxy carboxylic ester compound has higher weeding activity.
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Paragraph 0037; 0038; 0039
(2017/07/20)
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- Discovery of a butyrylcholinesterase-specific probe via a structure-based design strategy
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We report herein the structure-based design and application of a fluorogenic molecular probe (BChE-FP) specific to butyrylcholinesterase (BChE). This probe was rationally designed by mimicking the native substrate and optimized stepwise by manipulating the steric feature and the reactivity of the designed probe targeting the structural difference of the active pockets of BChE and AChE. The refined probe, BChE-FP, exhibits high specificity toward BChE compared to AChE, producing about 275-fold greater fluorescence enhancement upon the catalysis by BChE. Thus, BChE-FP is a specific BChE probe identified by the structure-based design and it can discriminate BChE from AChE. Furthermore, it has been successfully applied for imaging the endogenous BChE in living cells, as well as BChE inhibitor screening and characterization under physiological conditions.
- Yang, Shu-Hou,Sun, Qi,Xiong, Hao,Liu, Shi-Yu,Moosavi, Behrooz,Yang, Wen-Chao,Yang, Guang-Fu
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supporting information
p. 3952 - 3955
(2017/04/11)
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- Evaluation of Pseudoenantiomeric Mixed Carbonates as Efficient Fluorogenic Probes for Enantioselectivity Screening
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We report mixed carbonates as enzyme substrates and demonstrate their application as fluorogenic probes for lipase and esterase enantiopreference screening. By the application of pseudoenantiomers with distinct fluorescence behaviors, it is possible to evaluate the activity and enantiopreference of hydrolytic enzymes. In order to validate our method, enantioselectivities calculated from fluorometric measurements were compared with the results obtained from larger-scale kinetic resolution. Pseudoenantiomeric mixed carbonates with distinct fluorogenic properties are shown to be very useful probes for screening lipase and esterase enantioselectivity. The simultaneous use of pseudoenantiomeric substrates overcomes conventional assays with single enantiomer substrates, as the effects of competitive binding are taken into account.
- Zadlo, Anna,Koszelewski, Dominik,Borys, Filip,Ostaszewski, Ryszard
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- Design, synthesis and cytotoxicity of novel dihydroartemisinin-coumarin hybrids via click chemistry
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In order to develop novel chemotherapeutic agents with potent anticancer activities, we designed four series of novel compounds employing hybridization strategy. Twenty novel dihydroartemisinin-coumarin hybrids, 10a-e, 11a-e, 12a-e, 13a-e, were synthesized via click chemistry in this study and their structures were characterized by HRMS and NMR. The cytotoxic activities were measured by MTT assay against three cancer cell lines (HCT-116, MDA-MB-231, and HT-29) under normoxic or anoxic conditions, respectively. The target compounds exhibited moderate activity with IC50 values in the 0.05-125.40 μM range, and these compounds exhibited better activity against HT-29 cell line under anoxic condition. The cytotoxic activities of most compounds under anoxic condition displayed one- to 10-fold greater activity than under normoxic condition. Compounds 10a - e showed better selectivity against the HT-29 cell line than the other two cell lines. These results indicated that our design of CA IX inhibitors does correspond with its action mode to some degree and deserves further investigation.
- Tian, Ye,Liang, Zhen,Xu, Hang,Mou, Yanhua,Guo, Chun
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- Multi-target tacrine-coumarin hybrids: Cholinesterase and monoamine oxidase B inhibition properties against Alzheimer's disease
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A series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as multi-target agents against Alzheimer's disease. The biological assays indicated that most of compounds displayed potent inhibitory activity toward AChE and BuChE, and clearly selective inhibition for MAO-B. Among these compounds, 14c exhibited strong inhibitory activity for AChE (IC50 values of 33.63 nM for eeAChE and 16.11 nM for hAChE) and BuChE (IC50 values of 80.72 nM for eqBuChE and 112.72 nM for hBuChE), and the highest inhibitory activity against hMAO-B (IC50 value of 0.24 11/4M). Kinetic and molecular modeling studies revealed that 14c was a mixed-type inhibitor, binding simultaneously to catalytic, peripheral and mid-gorge sites of AChE. It was also a competitive inhibitor, which covered the substrate and entrance cavities of MAO-B. Moreover, 14c could penetrate the CNS and show low cell toxicity. Overall, these results suggested that 14c might be an excellent multi-target agent for AD treatment.
- Xie, Sai-Sai,Wang, Xiaobing,Jiang, Neng,Yu, Wenying,Wang, Kelvin D.G.,Lan, Jin-Shuai,Li, Zhong-Rui,Kong, Ling-Yi
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supporting information
p. 153 - 165
(2015/03/31)
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- Selective selenol fluorescent probes: Design, synthesis, structural determinants, and biological applications
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Selenium (Se) is an essential micronutrient element, and the biological significance of Se is predominantly dependent on its incorporation as selenocysteine (Sec), the genetically encoded 21st amino acid in protein synthesis, into the active site of selenoproteins, which have broad functions, ranging from redox regulation and anti-inflammation to the production of active thyroid hormones. Compared to its counterpart Cys, there are only limited probes for selective recognition of Sec, and such selectivity is strictly restricted at low pH conditions. We reported herein the design, synthesis, and biological evaluations of a series of potential Sec probes based on the mechanism of nucleophilic aromatic substitution. After the initial screening, the structural determinants for selective recognition of Sec were recapitulated. The follow-up studies identified that probe 19 (Sel-green) responds to Sec and other selenols with more than 100-fold increase of emission in neutral aqueous solution (pH 7.4), while there is no significant interference from the biological thiols, amines, or alcohols. Sel-green was successfully applied to quantify the Sec content in the selenoenzyme thioredoxin reductase and image endogenous Sec in live HepG2 cells. With the aid of Sel-green, we further demonstrated that the cytotoxicity of different selenocompounds is correlated to their ability metabolizing to selenols in cells. To the best of our knowledge, Sel-green is the first selenol probe that works under physiological conditions. The elucidation of the structure-activity relationship for selective recognition of selenols paves the way for further design of novel probes to better understand the pivotal role of Sec as well as selenoproteins in vivo.
- Zhang, Baoxin,Ge, Chunpo,Yao, Juan,Liu, Yaping,Xie, Huichen,Fang, Jianguo
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p. 757 - 769
(2015/01/30)
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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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- Effects of artemisinin antimalarials on Cytochrome P450 enzymes in vitro using recombinant enzymes and human liver microsomes: Potential implications for combination therapies
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1. Cytochrome P450 enzyme system is the most important contributor to oxidative metabolism of drugs. Modification, and more specifically inhibition, of this system is an important determinant of several drug-drug interactions (DDIs). 2. Effects of the antimalarial agent artemisinin and its structural analogues, artemether, artesunate and dihydroartemisinin, on seven of the major human liver CYP isoforms (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4) were evaluated using recombinant enzymes (fluorometric assay) and human liver microsomes (LC-MS/MS analysis). Inhibitory potency (IC50) and mechanisms of inhibition were evaluated using nonlinear regression analysis. In vitro-in vivo extrapolation using the [I]/Ki ratio was applied to predict the risk of DDI in vivo. 3. All compounds tested inhibited the enzymatic activity of CYPs, mostly through a mixed type of inhibition, with CYP1A2, 2B6, 2C19 and 3A4 being affected. A high risk of interaction in vivo was predicted if artemisinin is coadministrated with CYP1A2 or 2C19 substrates. 4. With respect to CYP1A2 inhibition in vivo by artemisinin compounds, our findings are in line with previously published data. However, reported risks of interaction may be overpredicted and should be interpreted with caution.
- Ericsson, Therese,Sundell, Jesper,Torkelsson, Angelica,Hoffmann, Kurt-Jürgen,Ashton, Michael
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p. 615 - 626
(2014/06/23)
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- Evaluation of coumarin-based fluorogenic P450 BM3 substrates and prospects for competitive inhibition screenings
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Fluorescence-based assays for the cytochrome P450 BM3 monooxygenase from Bacillus megaterium address an attractive biotechnological challenge by facilitating enzyme engineering and the identification of potential substrates of this highly promising biocatalyst. In the current study, we used the scarcity of corresponding screening systems as an opportunity to evaluate a novel and continuous high-throughput assay for this unique enzyme. A set of nine catalytically diverse P450 BM3 variants was constructed and tested toward the native substrate-inspired fluorogenic substrate 12-(4-trifluoromethylcoumarin-7- yloxy)dodecanoic acid. Particularly high enzyme-mediated O-dealkylation yielding the fluorescent product 7-hydroxy-4-trifluoromethylcoumarin was observed with mutants containing the F87V substitution, with A74G/F87V showing the highest catalytic efficiency (0.458 min-1 μM-1). To simplify the assay procedure and show its versatility, different modes of application were successfully demonstrated, including (i) the direct use of NADPH or its oxidized form NADP+ along with diverse NADPH recycling systems for electron supply, (ii) the use of cell-free lysates and whole-cell preparations as the biocatalyst source, and (iii) its use for competitive inhibition screens to identify or characterize substrates and inhibitors. A detailed comparison with known, fluorescence-based P450 BM3 assays finally emphasizes the relevance of our contribution to the ongoing research.
- Neufeld, Katharina,Zu Berstenhorst, Sonja Meyer,Pietruszka, J?rg
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- Synthesis of 7-alkoxy-4-trifluoromethylcoumarins via the von Pechmann reaction catalyzed by molecular iodine
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The synthesis of a series of 7-alkoxy-4-trifluoromethylcoumarins via the von Pechmann reaction catalyzed by molecular iodine is described. The reaction protocol is simple, inexpensive and leads to the formation of the corresponding coumarin derivatives in good yield and high purity. A key intermediate as well as several iodo byproducts were isolated.
- Degrote, Jami,Tyndall, Stephen,Wong, Koon Fai,Vanalstine-Parris, Melissa
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supporting information
p. 6715 - 6717
(2015/01/09)
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- BENZOPYRONE DERIVATIVE AND USE THEREOF
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The present invention relates to the field of pharmaceutical chemistry, and in particular, to a benzopyrone derivative and a use thereof. The benzopyrone derivative is compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof. It has been found by experiments that, this type of compounds is useful in prevention or treatment of neuropsychical diseases.
- -
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Paragraph 0025; 0052
(2014/03/22)
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- BENZOPYRONE DERIVATIVE AND USE THEREOF
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The present invention relates to the field of pharmaceutical chemistry, and in particular, to a benzopyrone derivative and a use thereof. The benzopyrone derivative is compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof. It has been found by experiments that, this type of compounds is useful in prevention or treatment of neuropsychical diseases.
- -
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Paragraph 0140
(2014/05/07)
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- Coumarin dye-embedded semiconducting polymer dots for ratiometric sensing of fluoride ions in aqueous solution and bio-imaging in cells
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This paper describes a simple platform that employs coumarin dye-encapsulated semiconducting polymer dots as a fluorescent probe for ratiometric and sensitive fluoride anion detection, in which the sensing mechanism is based on the deprotection of the tert-butyldimethylsilyl group on coumarin to induce Foerster resonance energy transfer. the Partner Organisations 2014.
- Huang, Ya-Chi,Chen, Chuan-Pin,Wu, Pei-Jing,Kuo, Shih-Yu,Chan, Yang-Hsiang
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supporting information
p. 6188 - 6191
(2014/10/15)
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- Pancreatic α-Amylase inhibition and free radical scavenging activity of substituted pyranochromenone derivatives
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Pyranochromenone derivatives 3a-d, 6a-j and 2H-chromenones 8a-b were synthesized and screened for their in vitro α-Amylase inhibitory and ABTS?+ [2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)] free radical scavenging activities. Compounds 3a, 3c, and 6d displayed dual function of ABTS?+ radical scavenging as well as α-Amylase inhibition. Compound 6h was found to be most potent α-Amylase inhibitor in present series of compounds. Docking studies suggest that these compounds occupy active site of the human pancreatic α-Amylase similar to that of acarbose which inhibits enzyme by hydrophobic interactions. These compounds have potential to be developed as therapeutics targeted against diet-induced hyperglycemia in diabetes. Graphical abstract: Series of pyranochromenone derivatives 3a-d, 6a-j, and 8a-b were synthesized, among these compound 6h shown potent intestinal α-Amylase inhibitory activity. Compounds 3a, 3c, and 6d were shown dual properties such as α-Amylase inhibitory and antioxidant activities. These derivatives may serve as a model compounds for design and development of therapeutics based agents.[Figure not available: see fulltext.]
- Ashok Kumar,Tiwari, Ashok K.,Saidachary,Kishor, Chandan,Kumar, D. Anand,Ali, Zehra,Sridhar,Addlagatta, Anthony,Raju, B. China
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p. 2821 - 2833
(2014/05/06)
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- Characterization of marmoset CYP2B6: CDNA cloning, protein expression and enzymatic functions
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The common marmoset is a promising species for evaluating the safety of drug candidates. To further understand the capacity for drug metabolism in marmosets, a cDNA encoding a CYP2B enzyme was cloned from the total RNA fraction of marmoset liver by 3′- and 5′-RACE methods. Nucleotide and deduced amino acid sequences showed 90.8 and 86.2% identity, respectively, with human CYP2B6. The marmoset CYP2B6 (marCYP2B6) protein was expressed in insect cells, and its enzymatic properties were compared with those of human (humCYP2B6) and cynomolgus monkey (cynCYP2B6) orthologs in liver and insect cell microsomes. Enzymatic functions were examined for the oxidation of 7-ethoxy-4-(trifluoromethyl)coumarin (7-ETC), bupropion (BUP) and efavirenz (EFV). The kinetic profiles for the oxidation of the three substrates by liver microsomal fractions were similar between humans and cynomolgus monkeys (biphasic for 7-ETC and monophasic for BUP and EFV), but that of marmosets was unique (monophasic for 7-ETC and biphasic for BUP and EFV). Recombinant enzymes, humCYP2B6 and cynCYP2B6, also yielded similar kinetic profiles for the oxidation of the three substrates, whereas marCYP2B6 showed activity only for 7-ETC hydroxylation. In silico docking simulations suggested that two amino acid residues, Val-114 and Leu-367, affect the activity of marCYP2B6. In fact, a marCYP2B6 mutant with substitutions V114I and L367V exhibited BUP hydroxylase activity that was 4-fold higher than that of humCYP2B6, while its EFV 8-hydroxylase activity was only 10% that of the human enzyme. These results indicate that the amino acids at positions 114 and 367 affect the enzymatic capacity of marmoset CYP2B6.
- Mayumi, Kei,Hanioka, Nobumitsu,Masuda, Kazufumi,Koeda, Akiko,Naito, Shinsaku,Miyata, Atsuro,Narimatsu, Shizuo
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p. 1182 - 1194
(2013/05/09)
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- The effect of ritonavir on human CYP2B6 catalytic activity: Heme modification contributes to the mechanism-based inactivation of CYP2B6 and CYP3A4 by ritonavir
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The mechanism-based inactivation of human CYP2B6 by ritonavir (RTV) in a reconstituted system was investigated. The inactivation is time, concentration, and NADPH dependent and exhibits a Kl of 0.9 μM, a k inact of 0.05 min-1, and a partition ratio of approximately 3. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that the protonated molecular ion of RTV exhibits an m/z at 721 and its two major metabolites are an oxidation product with MH+ at m/z 737 and a deacylated product with MH+at m/z 580. Inactivation of CYP2B6 by incubation with 10 μM RTV for 10 min resulted in an approximately 50% loss of catalytic activity and native heme, but no modification of the apoprotein was observed. RTV was found to be a potent mixed-type reversible inhibitor (Ki = 0.33 μM) and a type II ligand (spectral dissociation constant-Ks = 0.85 mM) of CYP2B6. Although previous studies have demonstrated that RTV is a potent mechanism-based inactivator of CYP3A4, the molecular mechanism responsible for the inactivation has not been determined. Here, we provide evidence that RTV inactivation of CYP3A4 is due to heme destruction with the formation of a heme-protein adduct. Similar to CYP2B6, there is no significant modification of the apoprotein. Furthermore, LC-MS/MS analysis revealed that both CYP3A4 and human liver microsomes form an RTV-glutathione conjugate having a MH+ at m/z 858 during metabolism of RTV, suggesting the formation of an isocyanate intermediate leading to formation of the conjugate. Copyright
- Lin, Hsia-Lien,D'Agostino, Jaime,Kenaan, Cesar,Calinski, Diane,Hollenberg, Paul F.
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p. 1813 - 1824
(2013/10/08)
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- Pharmacokinetic evaluation of the anticancer prodrug simmitecan in different experimental animals
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Aim: To investigate the pharmacokinetics and disposition of simmitecan (L-P) that was a water-soluble ester prodrug of chimmitecan (L-2-Z) with potent anti-tumor activities in different experimental animals, and to assess its drug-drug interaction potential. Methods: SD rats were injected with a single iv bolus doses of L-P (3.75, 7.5 and 15 mg/kg). The pharmacokinetics, tissue distribution, excretion and metabolism of L-P and its active metabolite L-2-Z were studied through quantitative measurements and metabolite profiling with LC/MS. The binding of L-P and L-2-Z to rat plasma proteins was examined using an ultrafiltration method. Systemic exposures of beagle dogs to L-P as well as drug distribution in tumors of the nude mice xenograft model of human hepatic cancer SMMC-7721 cells were also examined. The metabolism of L-P by liver mcirosomal carboxylesterase in vitro was investigated in different species. The effects of L-P and L-2-Z on cytochrome P450 enzymes were examined using commercial screening kits. Results: The in vivo biotransformation of L-P to L-2-Z showed a significant species difference, with a mean elimination half-life t1/2 of approximately 1.4 h in rats and 1.9 h in dogs. The systemic exposure levels of L-P and L-2-Z were increased in a dose-dependent manner. In rats, approximately 66% of L-P and 79% of L-2-Z were bound to plasma proteins. In rats and the nude mice bearing human hepatic cancers, most organ tissues had significantly higher concentrations of L-P than the corresponding plasma levels. In the tumor tissues, the L-P levels were comparable to those of plasma, whereas the L-2-Z levels were lower than the L-P levels. In rats, L-P was eliminated mainly via biliary excretion, but metabolism played an important role in elimination of the intact L-P. Finally, L-P and L-2-Z exerted moderate inhibition on the activity of CYP3A4 in vitro. Conclusion: L-P and L-2-Z have relatively short elimination half-lives and L-P is mainly eliminated via biliary excretion. The species difference in the conversion of L-P to L-2-Z and potential drug-drug interactions due to inhibition of CYP3A4 should be considered in further studies.
- Hu, Zhe-Yi,Li, Xiu-Xue,Du, Fei-Fei,Yang, Jun-Ling,Niu, Wei,Xu, Fang,Wang, Feng-Qing,Li, Chuan,Sun, Yan
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p. 1437 - 1448
(2013/11/19)
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- Magnesium bis(trifluoromethane)sulfonimide: An efficient catalyst for the synthesis of coumarins under solvent-free conditions
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Magnesium bis(trifluoromethane)sulfonimide [Mg(NTf2) 2] is an efficient catalyst for the synthesis of coumarins via the Pechmann condensation reaction of phenols and β-ketoesters under solvent-free conditions.
- Wang, Hongshe
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p. 411 - 414
(2013/05/21)
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- Synthesis and biological investigation of coumarin piperazine (piperidine) derivatives as potential multireceptor atypical antipsychotics
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The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine D2, D3, and serotonin 5-HT1A and 5-HT2A receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy) -4-methyl-8-chloro-2H-chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for 5-HT2C and H1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound 17m inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia.
- Chen, Yin,Wang, Songlin,Xu, Xiangqing,Liu, Xin,Yu, Minquan,Zhao, Song,Liu, Shicheng,Qiu, Yinli,Zhang, Tan,Liu, Bi-Feng,Zhang, Guisen
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supporting information
p. 4671 - 4690
(2013/07/19)
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- "Self-immolative" spacer for uncaging with fluorescence reporting
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Dual photoliberation: A caged, branched, self-immolative spacer (see scheme, gray box) was designed to rapidly and simultaneously release a desired compound (green) and a fluorophore (red) upon photoactivation. Careful kinetic analysis of the disassembly of the spacer shows that it occurs on the shortest time scale reported to date.
- Labruère, Rapha?l,Alouane, Ahmed,Le Saux, Thomas,Aujard, Isabelle,Pelupessy, Philippe,Gautier, Arnaud,Dubruille, Sylvie,Schmidt, Frédéric,Jullien, Ludovic
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supporting information
p. 9344 - 9347
(2012/11/07)
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- Analysis of fragmentations of coumarins in mass spectrometry using the electronic charges of atoms
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Recently, we examined a new approach to understand the fragmentations of monosubstituted and disubstituted coumarins with halogens and/or oxygenated moieties, through the electronic charges of their atoms, performed by AM1 method. A good correlation was found between electronic charges of atoms and fragmentation processes. In the present study, another series of coumarins with nitrogenated moieties is used to verify the reliability of this method.
- Cisse,Kabore,Tine,Saba
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experimental part
p. 305 - 310
(2011/11/29)
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- Coumarins as novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors for potential treatment of prostate cancer
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The synthesis and SAR studies of 3- and 4-substituted 7-hydroxycoumarins as novel 17β-HSD3 inhibitors are discussed. The most potent compounds from this series exhibited low nanomolar inhibitory activity with acceptable selectivity versus other 17β-HSD isoenzymes and nuclear receptors.
- Harada, Koichiro,Kubo, Hideki,Tomigahara, Yoshitaka,Nishioka, Kazuhiko,Takahashi, Junya,Momose, Mio,Inoue, Shinichi,Kojima, Atsuyuki
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scheme or table
p. 272 - 275
(2010/04/06)
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- Microwave-promoted automated synthesis of a coumarin library
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A 30-membered library of coumarins has been synthesized in a microwave-assisted Pechmann reaction using neat trifluoroacetic acid both as an acidic reagent and a reaction medium. Alternatively, polymer-supported sulfonic acid Amberlyst-15 could also be employed to facilitate the formation of coumarins. The use of a specially-built microwave synthesizer with liquid handling tools rendered the automated synthesis of a coumarin library feasible.
- Katkevi?s,Kontijevskis,Mutule,Sūna
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p. 151 - 159
(2008/12/20)
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- BENZOPYRONE COMPOUNDS, PREPARATION METHOD AND USE THEREOF
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The invention relates to pesticide and bactericide, specifically to the benzopyrone compounds and its preparation method and use thereof. The benzopyrone compounds of the invention having general formula (I): The present invention, having good pesticide activity and broad bactericide activity, applied for controlling various pests in plants such as army worm, diamond backmoth and aphid, carmine spider mite, two-spotted spider mite, ladybeetle, mites and mosquito larvae. Various disease in plants can be controlled by the invention and that of grape downy mildew, rice sheath and culm blight, rice blast, tomato early blight, tomato late blight ,wheat leaf rust, wheat leaf blotch, wheat powdery mildew, cucumber powdery mildew, cucumber downy mildew, cucumber grey mold and so on.
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Page/Page column 19
(2008/06/13)
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- Expeditious approach to coumarins via pechmann reaction catalyzed by molecular iodine or AgOTf
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An efficient and facile route for the synthesis of coumarins via the Pechmann reaction catalyzed by molecular iodine or AgOTf was described. Copyright Taylor & Francis Group, LLC.
- Wu, Jie,Diao, Tianning,Sun, Wei,Li, Yizhe
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p. 2949 - 2956
(2007/10/03)
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- METHOD FOR SYNTHESIZING COUMARIN AND THE DERIVATIVES THEREOF
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The invention relates to an environmentally friendly, heterocatalytic method for synthesizing coumarins based on phenols and carboxylic acids/carboxylic acid derivatives or ?-keto carboxylic acids/carboxylic acid derivatives. Alkylation of the aromatic phenol ring is assisted by an additional functional group of the carboxylic acids/carboxylic acid derivatives while the coumarin unit is formed. High yields can be obtained by using Nafion-silica composite materials. Particularly silica composites that are loaded with 20 to 80 percent of Nafion have a very high activity (compared with pure Nafion resin) due to the high number of acidic cores in connection with the improved active surface thereof. An efficient Pechmann reaction can be carried out by simple preparation in toluene, the catalyst being recyclable and/or regenerable.
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Page/Page column 20-22
(2008/06/13)
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- ZrCl4-catalyzed Pechmann reaction: Synthesis of coumarins under solvent-free conditions
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Zirconium (IV) chloride is used as an efficient catalyst in the Pechmann condensation reaction of phenols with β-keto esters leading to the formation of coumarin derivatives in good yields under solvent-free conditions.
- Smitha,Reddy, Ch. Sanjeeva
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p. 3997 - 4003
(2007/10/03)
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- The indium(III) chloride-catalyzed von Pechmann reaction: A simple and effective procedure for the synthesis of 4-substituted coumarins
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Indium(III) chloride is used as an efficient catalyst in the von Pechmann condensation of phenols with β-ketoesters leading to the formation of coumarin derivatives in excellent yields with good purity.
- Subhas Bose,Rudradas,Hari Babu, Mereyala
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p. 9195 - 9197
(2007/10/03)
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- Mechanism-based inactivation of cytochrome P450 2B1 by 7- ethynylcoumarin: Verification of apo-P450 adduction by electrospray ion trap mass spectrometry
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7-Ethynylcoumarin was synthesized as a potential mechanism-based inhibitor, and it was found to be an effective inactivator of 7-ethoxy-4- (trifluoromethyl)coumarin (7EFC) O-deethylation catalyzed by purified, reconstituted P450 2B1. In contrast, 7-ethynylcoumarin demonstrated minimal inactivation of P450 2A6-mediated 7-hydroxycoumarin formation. The inactivation of P450 2B1 demonstrated pseudo-first-order kinetics and was NADPH- and inhibitor-dependent. The maximal rate constant for the inactivation of 2B1 was 0.39 min-1 at 30 °C, and thus, the time required to inactivate 50% of the P450 2B1 that was present (t( 1/2 )) was 1.8 min. The estimated concentration which led to half-maximal inactivation (K(I)) was 25 μM. No protection from inactivation was seen in the presence of nucleophiles (glutathione and sodium cyanide), an iron chelator (deferroxamine), or superoxide dismutase and catalase. Addition of the substrate (7EFC) protected P450 2B1 from inactivation, in a concentration-dependent manner. The partition ratio for P450 2B1 was 25; i.e., the number of metabolic events was 25-fold higher than the number of inactivating events. Incubations of 7- ethynylcoumarin with P450 2B1 for 10 min resulted in an 80% loss in enzymatic activity, while 90% of the ability to form a reduced-CO complex remained. This activity loss was not recovered following dialysis, indicative of irreversible inactivation. Covalent attachment of the entire inhibitor and oxygen to apo-P450 2B1, in a 1:1 ratio, was shown via electrospray ion trap mass spectrometry. This method also verified the absence of modification to the heme or the cytochrome P450 reductase. Taken together, the characterization of the inhibition seen with P450 2B1 and 7-ethynylcoumarin was consistent with all of the criteria required to distinguish a mechanism- based inactivator. In addition, electrospray ion trap mass spectrometry has the potential to be applied to protein adducts above and beyond those associated with the mechanism-based inactivation of cytochrome P450s.
- Regal, Kelly A.,Schrag, Michael L.,Kent, Ute M.,Wienkers, Larry C.,Hollenberg, Paul F.
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p. 262 - 270
(2007/10/03)
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- Synthesis of novel fluorinated coumarins: Excellent UV-light excitable fluorescent dyes
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Two new fluorinated fluorescent dyes, 6,8-difluoro-7-hydroxy-4- methylcoumarin (Marina Blue(TM)) and 3-carboxy-6,8-difluoro-7- hydroxycoumarin (Pacific Blue(TM)), exhibit excellent photophysical properties among a series of novel fluorinated 7-hydroxycoumarins. Most of these fluorinated coumarins have quantum yields (0.63 to 0.89) equal to or higher than that of the parent compound (0.63), which, in combination with their lower pK(a)S and higher photostability, make them superior fluorescent dyes for use as reporter molecules in biological systems.
- Sun, Wei-Chuan,Gee, Kyle R.,Haugland, Richard P.
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p. 3107 - 3110
(2007/10/03)
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- Some 7-Substituted 4-(Trifluoromethyl)coumarins
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Preparation and spectral properties are given for 13 substituted 4-(trifluoromethyl)coumarins (7-hydroxy, 7,8-dihydroxy, 6-ethyl-7-hydroxy, 6-benzyl-7-hydroxy, 7-methoxy, 7-methyl, 7-amino, 7-(ethylamino), 7-(benzylamino), 7-anilino, 7-, 7-, and 2(1H)-isoindolyl).Three 7-(acylamido)-4-(trifluoromethyl)coumarins (acetyl, benzoyl, and bromoacetyl) were also prepared as well as two new phenol precursors, 3-phenol and 2-(3-hydroxyphenyl)-1H-isoindole.
- Bissell, Eugene R.,Larson, D. Kristin,Croudace, Michael C.
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p. 348 - 350
(2007/10/02)
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