- ECTONUCLEOTIDE PYROPHOSPHATASE/PHOSPHODIESTERASE 1 (ENPP1) MODULATORS AND USES THEREOF
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Provided herein are small molecule modulators of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.
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Paragraph 00631
(2021/07/02)
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- Modulation of DNA damage response by targeting ATM kinase using newly synthesized di-phenoxy acetamide (DPA) analogs to induce anti-neoplasia
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Background: Imbalance and instability in the structure of the DNA have become major characteristics of cancer. In response to DNA damage, DNA damage response (DDR) protein, ataxia telangiectasia mutated (ATM), plays a pivotal role in the modulation of regulatory regions responsible for inhibition of apoptosis, thereby neoplastic progression. Methods: A new series of DPA (7a–t) were synthesized, characterized. Anti-proliferative studies to identify the lead compound were carried out by LDH and MTT assay. Apoptosis/DNA damage was measured through FACS, Annexin-v staining, TUNEL and Comet assay. Elucidation of molecular mechanism through immunoblot and further validation of the drug effect through in vivo approaches. Results: Initial in vitro anti-proliferative screening of Compounds DPA (7a–t) against multiple cancer cell lines identified Compound DPA (7n) as a potent cytotoxic molecule with IC50 value of 4.3?μM. Down the line, in vitro and in vivo evaluation of Compound DPA (7n) inferred that it has apoptotic inducing potentiality. Further, evaluation of molecular mechanism inferred that Compound DPA (7n) effectively modulates ATM phosphorylation only, eventually altering downstream signalling pathways. Conclusions: Compound DPA (7n) emerged as a potent proapoptotic and anti-neoplastic agent by inhibiting ATM kinase activity both in vitro and in vivo. The conferring results ascertain that the drug could be developed as a new ATM kinase inhibitor with anti-cancer capacity. Graphic abstract: [Figure not available: see fulltext.]
- Al-Ostoot, Fares Hezam,Sherapura, Ankith,Malojirao, Vikas H.,Thirusangu, Prabhu,Al-Muhimeed, Tahani I.,Khanum, Shaukath Ara,Prabhakar
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p. 1344 - 1360
(2021/06/14)
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- Synthesis, crystal structure characterization, DFT calculations, Hirshfeld surface analysis and 3D energy frameworks of triazole pyridazine derivatives: Theoretical and experimental studies
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Recently, pyridazine derivatives have shown considerable biological properties such as anti-tumor and anti-inflammatory activity. The studied compounds 6-chloro-3-[(4-methylphenoxy)methyl][1,2,4] triazolo[4,3-b]pyridazine (8a) and 6-chloro-3-[(4-fluorophenoxy)methyl][1,2,4] triazolo[4,3-b]pyridazine (8b) have been synthesized and characterized by NMR, IR and mass spectral studies, and finally, the structures were confirmed by single crystal X-ray diffraction technique. The compounds 8a and 8b have crystallized in the same crystal system with different space groups. Density functional theory calculations were performed to compare the theoretical and experimental results obtained from XRD. Further, DFT calculations were employed to determine HOMO-LUMO energy levels, energy gap, softness, hardness, and other quantum chemical parameters of the compounds 8a and 8b. Hirshfeld surface analysis was carried out to distinguish the different intermolecular hydrogen bonds. Energy frameworks for the compounds were constructed through different intermolecular interaction energies to know the dominant interaction energy involved in the molecular packing strength.
- Al-Ostoot, Fares Hezam,Khanum, Shaukath Ara,M. A., Sridhar,Mohammed, Yasser Hussien Issa,Sallam, Hamdi Hamid
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- Ketoreductase catalyzed stereoselective bioreduction of α-nitro ketones
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We report here the stereoselective bioreduction of α-nitro ketones catalyzed by ketoreductases (KREDs) with publicly known sequences. YGL039w and RasADH/SyADH were able to reduce 23 class I substrates (1-aryl-2-nitro-1-ethanone (1)) and ten class II substrates (1-aryloxy-3-nitro-2-propanone (4)) to furnish both enantiomers of the corresponding β-nitro alcohols, with good-to-excellent conversions (up to >99%) and enantioselectivities (up to >99% ee) being achieved in most cases. To the best of our knowledge, KRED-mediated reduction of class II α-nitro ketones (1-aryloxy-3-nitro-2-propanone (4)) is unprecedented. Select β-nitro alcohols, including the synthetic intermediates of bioactive molecules (R)-tembamide, (S)-tembamide, (S)-moprolol, (S)-toliprolol and (S)-propanolol, were stereoselectively synthesized in preparative scale with 42% to 90% isolated yields, showcasing the practical potential of our developed system in organic synthesis. Finally, the advantage of using KREDs with known sequence was demonstrated by whole-cell catalysis, in which β-nitro alcohol (R)-2k, the key synthetic intermediate of hypoglycemic natural product (R)-tembamide, was produced in a space-time yield of 178 g L?1 d?1 as well as 95% ee by employing the whole cells of a recombinant E. coli strain coexpressing RasADH and glucose dehydrogenase as the biocatalyst.
- Wang, Zexu,Wu, Xiaofan,Li, Zhining,Huang, Zedu,Chen, Fener
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supporting information
p. 3575 - 3580
(2019/04/14)
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- Novel pyrazolone derivatives and corresponding europium(III) complexes: Synthesis and properties research
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A series of pyrazolone derivatives ligands L1?7 were successfully synthesized and validated by 1H NMR and MS, corresponding europium complexes [EuL1?7(NO3)2]NO3·EtOAc were synthesized. Physico-chemistry properties of title complexes were determined by Elemental analysis, Molar conductance, UV absorption spectra, IR spectra and Thermogravimetric analysis. The title complexes exhibit characteristic red fluorescence of Eu3+. The effect of various substituent groups in ligands on the of title Eu3+ complexes is ordered: Cl > -Br > -OCH3 > -F > -CH3 > -H > -NO2, and [EuL6(NO3)2]NO3·EtOAc containing Cl possesses the strongest fluorescence intensity, so does fluorescence quantum yield. The electrochemical properties indicate that energy gap Eg and LUMO energy level are huge affected by substituent groups, and variation trends of LUMO energy level affected by diverse substituent groups are also different. The prepared title europium complexes have potential application prospects in the fields of photoelectric functional materials and life sciences.
- Li, Dewei,Xiong, Suhao,Guo, Tiantong,Shu, Dehua,Xiao, Haihua,Li, Guizhi,Guo, Dongcai
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- The Novel 4-Phenyl-2-Phenoxyacetamide Thiazoles modulates the tumor hypoxia leading to the crackdown of neoangiogenesis and evoking the cell death
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Tumor microenvironment is a complex multistep event which involves several hallmarks that transform the normal cell into cancerous cell. Designing the novel antagonistic molecule to reverse the tumor microenvironment with specific target is essential in modern biological studies. The novel 4-phenyl-2-phenoxyacetamide thiazole analogues 8a-ab were synthesized in multistep process, then screened and assessed for cytotoxic and anti-proliferative effects in vitro against multiple cancer cells of different origin such as MCF-7, A549, EAC and DLA cells which revealed that compound 8f with fluoro and methyl substitute has potential cytotoxic efficacy with an average IC50 value of ? 13 μM. The mechanism of cytotoxicity assessed for anti-tumor studies both in ascites and solid tumor models in-vivo inferred the regressed tumor activity. This is due to changes in the cause of tumor microenvironment with crackdown of neovascularization and evoking apoptosis process as assessed by CAM, corneal vascularization and apoptotic hallmarks in 8f treated cells. The molecular gene studies inferred involvement of HIF-1upregulation and stabilization of p53 which are interlinked in signaling as conferred by immunoblot analysis.
- Mohammed, Yasser Hussein Eissa,Malojirao, Vikas H.,Thirusangu, Prabhu,Al-Ghorbani, Mohammed,Prabhakar,Khanum, Shaukath Ara
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p. 1826 - 1839
(2017/11/16)
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- The anti-invasive role of novel synthesized pyridazine hydrazide appended phenoxy acetic acid against neoplastic development targeting matrix metallo proteases
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Neoplastic metastasis is a major process where tumor cells migrate from the primary tumor and colonize at other parts of our body to form secondary tumor. Cancer incidences are rising and novel anti-neoplastic compounds with new mechanism of actions are essential for preventing cancer related deaths. In the current examination, a novel series of pyridazine analogues 6a-l was synthesized and evaluated against metastatic neoplastic cells. Experimental data postulated compound 6j has potential cytotoxic efficacy with prolonged activity against various cancer cells, including A549, HepG2, A498, CaSki and SiHa cells. Moreover, compound 6j arrests the A549 migration and invasions markedly by counteracting matrix metalloproteinase (MMP)-2 and MMP-9 expressions. Also, compound 6j proved its potentiality against Dalton's solid lymphoma progression in-vivo by abridging MVD and MMP expressions. Compound 6j interacts with MMP-2 and MMP-9 by H- bond in-silico, thereby down regulates the MMPs action in tumourigenesis. Altogether, we concluded that compound 6j down regulates MMP-2 and MMP-9 and thereby impairs metastatic cancer cell migration and invasions which can be translated into a potent anti-neoplastic agent.
- Eissa Mohammed, Yasser Hussein,Thirusangu, Prabhu,Zabiulla,Vigneshwaran,B.T, Prabhakar,Khanum, Shaukath Ara
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p. 375 - 386
(2017/09/02)
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- Synthesis and Biological Activity of Ethyl 4-Alkyl-2-(2-(substituted phenoxy)acetamido)thiazole-5-carboxylate
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(Chemical Equation Presented) A series of novel ethyl 4-(methyl or trifluoromethyl)-2-(2-(substituted phenoxy)acetamido)thiazole-5-carboxylates 7a, 7b, 7c, 7d, 7e and 8f, 8g, 8h, 8i, 8j, 8k, 8l, 8m, 8n, 8o, 8p, 8q, 8r were synthesized, and their structures were confirmed by IR, 1H-NMR, MS spectra and elemental analysis. The results of preliminary bioassays show that some of the title compounds exhibit moderate to good herbicidal activities. Compared with the fluorine free compounds 7a, 7b, and 7e, the compounds bearing fluorine 8g, 8j, and 8q showed higher herbicidal activities with 70-100% inhibition against Capsella bursa-pastoris, Amaranthus restroflexus, and Eclipta prostrata at the dosage of 150 g/ha, which indicated that the trifluoromethyl on the thiazole ring was beneficial for the herbicidal activity. Furthermore, compounds 8f, 8g, 8h, 8i, 8j, 8k, 8l, 8m, 8n, 8o, 8p, 8q, 8r were tested for fungicidal activity against Pseudoperonospora cubensis at 500 μg/mL. Compounds 8f and 8q showed the best fungicidal activity with more than 80% inhibition.
- Mo, Wenyan,Shi, Yanxia,He, Junbo,Li, Baoju,Peng, Hao,He, Hongwu
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p. 183 - 187
(2016/02/10)
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- Synthesis and properties of coumarin derivatives and their terbium complexes
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A series of coumarin derivatives obtained from salicylaldehyde and phenol were synthesized. Their corresponding terbium complexes were prepared and characterized by elemental analysis, EDTA titrations, molar conductivity, UVvis spectra, IR spectra, and thermal analysis. The luminescent properties and electrochemical properties of the terbium complexes were also investigated. The results showed that all the terbium complexes exhibited characteristic emissions of terbium ions. The introduction of electron-donating groups can improve the luminescent properties, decrease the HOMO and LUMO energy levels of the terbium complex, while electron-withdrawing groups can weaken the luminescent properties, and increase the HOMO and LUMO energy levels of terbium complex.
- Meng, Defen,Xu, De,Li, Dong,Dai, Ming,Li, Guizhi,Guo, Dongcai
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p. 5269 - 5280
(2016/06/01)
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- Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine derivatives as novel adenosine A1and A2Areceptor antagonists
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Based on a previous report that a series of 8-(phenoxymethyl)-xanthines may be promising leads for the design of A1adenosine receptor antagonists, selected novel and known 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine and 1,3,7-trimethyl-8-(phenoxymethyl)-xanthine analogs were synthesized and evaluated for their A1and A2Aadenosine receptor affinity. Generally, the study compounds exhibited affinity for both the A1and A2Aadenosine receptors. Replacement of the 1,3-dimethyl-substition with a 1,3-diethyl-substition pattern increased A1and A2Abinding affinity. Overall it was found that para-substitution on the phenoxymethyl side-chain of the 1,3-diethyl-xanthines decreased A1affinity except for the 4-Br analog (4f) exhibiting the best A1affinity in the submicromolar range. On the other hand A2Aaffinity for the 1,3-diethyl-xanthines were increased with para-substitution and the 4-OCH3(4b) analog showed the best A2Aaffinity with a Kivalue of 237?nM. The 1,3-diethyl-substituted analogs (4a, and 4f) behaved as A1adenosine receptor antagonists in GTP shift assays performed with rat whole brain membranes expressing A1adenosine receptors. This study concludes that para-substituted 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine analogs represent novel A1and A2Aadenosine receptor antagonists that are appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's and Alzheimer's disease.
- Harmse, Rozanne,van der Walt, Mietha M.,Petzer, Jacobus P.,Terre'Blanche, Gisella
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supporting information
p. 5951 - 5955
(2016/12/03)
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- Synthesis, Characterization and Properties of Novel Coumarin Derivatives and Their Europium Complexes
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Seven novel coumarin derivatives derived from salicylaldehyde and phenol were synthesized and characterized by 1H NMR and 13C NMR spectra, mass spectra, infrared spectra and elemental analysis. Their corresponding Eu(III) complexes having general formula EuL1-7(NO3)3·2H2O were successfully prepared and characterized by elemental analysis, EDTA titrimetric, molar conductivity, UV-Vis, FT-IR and thermal performance studies. The luminescence properties, fluorescence quantum yields and the electrochemical properties of the title complexes were investigated. The results showed that the title complexes exhibited characteristic emissions of europium ions and possessed relatively good fluorescence quantum yields. The luminescence intensity of the complex with bromine-substituted group is the strongest among all the title complexes. The introduction of electron-withdrawing groups can increase the luminescence properties and fluorescence quantum yields, decrease the HOMO and LUMO energy levels of the title europium complexes, but electron-withdrawing group conversely. And these title complexes may possibly be useful for studying in luminescent materials field.
- Yan, Dong,Li, Dong,Cheng, Guang,Yang, Zehui,Shi, Ling,Guo, Dongcai
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p. 849 - 859
(2015/08/24)
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- Synthesis and luminescence properties of pyrazolone derivatives and their terbium complexes
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Seven novel pyrazolone derivatives were synthesized and characterized by 1H NMR and 13C NMR spectra, mass spectra, infrared spectra and elemental analysis. Their terbium complexes were prepared and characterized by elemental analysis, EDTA titrimetric analysis, UV/vis spectra, infrared spectra and molar conductivity, as well as thermal analysis. The fluorescence properties and fluorescence quantum yields of the complexes were investigated at room temperature. The results indicated that pyrazolone derivatives had good energy-transfer efficiency for the terbium ion. All the terbium complexes emitted green fluorescence characteristic of terbium ions, possessed strong fluorescence intensity, and showed relatively high fluorescence quantum yields. Cyclic voltammograms of the terbium complexes were studied and the highest occupied molecular orbital (HOMO) and lowest occupied molecular orbital (LUMO) energy levels of these complexes were estimated.
- Xiao, Haihua,Jiang, Xi,Li, Dong,Wu, Limin,Zhang, Wu,Guo, Dongcai
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p. 677 - 685
(2015/12/04)
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- Synthesis, evaluation and in silico molecular modeling of pyrroyl-1,3,4-thiadiazole inhibitors of InhA
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Enoyl acyl carrier protein reductase (ENR) is an essential type II fatty acid synthase (FAS-II) pathway enzyme that is an attractive target for designing novel antitubercular agents. Herein, we report sixty-eight novel pyrrolyl substituted aryloxy-1,3,4-thiadiazoles synthesized by three-step optimization processes. Three-dimensional quantitative structure-activity relationships (3D-QSAR) were established for pyrrolyl substituted aryloxy-1,3,4-thiadiazole series of InhA inhibitors using the comparative molecular field analysis (CoMFA). Docking analysis of the crystal structure of ENR performed by using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of pyrrolyl substituted aryloxy 1,3,4-thiadiazole into hydrophobic pocket of InhA enzyme. Based on docking and database alignment rules, two computational models were established to compare their statistical results. The analysis of 3D contour plots allowed us to investigate the effect of different substituent groups at different positions of the common scaffold. In vitro testing of ligands using biological assays substantiated the efficacy of ligands that were screened through in silico methods.
- Joshi, Shrinivas D.,More, Uttam A.,Koli, Deepshikha,Kulkarni, Manoj S.,Nadagouda, Mallikarjuna N.,Aminabhavi, Tejraj M.
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p. 151 - 167
(2015/03/30)
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- Finding new elicitors that induce resistance in rice to the white-backed planthopper Sogatella furcifera
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Herein we report a new way to identify chemical elicitors that induce resistance in rice to herbivores. Using this method, by quantifying the induction of chemicals for GUS activity in a specific screening system that we established previously, 5 candidate elicitors were selected from the 29 designed and synthesized phenoxyalkanoic acid derivatives. Bioassays confirmed that these candidate elicitors could induce plant defense and then repel feeding of white-backed planthopper Sogatella furcifera.
- He, Xingrui,Yu, Zhaonan,Jiang, Shaojie,Zhang, Peizhi,Shang, Zhicai,Lou, Yonggen,Wu, Jun
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supporting information
p. 5601 - 5603
(2015/11/17)
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- Synthesis and biological activity of 1-(Substituted phenoxyacetoxy)- 1-(pyridin-2-yl or thien-2-yl)methylphosphonates
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A series of novel O,O-dimethyl 1-(substituted phenoxyacetoxy)-1-(pyridin-2-yl or thien-2-yl)methylphosphonates 6a-n and 7a-d were synthesized. Their structures were confirmed by IR, 1H NMR, mass spectroscopy, and elemental analyses. The results of preliminary bioassays show that some of the title compounds exhibit moderate to good herbicidal and fungicidal activities. For example, the title compounds 6a, 6c, 6l, 6m, and 7d possess 90-100% inhibition against most of the tested plants at the dosage of 1500 g ai/ha, whereas the title compounds 6b, 6g-h and 6n possess 92-100% inhibition against Fusarium oxysporum, Phyricularia grisea, Botrytis cinereapers, Gibberella zeae, Sclerotinia sclerotiorum, and Cercospora beticola at the concentration of 50mg/L.
- Wang, Tao,Wang, Wei,Peng, Hao,He, Hongwu
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p. 173 - 179
(2015/01/30)
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- Radical decarboxylative fluorination of aryloxyacetic acids using N-fluorobenzenesulfonimide and a photosensitizer
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Fluorinated methoxy arenes are emerging as important motifs in both agrochemicals and pharmaceuticals. A novel technique for the synthesis of monofluoromethoxy arenes through the direct fluorodecarboxylation of carboxylic acids was developed that uses photosensitizers and N-fluorobenzenesulfonimide (NFSI). Utilization of the oxidatively mild fluorine transfer agent NFSI enabled the synthesis of fluoromethyl ethers that were previously inaccessible with decarboxylative fluorinations performed with Selectfluor. Mechanistic studies are consistent with the photosensitizer effecting oxidation of the aryloxyacetic acid.
- Leung, Joe C. T.,Sammis, Glenn M.
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p. 2197 - 2204
(2015/04/14)
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- In silico and pharmacological screenings identify novel serine racemase inhibitors
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d-Serine is a coagonist of the N-methyl-d-aspartate (NMDA)-type glutamate receptor and its biosynthesis is catalyzed by serine racemase (SR). The overactivation of the NMDA receptor has been implicated in the development of neurodegenerative diseases, strokes, and epileptic seizures, thus, the inhibitors of SR have potential against these pathological states. Here, we have developed novel inhibitors of SR by in silico screening and in vitro enzyme assay. The newly developed inhibitors have lower IC50 value comparing with that of malonate, one of the standard SR inhibitor. The structural features of novel inhibitors suggest the importance of central amide structure having a phenoxy substituent in their structure for the SR inhibitory activity. The present findings suggest the importance and rational development of new drugs for diseases of NMDAR overactivation.
- Mori, Hisashi,Wada, Ryogo,Li, Jie,Ishimoto, Tetsuya,Mizuguchi, Mineyuki,Obita, Takayuki,Gouda, Hiroaki,Hirono, Shuichi,Toyooka, Naoki
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supporting information
p. 3732 - 3735
(2014/09/03)
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- Synthesis, characterization and properties of 1,2,4-triazolo[3,4-b][1,3,4] thiadiazole derivatives and their europium complexes
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Eight novel 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole derivatives and their corresponding Eu(III) complexes were synthesized and characterized. From the spectral studies it has been concluded that the title Eu(III) complexes display six coordination. The investigation of the luminescence properties of the title complexes showed that the ligands favor energy transfers to the emitting energy level of europium ions. The title Eu(III) complexes exhibited characteristic emissions of europium ions, and possessed strong luminescence intensities, good fluorescence quantum yields, and the highest fluorescence quantum yield is up to 0.522. Furthermore, the luminescence intensity of the complex with chlorine-substituted group is the strongest than that of other complexes. The exploration of the electrochemical properties of the title complexes shows that the introduction of electron-donating groups can increase the HOMO energy levels, LUMO energy levels and the oxidation potential of the complexes, however, the result of introduction of electron-withdrawing groups was just opposite.
- Yan, Dong,Xiang, Yu,Li, Kangyun,Chen, Yanwen,Yang, Zehui,Guo, Dongcai
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p. 487 - 495
(2014/07/21)
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- Synthesis and fluorescence properties of 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol derivatives and their terbium complexes
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Eight novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol derivatives have been designed and synthesized, and their corresponding Tb3+ complexes were also prepared successfully. The fluorescence properties and fluorescence quantum yields of the target complexes were investigated, the results showed that the ligands were an efficient sensitizer for Tb3+ luminescence, and the target complexes exhibited characteristic fluorescence emissions of Tb3+ ion. The fluorescence intensity of the complex substituted by chlorine was stronger than that of other complexes. The substituents' nature has a great effect upon the electrochemical properties of the target complexes. The results showed that the introduction of the electron-withdrawing groups tended to decrease the oxidation potential and highest occupied molecular orbital energy levels of the target Tb3+ complexes; however, introduction of the electron-donating groups can increase the corresponding complexes' oxidation potential and highest occupied molecular orbital energy levels.
- Zhang, Wu,Chai, Yuchao,Li, Kangyun,Chen, Yanwen,Yan, Dong,Guo, Dongcai
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p. 1113 - 1122
(2015/02/19)
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- Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors
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By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new 'open-chain' classes of E. coli PDHc-E1 inhibitors, amide and urea derivatives, were designed, synthesized, and evaluated. The amide derivatives of compound 6d, with 4-NO2 in the benzene ring, showed the most potent inhibition of E. coli PDHc-E1. The urea derivatives displayed more potent inhibitory activity than the corresponding amide derivatives with the same substituent. Molecular docking studies confirmed that the urea derivatives have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522.
- He, Jun-Bo,Ren, Yan-Liang,Sun, Qiu-Shuang,You, Ge-Yun,Zhang, Li,Zou, Peng,Feng, Ling-Ling,Wan, Jian,He, Hong-Wu
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p. 3180 - 3186
(2014/06/09)
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- Inhibition of group IVA cytosolic phospholipase A2by thiazolyl ketones in vitro, ex vivo, and in vivo
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Group IVA cytosolic phospholipase A2(GIVA cPLA2) is the rate-limiting provider of pro-inflammatory mediators in many tissues and is thus an attractive target for the development of novel anti-inflammatory agents. In this work, we present the synthesis of new thiazolyl ketones and the study of their activities in vitro, in cells, and in vivo. Within this series of compounds, methyl 2-(2-(4-octylphenoxy)acetyl)thiazole-4-carboxylate (GK470) was found to be the most potent inhibitor of GIVA cPLA2, exhibiting an XI(50) value of 0.011 mole fraction in a mixed micelle assay and an IC50of 300 nM in a vesicle assay. In a cellular assay using SW982 fibroblast-like synoviocytes, it suppressed the release of arachidonic acid with an IC50value of 0.6 μM. In a prophylactic collagen-induced arthritis model, it exhibited an anti-inflammatory effect comparable to the reference drug methotrexate, whereas in a therapeutic model, it showed results comparable to those of the reference drug Enbrel. In both models, it significantly reduced plasma PGE2levels.
- Kokotos, George,Feuerherm, Astrid J.,Barbayianni, Efrosini,Shah, Ishita,S?ther, Mari,Magrioti, Victoria,Nguyen, Thuy,Constantinou-Kokotou, Violetta,Dennis, Edward A.,Johansen, Berit
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p. 7523 - 7535
(2015/01/08)
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- 1,2-asymmetric induction in diastereoselective zwitterionic aza-Claisen rearrangements: Key steps in optically active alkaloid synthesis
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The zwitterionic aza-Claisen rearrangement of optically active N-allylpyrrolidines and α-phenoxyacetyl fluorides proceeds with complete simple diastereoselectivity (internal asymmetric induction) and complete 1,2-asymmetric induction to generate a new C-C bond adjacent to a chiral C-N-Boc functionality. The resulting γ,δ-unsaturated amides were cyclised to give the corresponding pyrrolizidinones, which enabled the determination of the relative configuration of the stereotriads. Vinyl group degradation and a final lactam reduction gave an optically active analogue of (+)-petasinine (a pyrrolizidine alkaloid). Furthermore, the stereotriad-containing amides should be useful key intermediates for the total synthesis of optically active elaeocarpin (an indolizidine alkaloid). Copyright
- Heescher, Carolin,Schollmeyer, Dieter,Nubbemeyer, Udo
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supporting information
p. 4399 - 4404
(2013/07/26)
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- Synthesis and herbicidal activity of [(Substituted Phenoxyacetoxy) (Substituted Phenyl)Methyl](Methyl) phosphinates containing fluorine
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A series of [(substituted phenoxyacetoxy)(substituted phenyl)methyl] (methyl)phos- phinates containing fluorine were designed and synthesized. All the synthesized compounds were identified by elemental analysis, IR, 1H NMR, mass spectrometry. O-methyl [(2-fluorophenoxyacetoxy)(2,4- dichlorophenyl)methyl](methyl)phosphinate was further analyzed by X-ray single-crystal diffraction. Their herbicidal activity against a set of weed species was examined. Some of the compounds showed potential herbicidal activity, which provided some indications for further studies on structure modification. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
- Deng, Xiaoyan,Liao, Guihong,Long, Qingwu,Gao, Yujiao,Peng, Hao,He, Hongwu
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p. 663 - 671
(2013/07/26)
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- Synthesis and herbicidal activity of 2-(substituted phenoxyacetoxy)alkyl-5, 5-dimethyl-1,3,2-dioxaphosphinan-2-one containing fluorine
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A series of novel 2-(substituted phenoxyacetoxy)alkyl-5,5-dimethyl-1,3,2- dioxaphosphinan-2-one bearing fluorine 5a-n and fluorine free 5o-q were designed and synthesized. The results of bioassay showed that some of the target compounds exhibited excellent herbicidal activities to Abutilon theophrasti, Brassica juncea, Amaranthus retroflexus and Eclipta prostrata in post-emergence treatment at a dosage of 150 g ai/ha. It could be found that the type and position of fluorine-containing group as X or Y on benzene ring had a very important effect on herbicidal activity. Compound 5l 2-[(2-chloro-4- fluorophenoxy)acetoxy](methyl)methyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one showed notable herbicidal activity, with 100% inhibition against A. theophrasti and A. retroflexus; and compound 5m 2-(3-trifluoromethylphenoxyacetoxy)(methyl) methyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one with 100% inhibition against A. theophrasti even at a dosage of 75 g ai/ha. Additional crop selectivity testing showed that compounds 5g 2-(3-trifluoromethylphenoxyacetoxy)(phenyl)methyl-5,5- dimethyl-1,3,2-dioxaphosphinan-2-one and 5l are safe to rice, corn, cotton, rape and wheat.
- Wang, Wei,He, Hong-Wu,Zuo, Na,Zhang, Xin,Lin, Ji-Sheng,Chen, Wei,Peng, Hao
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- Design, synthesis and in vitro antibacterial/antifungal evaluation of novel 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic acid derivatives
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A series of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic acid (norfloxacin) derivatives were prepared according to the principle of combinating bioactive substructures and tested for their activities against five plant pathogenic bacteria and three fungi in vitro. The preliminary bioassays indicated that almost all synthesized target compounds retained the antibacterial activities of norfloxacin and had some antifungal activities as carboxylic acid amide compounds. The activities of compounds 1 and 22 against Xanthomonas oryzae were better than norfloxacin and all tested compounds had better antibacterial activities as compared to the agricultural streptomycin sulfate (a commercial bactericide) against X. oryzae, Xanthomonas axonopodis and Erwinia aroideae. Additionally, compounds 2 and 20 displayed good antifungal activities against Rhizoctonia solani and their inhibition of growth reached 83% and 94% respectively at the concentration of 200 mg/L.
- Yu, Zhiyi,Shi, Guanying,Sun, Qiu,Jin, Hong,Teng, Yun,Tao, Ke,Zhou, Guoping,Liu, Wei,Wen, Fang,Hou, Taiping
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scheme or table
p. 4726 - 4733
(2010/01/06)
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- Synthesis and anti-inflammatory activity of 2-aryloxy methyl oxazolines
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A series of potential biologically active 2-aryloxy methyl oxazolines 3a-n have been synthesized from substituted hydroxybenzenes 1a-n with good chemical yield. The compounds 3a-n were screened for their anti-inflammatory, ulcerogenic, cyclooxygenase activities and also for their acute toxicity. The potency of the compounds was compared with that of the standard drugs, aspirin and phenyl butazone. The outcome indicates that compounds 3b (48.2%), 3h (48.5%) and 3l (46.5%) offered significant anti-inflammatory activity with low ulcerogenic activity than the standard drugs.
- Khanum, Shaukath Ara,Khanum, Noor Fatima,Shashikanth
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p. 4597 - 4601
(2009/04/06)
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- THIADIAZOLE DERIVATIVES, INHIBITORS OF STEAROYL-COA DESATURASE
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The present invention relates to substituted thiadiazole compounds of the formula (I) and pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing them and their use in medicine. In particular, the invention relates to compounds for modulating SCD activity.
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Page/Page column 46
(2008/12/07)
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- (Aryloxyacetylamino)benzoic acid analogues: A new class of hypoxia-inducible factor-1 inhibitors
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Structural modification of a compound discovered during screening using an HRE-dependent reporter assay has revealed a novel class of HIF-1 inhibitors, which potently inhibit the HIF-1α protein accumulation and its target gene expression under hypoxic conditions in human hepatocellular carcinoma Hep3B cells.
- Lee, Kyeong,Lee, Jeong Hyung,Boovanahalli, Shanthaveerappa K.,Jin, Yinglan,Lee, Mijeoung,Jin, Xuejun,Kim, Jin Hwan,Hong, Young-Soo,Lee, Jung Joon
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p. 1675 - 1684
(2008/02/01)
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- The synthesis and herbicidal evaluation of fluorine-containing phenoxyacetoxyalkylphosphonate derivatives
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To investigate the influence of a fluorine moiety on the biological activity of phenoxyacetoxyalkylphosphonates, a series of fluorine-containing phenoxyacetoxyalkylphosphonates were synthesized and screened for herbicidal activity in a greenhouse. The majority of the title compounds showed better preemergence activity than postemergence activity against the test plants, especially on monocotyledon. Compound 5l exhibited notable activity. Results showed that by introducing a fluorine moiety to the parent structure of phenoxyacetoxyalkylphosphonates, a series of new compounds with satisfactory herbicidal activity could be synthesized. A reasonable combination of a fluorine moiety and other substituents on the benzene ring had a great influence on the herbicidal activity. Copyright Taylor & Francis Group, LLC.
- Chen, Ting,Shen, Ping,Li, Yanjun,He, Hongwu
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p. 2135 - 2145
(2007/10/03)
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- One-pot synthesis of fluorine containing 3-cyano/ethoxycarbonyl-2-methyl- benzo[b]furans
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Fluoro-substituted 3-cyano-2-methyl-benzo[b]furans and ethyl 2-methyl-benzo[b]furan-3-carboxylates are conveniently prepared in a single step in good yield by the microwave induced tandem intramolecular Wittig and Claisen rearrangement reactions of the corresponding [(aryloxyacetyl) (cyano) methylene] triphenylphosphorane and [(aryloxyacetyl) (ethoxycarbonyl) methylene] triphenylphosphoranes, respectively. Graphical Abstract
- RamaRao,Venkat Reddy,Maitraie,Ravikanth,Yadla,Narsaiah,Shanthan Rao
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p. 12231 - 12237
(2007/10/03)
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- Skeletal Rearrangements Preceding CO Loss from Metastable Phenoxymethylene Ions Derived from Phenoxyacetic Acid and Anisole
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The loss of CHO2(.) from the molecular ion of phenoxyacetic acid and the expulsion of an H(.) atom from ionized anisole lead to phenoxymethylene ions, which fragment predominantly by CO loss on the microsecond time-scale.Carbon-13 labelling reveals that ca. 90percent of the CO molecules expelled from the metastable ions derived from phenoxyacetic acid incorporate the carbon atom from the 1-position of the phenyl group of the parent compound, whereas the residual CO molecules contain one of the other carbon atoms of the aromatic ring.The 2-fluoro- and 2-methylphenoxymethylene ions derived from the appropriate aryloxyacetic acids behave similarly, i.e. the carbon atom of the methylene group of the parent compound is not incorporated in the expelled CO molecules.In contrast, ca. 45percent of the CO molecules eliminated from the metastable phenoxymethylene ions formed from ionized anisole contain the carbon atom of the methyl group, while the remaining part contains the carbon atom from the 1-position of the phenyl ring of the parent compound.This result is taken as evidence for the occurrence of a skeletal rearrangement of the anisole molecular ion leading to an interchange between the carbon atom of the methyl group and the carbon atom at the 1-position of the ring.The elimination of CO from the metastable ions generated from either phenoxyacetic acid or anisole gives rise to a composite metastable peak.Conclusive evidence as to the formation of (+) isomers other than the phenoxymethylene ion is not obtained, indicating that the composite metastable peak is a result of two competing reactions both leading to CO loss.Possible mechanisms of these reactions are discussed together with the mechanism of the skeletal rearrangement of the molecular ion of anisole prior to H(.) loss.
- Molenaar-Langeveld, Tineke A.,Ingemann, Steen,Nibbering, Nico M. M.
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p. 1167 - 1178
(2007/10/02)
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- 1-carbalkoxyalkyl-3-aryloxy-4-(substituted-2'-carboxyphenyl)-azet-2-ones as plant growth regulators and herbicides
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Compounds of the formula: STR1 wherein R1 is lower alkyl or benzyl; R2 is lower alkoxy, benzyloxy or the group STR2 where R3 is lower alkoxy; Ar is phenyl or phenyl substituted with 1 to 3 substituents independently selected from halogen, trihalomethyl, nitro, phenyl, lower alkoxy and lower alkyl; and X1 and X2 are independently hydrogen, halogen, lower alkoxy, or lower alkyl, or X1 and X2 taken together form an aromatic ring fused with the phenyl ring, provided that both X1 and X2 are not hydrogen show activity as plant growth regulators.
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- Applicability of Hammett Equation to Insulated Systems - Kinetics of Alkaline Hydrolysis of meta- and para-Substituted Methyl Phenoxyacatates
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The kinetics of alkaline hydrolysis of some meta- and para-substituted methyl phenoxyacetates have been determined in 85percent (wt/wt) methanol-water at 10 deg C, 15 deg C, and 20 deg C.The activation parameters have been evaluated from Arrhenius plots and the isokinetic temperature has been analysed.The applicability of Hammett equation to the above reaction has been discussed.The interesting behaviour of halogeno substituents is also discussed.
- Gurumurthy, R.,Balakrishnan, N.
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p. 154 - 156
(2007/10/02)
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