- Design, Synthesis, and Anticancer Activity of Cinnamoylated Barbituric Acid Derivatives
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This work deals with the design and synthesis of 18 barbituric acid derivatives bearing 1,3-dimethylbarbituric acid and cinnamic acid scaffolds to find potent anticancer agents. The target molecules were obtained through Knoevenagel condensation and acylation reaction. The cytotoxicity was assessed by the MTT assay. Flowcytometry was performed to determine the cell cycle arrest, apoptosis, ROS levels and the loss of MMP. The ratios of GSH/GSSG and the MDA levels were determined by using UV spectrophotometry. The results revealed that introducing substitutions (CF3, OCF3, F) on the meta- of the benzyl ring of barbituric acid derivatives led to a considerable increase in the antiproliferative activities compared with that of corresponding ortho- and para-substituted barbituric acid derivatives. Mechanism investigation implied that the 1c could increase the ROS and MDA level, decrease the ratio of GSH/GSSG and MMP, and lead to cell cycle arrest. Further research is needed for structural optimization to enhance hydrophilicity, thereby improve the biological activity of these compounds.
- Liu, Yue,Li, Peng-Xiao,Mu, Wen-Wen,Sun, Ya-Lei,Liu, Ren-Min,Yang, Jie,Liu, Guo-Yun
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- Iron-catalyzed domino decarboxylation-oxidation of α,β-unsaturated carboxylic acids enabled aldehyde C-H methylation
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A practical and general iron-catalyzed domino decarboxylation-oxidation of α,β-unsaturated carboxylic acids enabling aldehyde C-H methylation for the synthesis of methyl ketones has been developed. This mild, operationally simple method uses ambient air as the sole oxidant and tolerates sensitive functional groups for the late-stage functionalization of complex natural-product-derived and polyfunctionalized molecules.
- Gong, Pei-Xue,Xu, Fangning,Cheng, Lu,Gong, Xu,Zhang, Jie,Gu, Wei-Jin,Han, Wei
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supporting information
p. 5905 - 5908
(2021/06/18)
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- A novel phenylalanine ammonia-lyase from Pseudozyma antarctica for stereoselective biotransformations of unnatural amino acids
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A novel phenylalanine ammonia-lyase of the psychrophilic yeast Pseudozyma antarctica (PzaPAL) was identified by screening microbial genomes against known PAL sequences. PzaPAL has a significantly different substrate binding pocket with an extended loop (26 aa long) connected to the aromatic ring binding region of the active site as compared to the known PALs from eukaryotes. The general properties of recombinant PzaPAL expressed in E. coli were characterized including kinetic features of this novel PAL with L-phenylalanine (S)-1a and further racemic substituted phenylalanines rac-1b-g,k. In most cases, PzaPAL revealed significantly higher turnover numbers than the PAL from Petroselinum crispum (PcPAL). Finally, the biocatalytic performance of PzaPAL and PcPAL was compared in the kinetic resolutions of racemic phenylalanine derivatives (rac-1a-s) by enzymatic ammonia elimination and also in the enantiotope selective ammonia addition reactions to cinnamic acid derivatives (2a-s). The enantiotope selectivity of PzaPAL with o-, m-, p-fluoro-, o-, p-chloro- and o-, m-bromo-substituted cinnamic acids proved to be higher than that of PcPAL.
- Varga, Andrea,Csuka, Pál,Sonesouphap, Orlavanah,Bánóczi, Gergely,To?a, Monica Ioana,Katona, Gabriel,Molnár, Zsófia,Bencze, László Csaba,Poppe, László,Paizs, Csaba
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p. 185 - 194
(2020/04/28)
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- Design, synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase
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Background: Acetylcholine deficiencies in hippocampus and cortex, aggregation of β-amyloid, and β-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer’s disease. Methods: Colorimetric Ellman’s method was used for determination of IC50 value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and β-secretase inhibitory activities, evaluation of inhibitory potency on β-amyloid (Aβ) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action. Result and discussion: A new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC50 = 11.51?μM) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC50 = 1.95?μM) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak β-secretase inhibitory activities. This compound also inhibited aggregation of β-amyloid (Aβ) in self-induced peptide aggregation test at concentration of 10?μM. Conclusion: It is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay. [Figure not available: see fulltext.]
- Ghafary, Shahrzad,Ghobadian, Roshanak,Mahdavi, Mohammad,Nadri, Hamid,Moradi, Alireza,Akbarzadeh, Tahmineh,Najafi, Zahra,Sharifzadeh, Mohammad,Edraki, Najmeh,Moghadam, Farshad Homayouni,Amini, Mohsen
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p. 463 - 477
(2020/05/25)
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- Design, synthesis and biological evaluation of (E)-5-styryl-1,2,4-oxadiazoles as anti-tubercular agents
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Cinnamic acid and its derivatives are known for anti-tubercular activity. The present study reports the synthesis of cinnamic acid derivatives via bioisosteric replacement of terminal carboxylic acid with “oxadiazole”. A series of cinnamic acid derivatives (styryl oxadiazoles) were designed and synthesized in good yields by reaction of substituted cinnamic acids (2, 15a-15s) with amidoximes. The synthesized styryl oxadiazoles were evaluated in vitro for anti-tubercular activity against Mycobacterium tuberculosis (Mtb) H37Ra strain. The structure-activity relationship (SAR) study has identified several compounds with mixed anti-tubercular profiles. The compound 32 displayed potent anti-tubercular activity (IC50 = 0.045 μg/mL). Molecular docking studies on mycobacterial enoyl-ACP reductase enzyme corroborated well with the experimental findings providing a platform for structure based hit-to-lead development.
- Atmaram Upare, Abhay,Gadekar, Pradip K.,Sivaramakrishnan,Naik, Nishigandha,Khedkar, Vijay M.,Sarkar, Dhiman,Choudhari, Amit,Mohana Roopan
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supporting information
p. 507 - 512
(2019/02/19)
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- Cinnamic acid derivative and preparation method and application thereof
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The invention provides a cinnamic acid derivative. The cinnamic acid derivative is of the structure as shown in the formula I. The invention also provides two methods for preparing the cinnamic acid derivative. The two methods depend on a single bond or double bonds in the structure shown in the formula I. The invention further provides a pesticide. The pesticide comprises the cinnamic acid derivative. In addition, the invention provides a sterilization method. The sterilization method includes the step of applying the cinnamic acid derivative or the pesticide to crops. The crops include rice,wheat, fruit trees and vegetables. The low-toxicity, low-residue-content and high-activity environment-friendly cinnamic acid derivative is developed, and the cinnamic acid derivative pesticide can replace traditional high-toxicity and high-residue-content pesticides.
- -
-
Paragraph 0138-0140
(2019/10/22)
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- Lithium perchlorate catalyzed electrophilic activation: A convenient one-pot synthesis of trans-cinnamic acids
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Background: Currently perchlorate catalysts gain much attention in organic synthesis due to ease of operation, wide applicability, high yield, and economy. This is evident through increasing number of citation related to their application in industry as well as other allied fields. The aim of this paper is to describe a methodology using lithium perchlorate to catalyze the Knoevenagel condensation reaction for the synthesis of biologically active trans-cinnamic acid in good to excellent yield. Methods: We discuss herein an economic, user-friendly one-pot synthesis of trans-cinnamic acids by refluxing a mixture of a malonic acid with aryl aldehyde in pyridine. The product was easily isolated via filtration and thereafter washed and characterized by spectroscopic methods. Results: This method is robust, stereoselective and high yielding. It can be utilized to synthesize a wide array of trans-cinnamic acids in good to excellent yield using 20% of lithium perchlorate catalyst. It is also useful in the synthesis of aliphatic α,β-unsaturated carboxylic acid. Conclusion: The role of lithium perchlorate as a mild catalyst in the synthesis of trans-cinnamic acid was explored. The reactions afforded a good yield of various products with simpler isolation.
- Kaur, Paranjeet,Khatik, Gopal L.
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p. 688 - 692
(2018/07/13)
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- Synthesis, Crystallization Studies, and in vitro Characterization of Cinnamic Acid Derivatives as SmHDAC8 Inhibitors for the Treatment of Schistosomiasis
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Schistosomiasis is a neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy relies on mass treatment with only one drug: praziquantel. Based on the 3-chlorobenzothiophene-2-hydroxamic acid J1075, a series of hydroxamic acids with different scaffolds were prepared as potential inhibitors of Schistosoma mansoni histone deacetylase 8 (SmHDAC8). The crystal structures of SmHDAC8 with four inhibitors provided insight into the binding mode and orientation of molecules in the binding pocket as well as the orientation of its flexible amino acid residues. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs. The most promising compounds were further investigated for their activity toward the major human HDAC isotypes. The most potent inhibitors were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Two of the compounds showed significant, dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
- Bayer, Theresa,Chakrabarti, Alokta,Lancelot, Julien,Shaik, Tajith B.,Hausmann, Kristin,Melesina, Jelena,Schmidtkunz, Karin,Marek, Martin,Erdmann, Frank,Schmidt, Matthias,Robaa, Dina,Romier, Christophe,Pierce, Raymond J.,Jung, Manfred,Sippl, Wolfgang
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p. 1517 - 1529
(2018/08/01)
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- Chiral phosphoric acid catalyzed enantioselective annulation of acyclic enecarbamates to: In situ -generated ortho -quinone methides
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The first organocatalytic asymmetric reaction of acyclic enecarbamates with o-quinone methides is disclosed. BINOL-based phosphoric acid catalysts were found to be suitable for the annulation reaction. With 10 mol% of the TRIP catalyst, high yields as well as excellent diastereo- and enantioselectivities are achieved for a variety of 2,3,4-trisubstituted chroman products.
- Gharui, Chandan,Singh, Shreya,Pan, Subhas Chandra
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supporting information
p. 7272 - 7276
(2017/09/25)
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- Kinetic Resolution of Aromatic β-Amino Acids Using a Combination of Phenylalanine Ammonia Lyase and Aminomutase Biocatalysts
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An enzymatic strategy for the preparation of (R)-β-arylalanines employing phenylalanine aminomutase and ammonia lyase (PAM and PAL) enzymes has been demonstrated. Candidate PAMs with the desired (S)-selectivity from Streptomyces maritimus (EncP) and Bacillus sp. (PabH) were identified via sequence analysis using a well-studied template sequence. The newly discovered PabH could be linked to the first ever proposed biosynthesis of pyloricidin-like secondary metabolites and was shown to display better β-lyase activity in many cases. In spite of this, a method combining the higher conversion of EncP with a strict α-lyase from Anabaena variabilis (AvPAL) was found to be more amenable, allowing kinetic resolution of five racemic substrates and a preparative-scale reaction with >98% (R) enantiomeric excess. This work represents an improved and enantiocomplementary method to existing biocatalytic strategies, allowing simple product separation and modular telescopic combination with a preceding chemical step using an achiral aldehyde as starting material. (Figure presented.).
- Weise, Nicholas J.,Ahmed, Syed T.,Parmeggiani, Fabio,Turner, Nicholas J.
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p. 1570 - 1576
(2017/05/05)
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- Synthesis and bioactivities of novel piperazine-containing 1,5-Diphenyl-2-penten-1-one analogues from natural product lead
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A series of novel 1,5-Diphenyl-2-penten-1-one analogues (7a–h, 8a–h) with piperazine moiety have been designed and synthesized on the basis of natural product 1,5-Diphenyl-2-penten-1-one (I). All the synthesized compounds were evaluated in vitro for anti-plant pathogenic fungi activities and insecticidal activities. The results indicated that most of these analogues exhibited moderate antifungal activities and moderate to good insecticidal activities. Amongst them, the most potent 7c, 7e and 7h keep a mortality of 100% against larva of mosquito at the concentration of 1?mg/L. Initial structure–activity relationship (SAR) analysis showed that, a methyl group can influence the biological activities of these compounds significantly, the compounds with N′-unsubstituted piperazine showed much better antifungal activities and larvicidal activity against mosquito than the compounds with N′-methylated piperazine. In addition, the larvicidal activity against mosquito had sharply decline when the substituent on benzene ring was changed from 4-position to 2 or 3-position.
- Xu, Gaofei,Yang, Xinling,Jiang, Biaobiao,Lei, Peng,Liu, Xili,Wang, Qingmin,Zhang, Xuebo,Ling, Yun
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p. 1849 - 1853
(2016/07/27)
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- Design, synthesis, and evaluation of 2-piperidone derivatives for the inhibition of β-amyloid aggregation and inflammation mediated neurotoxicity
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A series of novel multipotent 2-piperidone derivatives were designed, synthesized and biologically evaluated as chemical agents for the treatment of Alzheimer's disease (AD). The results showed that most of the target compounds displayed significant potency to inhibit Aβ1-42 self-aggregation. Among them, compound 7q exhibited the best inhibition of Aβ1-42 self-aggregation (59.11% at 20 μM) in a concentration-dependent manner. Additionally, the compounds 6b, 7p and 7q as representatives were found to present anti-inflammation properties in lipopolysaccharide (LPS)-induced microglial BV-2 cells. They could effectively suppress the production of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6. Meanwhile, compound 7q could prevent the neuronal cell SH-SY5Y death by LPS-stimulated microglia cell activation mediated neurotoxicity. The molecular modeling studies demonstrated that compounds matched the pharmacophore well and had good predicted physicochemical properties and estimated IC50 values. Moreover, compound 7q exerted a good binding to the active site of myeloid differentiation factor 88 (MyD88) through the docking analysis and could interfere with its homodimerization or heterodimerization. Consequently, these compounds emerged as promising candidates for further development of novel multifunctional agents for AD treatment.
- Li, Lei,Chen, Ming,Jiang, Feng-Chao
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p. 1853 - 1865
(2016/04/05)
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- Telescopic one-pot condensation-hydroamination strategy for the synthesis of optically pure L-phenylalanines from benzaldehydes
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A chemo-enzymatic telescopic approach was designed for the synthesis of L-arylalanines in high yield and optical purity, starting from commercially available and inexpensive substituted benzaldehydes. The method exploits a chemical Knoevenagel–Doebner condensation (optimised to give complete conversions in a short reaction time, employing microwave irradiation) and a biocatalytic phenylalanine ammonia lyase mediated hydroamination (for the stereoselective addition of ammonia). The two reactions can be run sequentially in one pot, bringing together the advantages of chemical and biological catalysis. The preparative applicability was demonstrated with the synthesis of five L-dihalophenylalanines (71–84% yield, 98–99% ee) of relevance as molecular probes, for medicinal chemistry and for the synthesis of pharmaceutical ingredients.
- Parmeggiani, Fabio,Ahmed, Syed T.,Weise, Nicholas J.,Turner, Nicholas J.
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p. 7256 - 7262
(2016/10/26)
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- Influence of the aromatic moiety in α- And β-arylalanines on their biotransformation with phenylalanine 2,3-aminomutase from: Pantoea agglomerans
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In this study enantiomer selective isomerization of various racemic α- and β-arylalanines catalysed by phenylalanine 2,3-aminomutase from Pantoea agglomerans (PaPAM) was investigated. Both α- and β-arylalanines were accepted as substrates when the aryl moiety was relatively small, like phenyl, 2-, 3-, 4-fluorophenyl or thiophen-2-yl. While 2-substituted α-phenylalanines bearing bulky electron withdrawing substituents did not react, the corresponding substituted β-aryl analogues were converted rapidly. Conversion of 3- and 4-substituted α-arylalanines happened smoothly, while conversion of the corresponding β-arylalanines was poor or non-existent. In the range of pH 7-9 there was no significant influence on the conversion of racemic α- or β-(thiophen-2-yl)alanines, whereas increasing the concentration of ammonia (ammonium carbonate from 50 to 1000 mM) inhibited the isomerization progressively and decreased the amount of the by-product (i.e. (E)-3-(thiophen-2-yl)acrylic acid was detected). In all cases, the high ee values of the products indicated excellent enantiomer selectivity and stereospecificity of the isomerization except for (S)-2-nitro-α-phenylalanine (ee 92%) from the β-isomer. Substituent effects were rationalized by computational modelling revealing that one of the main factors controlling biocatalytic activity was the energy difference between the covalent regioisomeric enzyme-substrate complexes.
- Varga, Andrea,Bánóczi, Gergely,Nagy, Botond,Bencze, László Csaba,To?a, Monica Ioana,Gellért, ákos,Irimie, Florin Dan,Rétey, János,Poppe, László,Paizs, Csaba
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p. 56412 - 56420
(2016/07/06)
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- Design, synthesis and cytotoxic evaluation of novel imatinib amide derivatives that target Abl kinase
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Novel imatinib amide derivatives (a1-28, b1-9) were synthesized and evaluated for their biological activities. All compounds were characterized by 1H NMR, MS and elemental analysis. Among all the derivatives, compounds a4, a10, a21, b1 and b2 displayed the most significant ability of inhibiting K562 cell proliferation with the IC50 values of 0.67, 0.66, 0.65, 0.59 and 0.62 μM, respectively, indicating that these compounds were potent inhibitors of Bcr-Abl in leukemic K562 cells, comparable to the reference compound imatinib. Molecular docking study was performed to position compounds a21 and b1 into the active site of Abl to determine the probable binding modes
- Yao, Ri-Sheng,Guan, Qiu-Xiang,Lu, Xiao-Qin,Ruan, Ban-Feng
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- Design, synthesis and antibacterial activity of cinnamaldehyde derivatives as inhibitors of the bacterial cell division protein FtsZ
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In an attempt to discover potential antibacterial agents against the increasing bacterial resistance, novel cinnamaldehyde derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activity against nine significant pathogens using broth microdilution method, and their cell division inhibitory activity against four representative strains. In the in vitro antibacterial activity, the newly synthesized compounds generally displayed better efficacy against Staphylococcus aureus ATCC25923 than the others. In particular, compounds 3, 8 and 10 exerted superior or comparable activity to all the reference drugs. In the cell division inhibitory activity, all the compounds showed the same trend as their in vitro antibacterial activity, exhibiting better activity against S. aureus ATCC25923 than the other strains. Additionally, compounds 3, 6, 7 and 8 displayed potent cell division inhibitory activity with an MIC value of below 1 1/4g/mL, over 256-fold better than all the reference drugs.
- Li, Xin,Sheng, Juzheng,Huang, Guihua,Ma, Ruixin,Yin, Fengxin,Song, Di,Zhao, Can,Ma, Shutao
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- Unravelling the structural and molecular basis responsible for the anti-biofilm activity of zosteric acid
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The natural compound zosteric acid, or p-(sulfoxy)cinnamic acid (ZA), is proposed as an alternative biocide-free agent suitable for preventive or integrative anti-biofilm approaches. Despite its potential, the lack of information concerning the structural and molecular mechanism of action involved in its anti-biofilm activity has limited efforts to generate more potent anti-biofilm strategies. In this study a 43-member library of small molecules based on ZA scaffold diversity was designed and screened against Escherichia coli to understand the structural requirements necessary for biofilm inhibition at sub-lethal concentrations. Considerations concerning the relationship between structure and anti-biofilm activity revealed that i) the para-sulfoxy ester group is not needed to exploit the anti-biofilm activity of the molecule, it is the cinnamic acid scaffold that is responsible for anti-biofilm performance; ii) the anti-biofilm activity of ZA derivatives depends on the presence of a carboxylate anion and, consequently, on its hydrogen-donating ability; iii) the conjugated aromatic system is instrumental to the anti-biofilm activities of ZA and its analogues. Using a protein pull-down approach, combined with mass spectrometry, the herein-defined active structure of ZA was matrix-immobilized, and was proved to interact with the E. coli NADH:quinone reductase, WrbA, suggesting a possible role of this protein in the biofilm formation process.
- Cattò, Cristina,Dell'Orto, Silvia,Villa, Federica,Villa, Stefania,Gelain, Arianna,Vitali, Alberto,Marzano, Valeria,Baroni, Sara,Forlani, Fabio,Cappitelli, Francesca
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- Aromatic diacylhydrazine derivatives as a new class of polo-like kinase 1 (PLK1) inhibitors
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A novel class of aromatic diacylhydrazine derivatives was designed as PLK1 inhibitors. All the 19 new synthesized compounds were assayed for antitumor activity against the respective cervical cancer cells. In which, nine compounds with better antitumor activities were further tested for their PLK1 inhibitory activity. Last, we have successfully found that compound 7k showed both the promising antitumor activity with IC50 of 0.17 μM against the cervical cancer cells, and also processed the most potent PLK1 inhibitory activity with IC50 of 0.03 μM. In addition, docking simulation also carried out in this study to give a potent prediction binding mode between the small molecule and PKL1 (PDB code: 1umw) protein.
- Sun, Juan,Lv, Peng-Cheng,Guo, Feng-Jiao,Wang, Xin-Yi,Han, Xiao-,Zhang, Yang,Sheng, Gui-Hua,Qian, Shao-Song,Zhu, Hai-Liang
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p. 420 - 426
(2014/06/09)
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- Sodium tetraborate/benzyltriethylammonium chloride-mediated synthesis of substituted cinnamic acids from aromatic aldehydes and aliphatic carboxylic acids
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A simple, efficient, and cost-effective method has been developed for the synthesis of some cinnamic acid derivatives in moderate to high yields (63-86%) by a one-pot condensation reaction of benzaldehyde and aliphatic carboxylic acids in the presence of sodium tetraborate and benzyltriethylammonium chloride, and N-methyl-pyrrolidinone as solvent. The reaction requires high temperatures (reflux at 180-190°C) and strong basic conditions, which have been generated by pyridine and 4-dimethylaminopyridine added to the reaction medium.
- Nechifor, Marioara,Chiriac, Constantin I.,Tanasa, Fulga
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p. 161 - 164
(2014/04/03)
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- Design, synthesis and biological evaluation of cinnamic acyl shikonin derivatives
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Inducing apoptosis is an important and promising therapeutic approach to overcome cancer. Here, we described a series of novel synthesized compounds, cinnamic acyl shikonin derivatives (1b-19b), which were synthesized starting from shikonin and cinnamic acids, which exhibit anticancer activity via inducing apoptosis in vitro. Our flow cytometry results showed that compound 8b((E)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent -3-enyl-3-(3-(trifluoromethyl) phenyl)acrylate) (IC50=0.69, 0.65, 1.62 μm for human SW872-s, A875 and A549 cell lines, respectively) exhibited conspicuous anticancer activities and has low cell toxicity in vitro. Therefore, we considered that compound 8b is potentially to be a candidate of anticancer agent. The proliferation inhibitory effect of compound 8b was associated with its apoptosis-inducing effect by activating caspase-3, caspase-7, caspase-9, and PARP. When the level of cleaved caspase-3, cleaved caspase-7, cleaved caspase-9, and cleaved PARP are rise, apoptosis of cancer cells will be induced.
- Lin, Hong-Yan,Chen, Wei,Shi, Jing,Kong, Wen-Yao,Qi, Jin-Liang,Wang, Xiao-Ming,Yang, Yong-Hua
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p. 275 - 283
(2013/03/13)
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- Synthesis and antitumor activity of 1,3,4-oxadiazole possessing 1,4-benzodioxan moiety as a novel class of potent methionine aminopeptidase type II inhibitors
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A series of 1,3,4-oxadiazole derivatives containing 1,4-benzodioxan moiety (7a-7q) have been designed, synthesized and evaluated for their antitumor activity. Most of the synthesized compounds were proved to have potent antitumor activity and low toxicity. Among them, compound 7a showed the most potent biological activity against Human Umbilical Vein Endothelial cells, which was comparable to the positive control. The results of apoptosis and flow cytometry (FCM) demonstrated that compound 7a induce cell apoptosis by the inhibition of MetAP2 pathway. Molecular docking was performed to position compound 7a into MetAP2 binding site in order to explore the potential target.
- Sun, Juan,Li, Ming-Hui,Qian, Shao-Song,Guo, Feng-Jiao,Dang, Xiao-Fang,Wang, Xiao-Ming,Xue, Ya-Rong,Zhu, Hai-Liang
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supporting information
p. 2876 - 2879
(2013/06/26)
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- Substituent effects of cis-cinnamic acid analogues as plant growh inhibitors
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1-O-cis-Cinnamoyl-β-d-glucopyranose is one of the most potent allelochemicals that has been isolated from Spiraea thunbergii Sieb by Hiradate et al. It derives its strong inhibitory activity from cis-cinnamic acid (cis-CA), which is crucial for phytotoxicity. By preparing and assaying a series of cis-CA analogues, it was previously found that the key features of cis-CA for lettuce root growth inhibition are a phenyl ring, cis-configuration of the alkene moiety, and carboxylic acid. On the basis of a structure-activity relationship study, the substituent effects on the aromatic ring of cis-CA were examined by systematic synthesis and the lettuce root growth inhibition assay of a series of cis-CA analogues having substituents on the aromatic ring. While ortho- and para-substituted analogues exhibited low potency in most cases, meta-substitution was not critical for potency, and analogues having a hydrophobic and sterically small substituent were more likely to be potent. Finally, several cis-CA analogues were found to be more potent root growth inhibitors than cis-CA.
- Nishikawa, Keisuke,Fukuda, Hiroshi,Abe, Masato,Nakanishi, Kazunari,Taniguchi, Tomoya,Nomura, Takashi,Yamaguchi, Chihiro,Hiradate, Syuntaro,Fujii, Yoshiharu,Okuda, Katsuhiro,Shindo, Mitsuru
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p. 132 - 147
(2014/01/06)
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- Alum [KA1(S04)2. 12H20]: An efficient, novel, clean, catalyst for Doebner Knoevenagel reaction for the efficient production of αβ-unsaturated acids
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Alum mediated solvent free, microwave enhanced, clean process for the production of -unsaturated acids 3, 5 and 7 is described. Only 10 mole % of alum is enough in this protocol to achieve optimal yields and this protocol is fairly general and applicable to heterocyclic aldehydes and benzopyran 3-aldehydes.
- Suresh, Dhruva Kumar,Sandhu, Jagir S.
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experimental part
p. 1479 - 1483
(2011/12/02)
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- Synthesis of cinnamic acid derivatives in a water-insoluble ionic liquid
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A number of cinnamic acid derivatives have been synthesised from commercially available aromatic aldehydes and propanedioic acid in a water-insoluble ionic liquid (1-butyl-3-methylimidazolium hexafluorophosphate, [bmim]PF6) in high yields in the presence of small catalytic amounts of piperidine. The ionic liquid can be reused at least five times.
- Zhang, Wensheng,Xu, Wenjing,Liu, Mei,Yan, Yuerong,Sun, Yuezhi,Zhang, Sheli
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experimental part
p. 723 - 725
(2012/03/09)
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- The combination of 4-anilinoquinazoline and cinnamic acid: A novel mode of binding to the epidermal growth factor receptor tyrosine kinase
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A novel type of cinnamic acid quinazoline amide derivatives (20-42), which designed the combination between quinazoline as the backbone and various substituted cinnamic acid as the side chain, have been synthesized and their biological activities were evaluated within cytotoxicity assay firstly and then potent EGFR inhibitory activity. Compound 42 demonstrated the most potent inhibitory activity (IC50 = 0.94 μM for EGFR), which could be optimized as a potential EGFR inhibitor in the further study. Docking simulation was performed to position compound 42 into the EGFR active site to determine the probable binding model. Analysis of the binding conformation of 42 in active site displayed compound 42 was stabilized by hydrogen bonding interactions with Lys822, which was different from other derivatives. In the further study, Compounds 43 and 44 had been synthesized and their biological activities were also evaluated, which were the same as that we expected. Compound 43 has demonstrated significant EGFR (IC50 = 0.12 μM) and tumor growth inhibitory activity as a potential anticancer agent.
- Li, Dong-Dong,Lv, Peng-Cheng,Zhang, Hui,Zhang, Hong-Jia,Hou, Ya-Ping,Liu, Kai,Ye, Yong-Hao,Zhu, Hai-Liang
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experimental part
p. 5012 - 5022
(2011/10/04)
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- Regioselective addition of thiophenol to α,β-unsaturated N-acylbenzotriazoles
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Regioselective addition of thiophenol to α,β-unsaturated N-acylbenzotriazoles has been achieved by controlling the conditions. Thus, three types of products, namely α,β-unsaturated thioesters, β-thiophenoxy substituted N-acylbenzotriazoles, and β-thiophenoxy substituted thioesters were selectively obtained in good to excellent yields.
- Xia, Ziming,Lv, Xin,Wang, Wencun,Wang, Xiaoxia
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supporting information; experimental part
p. 4906 - 4910
(2011/10/07)
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- Bismuth(III) chloride-mediated, efficient, solvent-free, mwi-enhanced doebner condensation for the synthesis of (E)-cinnamic acids
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A bismuth(III) chloride-mediated green process for the production of (E)-cinnamic acid derivatives using microwave irradiation under solvent-free conditions is described. The (E)-cinnamic acids are obtained in excellent yields. This protocol is green because it employs an established environmentally benign procedure, microwave irradiation. Solvent vapor pollution is not there because it is solvent free, and bismuth(III) chloride is an established nontoxic catalyst. Copyright
- Suresh,Kumar, Dhruva,Sandhu, Jagir S.
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experimental part
p. 1915 - 1919
(2010/09/14)
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- Synthesis, molecular modeling, and biological evaluation of cinnamic acid metronidazole ester derivatives as novel anticancer agents
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A series of novel cinnamic acid metronidazole ester derivatives have been designed and synthesized, and their biological activities were also evaluated as potential EGFR and HER-2 kinase inhibitors. Compound 3h showed the most potent biological activity (IC50 = 0.62 μM for EGFR and IC50 = 2.15 μM for HER-2). Docking simulation was performed to position compound 3h into the EGFR active site to determine the probable binding model. Antiproliferative assay results demonstrated that some of these compounds possessed good antiproliferative activity against MCF-7. Compound 3h with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent.
- Qian, Yong,Zhang, Hong-Jia,Zhang, Hao,Xu, Chen,Zhao, Jing,Zhu, Hai-Liang
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experimental part
p. 4991 - 4996
(2010/09/05)
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- Selective bromination of 4-chloro-1-indanone and synthesis of (4-chloro-2, 3-dihydro-1H-indene-2-yl)methanamine
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The synthesis of 4-chloro-1-indanone in four steps from 2-chlorobenzaldehyde was investigated. Bromination of this compound under various conditions occurred in the cyclopentanone ring, producing mono- and dibromo derivatives. Cyanation of 2-bromo-4-chlor
- Jasouri,Khalafy,Badali,Piltan
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experimental part
p. 83 - 87
(2011/06/09)
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- Phenylalanine aminomutase-catalyzed addition of ammonia to substituted cinnamic acids: A route to enantiopure α- and β-amino acids
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(Chemical Equation Presented) An approach is described for the synthesis of aromatic α- and β-amino acids that uses phenylalanine aminomutase to catalyze a highly enantioselective addition of ammonia to substituted cinnamic acids. The reaction has a broad scope and yields substituted α- and β-phenylalanines with excellent enantiomeric excess. The regioselectivity of the conversion is determined by substituents present at the aromatic ring. A box model for the enzyme active site is proposed, derived from the influence of the hydrophobicity of substituents on the enzyme affinity toward various substrates.
- Szymanski, Wiktor,Wu, Bian,Weiner, Barbara,De Wildeman, Stefaan,Feringa, Ben L.,Janssen, Dick B.
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supporting information; experimental part
p. 9152 - 9157
(2010/03/01)
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- Cinnamoyl inhibitors of tissue transglutaminase
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(Figure Presented) Transglutaminases (TGases) catalyze the intermolecular cross-linking of certain proteins and tissue TGases (TG2) are involved in diverse biological processes. Unregulated, high TGase activities have been implicated in several physiological disorders, but few reversible inhibitors of TG2 have been reported. Herein, we report the synthesis of a series of novel trans-cinammoyl derivatives, discovered to be potent inhibitors of guinea pig liver transglutaminase. The most effective inhibitors evaluated can be sorted into two subclasses: substituted cinnamoyl benzotriazolyl amides and the 3-(substituted cinnamoyl)pyridines, referred to more commonly as azachalcones. Kinetic evaluation of both of these subclasses revealed that they display reversible inhibition and are competitive with acyl donor TGase substrates at IC50 values as low as 18 μM. An analysis of structure - activity relationships within these series of inhibitors permitted the identification of potentially important binding interactions. Further testing of some of the most potent inhibitors demonstrated their selectivity for TG2 and their potential for further development.
- Pardin, Christophe,Pelletier, Joelle N.,Lubell, William D.,Keillor, Jeffrey W.
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p. 5766 - 5775
(2008/12/22)
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- Design and synthesis of non-cytotoxic tetrahydrothieno[3,2-c]pyridine derivatives exhibiting complement inhibition activity
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A series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivatives have been synthesized and evaluated for their activity on the activation of human complement (classical pathway) and their intrinsic haemolytic activity. The in vitro assay results of these analogues for inhibition of complement activity reveals improved inhibitory activity for some of the analogues over existing tetrahydrothienopyridine derivatives like Ticlopidine and Clopidogrel. Significantly, these analogues did not exhibit any haemolytic activity and are non-cytotoxic to human cell lines.
- Master, Hoshang E.,Khan, Shabana I.,Poojari, Krishna A.
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- Synthesis of trans-cinnamic acids from aryl aldehydes and aryl aldehyde bisulfite adducts with malonic acid using piperazine
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Piperazine as a new reagent for the condensation of aryl aldehydes and their bisulfite adducts with malonic acid are described which afford the corresponding cinnamic acids in excellent yields and short reaction times in the absence of solvents under microwave irradiation.
- Khosropour, Ahmad Reza,Khodaei, Mohammad Mehdi,Moghanian, Hassan
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p. 364 - 365
(2007/10/03)
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- Competitive formation of β-amino acids, propenoic, and ylidenemalonic acids by the Rodionov reaction from malonic acid, aldehydes, and ammonium acetate in alcoholic medium
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The Rodionov reaction of 49 available aliphatic and aromatic aldehydes with malonic acid and ammonium acetate in alcoholic medium, resulting in formation of β-amino acids, propenoic, and ylidenemalonic acids, was studied. Certain regioselectivity regularities of the reaction were revealed. Among the variety of ketones studied, cyclohexanone is the only whose reaction yields a β-amino acid. Unusual dehydrofluorination of 6-chloro-2-fluorocinnamic acid under the Rodionov reaction was discovered. 2005 Pleiades Publishing, Inc.
- Lebedev,Lebedeva,Sheludyakov,Kovaleva,Ustinova,Kozhevnikov
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p. 1113 - 1124
(2007/10/03)
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- Large molecular motions are tolerated in crystals of diamine double salt of trans-chlorocinnamic acids with trans-1,2-diaminocyclohexane
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(Chemical Equation Presented) Contrary to the general assumption that photoreactions in crystals may not proceed with large molecular motions, a pedal-like motion prompted by electronic excitation is believed to be involved during the β-dimer formation from the crystals of the diamine double salt of trans-2,4-dichlorocinnamic acid and trans-1,2-diaminocyclohexane.
- Natarajan, Arunkumar,Mague, Joel T.,Venkatesan,Ramamurthy
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p. 1895 - 1898
(2007/10/03)
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- Microwave-Assisted Solvent-Free Synthesis of trans-Cinnamic Acids Using Lithium Chloride as Catalyst
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A simple and efficient procedure has been developed for the synthesis of trans-cinnamic acids 3 by the condensation of aromatic aldehydes 1 with malonic acid 2 using LiCl as catalyst under solvent-free conditions using microwave irradiation. The products are obtained in excellent yields and in a state of high purity.
- Mogilaiah,Reddy, G. Randheer
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p. 205 - 210
(2007/10/03)
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- Synthesis of heterocycles from the products of anionic arylation of unsaturated compounds. 7*. Products of haloarylation of acrylic acid and its esters in the synthesis of benzo[b]thiophene derivatives
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3-Chloro-2-chlorocarbonylbenzo[b]thiophenes were obtained on oxidation of Meerwein reaction products, viz. 3-aryl-2-halopropionic acids and their esters, with thionyl chloride in the presence of N-benzyl-N-methylmorpholinium chloride. Disubstituted thioureas were synthesized by the reaction of these compounds with ammonium thiocyanate and aromatic amines, and were cyclized by interaction with iodoacetic acid with the formation of 4-thiazolidinone derivatives. The same cyclization in the presence of aromatic aldehydes leads to the formation of the corresponding 5-arylidene-substituted 4-thiazolidinones.
- Obushak,Matiichuk,Martyak
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p. 878 - 884
(2007/10/03)
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- KF-Al2O3 catalysed synthesis of 3-phenyl-2-propenoic acids in dry media under microwave irradiation
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Malonic acid was condensed with several aryl - substituted aldehydes to the corresponding 3-phenyl-2-propenoic acids under microwave irradiation in solvent-free conditions on potassium fluoride impregnated alumina. Yields were dramatically improved in comparison with classical heating under the same conditions.
- Perez, Taimirys Mamposo,Pellon Comdom, Rolando F.,Mesa, Miriam,Velez, Herman
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p. 240 - 241
(2007/10/03)
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- A one-pot synthesis of 3-amino-3-arylpropionic acids
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3-Aminopropionic acids (β-amino acids) are biologically active compounds of interest in medicinal and pharmaceutical chemistry. Twenty-one 3-amino-3-arylpropionic acids were synthesized via a facile one-pot synthesis. In addition, a series of mechanistic studies have been performed to optimize the production of these β-amino acids. The reaction mechanism of this one-pot synthesis of β-amino acids, as well as the electronic effect of para-substitution and the influence of solvent polarity on the proposed reaction mechanism are discussed.
- Tan,Weaver
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p. 7449 - 7461
(2007/10/03)
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- Photocyclization of Ortho-Substituted Cinnamic Acids
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Mono and di (i.e. 2,6) o-chloro- and o-methoxycinnamic acids undergo photocyclization to give the corresponding coumarins.The reaction occurs in aqueous and organic media, with a prototypical reaction giving evidence of being favored at pH > 6.Cyclization of the dimethoxy acid is relatively inefficient (Φ for the PSS = 0.0015), and a photostationary state of the cis/trans acids is formed early into the reaction.The photocyclization of the dichloro analog is more efficient (Φ exceeds 0.04) and therefore time dependent since product formation competes with trans/cis isomerization.Methyl o-chlorocinnamate also photocyclizes (Φ for the PSS = 0.0022 in acetonitrile) but the o-methoxy ester is virtually photoinert.It is proposed that the acid photocyclizes through intramolecular nucleophilic attack by the carboxylate group followed by heterolysis of the nucleofuge.Methyl o-chlorocinnamate appears to photocyclize through a cycloaddition of the carbonyl group followed by homolysis of the Cl and Me moieties, possibly through the intermediacy of a ketene as proposed by earlier workers.
- Terrian, Deborah L.,Mohammad, Taj,Morrison, Harry
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p. 1981 - 1984
(2007/10/02)
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- Control of the Solid-state photodimerization of some derivatives and analogs of transcinnamic acid by ethylenediamine
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Some of double salts derived from ethylenediamine (en) and a variety of trans-cinnamic acids and their analogs underwent photodimerization in the solid state, giving predominantly β-truxinic dimers. X-Ray studies demonstrate that (a) the conformation of en is gauche for the highly photoreactive double salts (o-1b·en and m-le·en), whereas it is anti for lessphotoreactive o-la·en or photoinert Id·en and (b) for highly reactive o-lb·en and m-le·en, the monomer acid molecules are arranged in an overlap configuration and a reactive monomer pair is hydrogendashbonded to the same en molecule.
- Ito, Yoshikatsu,Borecka, Bozena,Olovsson, Gunnar,Trotter, James,Scheffer, John R.
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p. 6087 - 6090
(2007/10/02)
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- Iodide-promoted Debromination of Vicinal Dibromides. Part-I. In DMF
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The specific rate constants and the activation parameters ΔH*, ΔS* and ΔG*, for the iodide-induced debromination reaction of erythro-2,3-dibromo-3-phenylpropanoic acids (o-Cl, -F, -Br, -NO2, -CH3; m-OCH3, -F, -NO2, -CH3 and p-NO2, -F, -Cl, -CH3) and erythro-2,3-dibromobutanoic acid in dimethylformamide are reported.Ortho-substituted compounds were found to react faster than the unsubstituted ones irrespective of the nature of the substituent.Results indicate that the bromine attached to the α-carbon atom is attacked by I- and the transition state is between non-synchronous nearly E1 type and synchronous E2 type.
- Philip, V. J.,Mathai, I.M.,Raj, D. Joshwa Anthony,Jacob, G. Carol
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p. 350 - 353
(2007/10/02)
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- THE OXIDATION OF ALDEHYDES TO ACIDS WITH CALCIUM HYPOCHLORITE
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Calcium hypochlorite is an efficient reagent for the oxidation of aldehydes to the corresponding acids.Reactions are carried out at ambient temperature in aqueous acetonitrile-acetic acid solution.Aliphatic aldehydes and aromatic aldehydes with electron withdrawing groups afford good to excellent yields.Nuclear chlorination is the preferred reaction in aromatic aldehydes with electron donating groups.
- Nwaukwa, Stephen O.,Keehn, Philip M.
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p. 3131 - 3134
(2007/10/02)
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- Tha Use of 3,5-Dimethyl-4-nitroisoxazole for the Preparation of α,β-Unsaturated Aromatic Acids
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A series of α,β-unsaturated aromatic acids were preparaed by alkaline hydrolysis of 3-methyl-4-nitro-5-styrylisoxazoles.
- Sarti-Fantoni, P.,Donati, D.,Fiorenza, M.,Moschi, E.,Dal Piaz, V.
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p. 621 - 622
(2007/10/02)
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