- Study on the interaction of 1,5-diaryl pyrrole derivatives with αglucosidase; synthesis, molecular docking, and kinetic study
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Background: The delaying of absorption of glucose is one of the principal therapeutic approaches of type 2 diabetes. α-glucosidase inhibitors compete with the α-glucosidase enzyme activity, which helps to reduce the conversion of carbohydrates into glucose and thereby control the postprandial hyperglycemia incidence. Objective: The aim of this study was to synthesize a series of novel 1,5-diphenyl pyrrole derivatives and evaluate their in vitro α-glucosidase inhibitory activities. Methods: Compounds were synthesized through a multistep reaction and were evaluated for αglucosidase inhibitory activities. Molecular docking and kinetic studies were carried out to predict the mode of binding and mechanism of inhibition for the most active compounds, 5g and 5b, against α-glucosidase. Results: Synthesized compounds showed good in vitro α-glucosidase inhibitory activity with IC50 values in the range of (117.5 ± 3.8 to 426.0 ± 10.2 μM) as compared to acarbose, the standard drug, (750 ± 8.7 μM). Compound 5g (117.5 ± 3.8 μM) ascertained as the most potent inhibitor of α-glucosidase in a competitive mode. The binding energies of compounds 5g and 5b (119.0 ± 7.5 μM), as observed from the best docking conformations, indicate that they have a lower free binding energy (-3.26 kcal/mol and-3.0 kcal/mol, respectively) than acarbose (2.47 kcal/mol). Conclusion: The results of our study revealed that the synthesized compounds are a potential candidate for α-glucosidase inhibitors for the management of postprandial hyperglycemia for further investigation.
- Tafesse, Tadesse Bekele,Moghadam, Ebrahim Saeedian,Bule, Mohammed Hussen,Faramarzi, Mohammad Ali,Abdollahi, Mohammad,Amini, Mohsen
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p. 545 - 553
(2021/03/26)
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- Synthesis and biological evaluation of 2-(2-methyl-1H-pyrrol-3-yl)-2-oxo-N-(pyridine-3-yl) acetamide derivatives: in vitro α-glucosidase inhibition, and kinetic and molecular docking study
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One of the therapeutic approaches in the management of type 2 diabetes is delaying the glucose absorption through α-glucosidase enzyme inhibition, which can reduce the occurrence of postprandial hyperglycemia. Based on this thought, a series of novel chloro-substituted 2-(2-methyl-1-phenyl-1H-pyrrol-3-yl)-2-oxo-N-(pyridin-3-yl) acetamide derivatives 5a–i were synthesized and their α-glucosidase inhibitory activities were evaluated. All the synthesized compounds have shown moderate to excellent in vitro α-glucosidase inhibitory activity with IC50 values in the range of 111–673?μM) as compared to acarbose, the standard drug (750 ± 9?μM). Compound 5e (111 ± 12?μM), among the series, was the most potent inhibitor of α-glucosidase in a competitive mode of action based on the kinetic study. The molecular docking study of compounds 5e and 5a revealed that they have a lower free binding energy (? 4.27?kcal/mol and ? 3.17?kcal/mol, respectively) than acarbose (? 2.47?kcal/mol), which indicates that the target compound binds more easily to the enzyme than acarbose does. The outcomes from the molecular docking studies supported the results obtained from the in vitro assay. In conclusion, the overall results of our study reveal that the synthesized compounds could be a potential candidate in the search for novel α-glucosidase inhibitors to manage postprandial hyperglycemia incidence.
- Tafesse, Tadesse Bekele,Moghadam, Ebrahim Saeedian,Bule, Mohammed Hussen,Abadian, Neda,Abdollahi, Mohammad,Faramarzi, Mohammad Ali,Amini, Mohsen
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p. 1583 - 1596
(2019/12/11)
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- Design, synthesis and in-vitro anti-cancer evaluation of novel derivatives of 2-(2-methyl-1,5-diaryl-1h-pyrrol-3-yl)-2-oxo-n-(pyridin-3-yl)acetamide
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Objective: Several anti-tubulin agents were introduced for the cancer treatment so far. Despite successes in the treatment of cancer, these agents cause toxic side effects, including peripheral neuropathy. Comparing anti-tubulin agents, indibulin seemed to cause minimal peripheral neuropathy, but its poor aqueous solubility and other potential clinical problems have led to its remaining in a preclinical stage. Methods: Herein, indibulin analogues were synthesized and evaluated for their in vitro anti-cancer activity using MTT assay (on the MCF-7, T47-D, MDA-MB231 and NIH-3T3 cell lines), annexin V/PI staining assay, cell cycle analysis, anti-tubulin assay and caspase 3/7 activation assay. Results: One of the compounds, 4a, showed good anti-proliferative activity against MCF-7 cells (IC50: 7.5 μM) and low toxicity on a normal cell line (IC50 > 100μM). All of the tested compounds showed lower cytotoxicity on normal cell line in comparison to reference compound, indibulin. In the annexin V/PI staining assay, induction of apoptosis in the MCF-7 cell line was observed. Cell cycle analysis illustrated an increasing proportion of cells in the sub-G-1 phase, consistent with an increasing proportion of apoptotic cells. No increase in G2/M cells was observed, consistent with the absence of anti-tubulin activity. A caspase 3/7 assay protocol showed that apoptosis induction by more potent compounds was due to activation of caspase 3. Conclusion: newly synthesized compounds exerted acceptable anticancer activity and further investigation of current scaffold would be beneficial.
- Alipour, Mohsen,Amini, Mohsen,Hamel, Ernest,Hosseinkhani, Saman,Moghadam, Ebrahim Saeedian,Ostad, Seyednasser,Saravani, Farhad,Shahsavari, Zahra
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p. 340 - 349
(2020/04/17)
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- Visible-Light Photocatalytic Preparation of 1,4-Ketoaldehydes and 1,4-Diketones from α-Bromoketones and Alkyl Enol Ethers
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A Ru2+-photocatalyzed, visible-light-mediated ATRA reaction for the straightforward preparation of 1,4-ketoaldehydes, 1,4-diketones, and 1,4-ketoesters, which are of difficult access by other means, is reported herein. This method employs readily accessible α-bromoketones and alkyl vinyl ethers as starting materials, allowing the construction of secondary, tertiary, and challenging quaternary centers. In addition, the synthetic usefulness of this method is illustrated by applying it to the construction of substituted pyrroles.
- García-Santos, William H.,Mateus-Ruiz, Jeferson B.,Cordero-Vargas, Alejandro
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supporting information
p. 4092 - 4096
(2019/06/17)
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- Copper-Catalyzed Decarboxylative Oxyalkylation of Alkynyl Carboxylic Acids: Synthesis of ?-Diketones and ?-Ketonitriles
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A novel copper-catalyzed decarboxylative oxyalkylation of alkynyl carboxylic acids with ketones and alkylnitriles via direct C(sp3)-H bond functionalization to construct new C-C bonds and C-O double bonds was developed. This transformation is featured by wide functional group compatibility and the use of readily available reagents, thus affording a general approach to ?-diketones and ?-ketonitriles. A possible mechanism is proposed.
- Li, Yi,Shang, Jia-Qi,Wang, Xiang-Xiang,Xia, Wen-Jin,Yang, Tao,Xin, Yangchun,Li, Ya-Min
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supporting information
p. 2227 - 2230
(2019/03/26)
-
- Nonclassical Mechanism in the Cyclodehydration of Diols Catalyzed by a Bifunctional Iridium Complex
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1,4- and 1,5-diols undergo cyclodehydration upon treatment with cationic N-heterocyclic carbene (NHC)–IrIII complexes to give tetrahydrofurans and tetrahydropyrans, respectively. The mechanism was investigated, and a metal-hydride-driven pathway was proposed for all substrates, except for very electron-rich ones. This contrasts with the well-established classical pathways that involve nucleophilic substitution.
- González Miera, Greco,Bermejo López, Aitor,Martínez-Castro, Elisa,Norrby, Per-Ola,Martín-Matute, Belén
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supporting information
p. 2631 - 2636
(2019/02/01)
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- Synthesis and anti-breast cancer activity of novel indibulin related diarylpyrrole derivatives
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Background: During recent years, a number of anti-tubulin agents were introduced for treatment of diverse types of cancer. Despite their potential in the treatment of cancer, drug resistance and adverse toxicity, such as peripheral neuropathy, are some of the negative effects of anti-tubulin agents. Among anti-tubulin agents, indibulin was found to cause minimal peripheral neuropathy. Thus far, however, indibulin has not entered clinical usage, caused in part by its poor aqueous solubility and other developmental problems in preclinical evaluation. Objectives: With respect to need for finding potent and safe anticancer agents, in our current research work, we synthesized several indibulin-related diarylpyrrole derivatives and investigated their anti-cancer activity. Methods: Cell cultur studies were perfomred using the MTT cell viability assay on the breast cancer cell lines MCF-7, T47-D, and MDA-MB231 and also NIH-3?T3 cells as representative of a normal cell line. The activity of some of the synthesized compounds for tubulin interaction was studied using colchicine binding and tubulin polymerization assays. The annexin V-FITC/PI method and flow cytometric analysis were used for studying apoptosis induction and cell cycle distribution. Results and conclusion: Two of the synthesized compounds, 4f and 4?g, showed high activity on the MDA-MB231 cell line (IC50?= 11.82 and 13.33?μM, (respectively) and low toxicity on the normal fibroblast cells (IC50?> 100?μM). All of the tested compounds were more potent on T47-D cancer cells and less toxic on NIH-3?T3 normal cells in comparison to reference compound, indibulin. The tubulin polymerization inhibition assay and [3H]colchicine binding assay showed that the main mechanism of cell death by the potent synthesized compounds was not related to an interaction with tubulin. In the annexin V/PI staining assay, the induction of apoptosis in the MCF-7 and MDA-MB231 cell lines was observed. Cell cycle analysis illustrated an increased percentage of sub-G-1 cells in the MDA-MB231 cell line as a further indication of cell death through induction of apoptosis. [Figure not available: see fulltext.].
- Saeedian Moghadam, Ebrahim,Hamel, Ernest,Shahsavari, Zahra,Amini, Mohsen
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p. 179 - 189
(2019/03/26)
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- Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies
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Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.
- Masci, Domiziana,Hind, Charlotte,Islam, Mohammad K.,Toscani, Anita,Clifford, Melanie,Coluccia, Antonio,Conforti, Irene,Touitou, Meir,Memdouh, Siham,Wei, Xumin,La Regina, Giuseppe,Silvestri, Romano,Sutton, J. Mark,Castagnolo, Daniele
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p. 500 - 514
(2019/06/18)
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- Design, synthesis and anticancer evaluation of novel series of indibulin analogues
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Background: Cancer is an important cause of human death worldwide. During the last decades, many anticancer agents with anti-tubulin mechanism have been synthesized or extracted from nature and some of them also entered clinical use. Indibulin is one of the most potent tubulin polymerization inhibitors with minimal peripheral neuropathy, which is a big problem by some of the antimitotic agents such as taxanes and vinka alkaloids. With respect to this giant benefit, herein we decided to design and synthesize novel indibulin related compounds and investigate their anticancer activity against HT-29, Caco-2 and T47-D cancerous cell lines as well as NIH-T3T as normal cell line. Objective: The aim of this study was to synthesize new anti-cancer agents and evaluates their cytotoxic activity on diverse cancerous and normal cell lines. Method: Target compounds were synthesized in multistep reaction and cytotoxic activity was investigated by MTT cell viability assay. Results: Herein, nine novel target compounds were synthesized in moderate to good yield. Some of the compounds exerted good cytotoxic activity against cancerous cell lines. Annexin V/PI staining showed that compound 4g could induce apoptosis and necrosis in HT-29 cell line. Conclusion: It is valuable to do further investigation on compound 4g which showed the highest activity against HT-29 and Caco-2 (IC50 values are 6.9 and 7 μM respectively). Also, synthesis of new derivatives of current synthesized compounds is suggested.
- Amini, Mohsen,Hamedani, Morteza P.,Moghadam, Ebrahim S.,Ostad, Seyednasser,Saravani, Farhad,Tavajohi, Shohreh
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p. 231 - 239
(2019/07/12)
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- In vivo potent BM635 analogue with improved drug-like properties
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BM635 is the hit compound of a promising anti-TB compound class. Herein we report systematic variations around the central pyrrole core of BM635 and we describe the design, synthesis, biological evaluation, pharmacokinetic analysis, as well as in vivo TB mouse efficacy studies of novel BM635 analogues that show improved physicochemical properties. This hit-to-lead campaign led to the identification of a new analogue, 4-((1-isopropyl-5-(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)morpholine (17), that shows excellent activity (MIC = 0.15 μM; SI = 133) against drug-sensitive Mycobacterium tuberculosis strains, as well as efficacy in a murine model of TB infection.
- Poce, Giovanna,Cocozza, Martina,Alfonso, Salvatore,Consalvi, Sara,Venditti, Giulia,Fernandez-Menendez, Raquel,Bates, Robert H.,Barros Aguirre, David,Ballell, Lluis,De Logu, Alessandro,Vistoli, Giulio,Biava, Mariangela
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supporting information
p. 539 - 550
(2018/01/17)
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- Design, synthesis and cytotoxicity evaluation of indibulin analogs
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Indibulin is one of the most potent tubulin polymerization inhibitors with minimal peripheral neuropathy. The design and synthesis of new indibulin analogs were carried out in order to investigate their anti-cancer activity. The target compounds 4a-i were synthesized in multistep reactions starting with the related indole derivatives. Compound 4f shows the highest cytotoxic activity on HT-29 and Caco-2 cell lines with the respective half maximal inhibitory concentration (IC50) values of 5.1 μm and 7.3 μm. In the case of the T47-D cell line, compound 4c exerts the best cytotoxic activity with an IC50 value of 11.5 μm. In the cell cycle analysis on HT-29 cells, compound 4f at 5.1 μm showed an increase in the percentage of cells in the sub-G1 phase. Altogether, nine target compounds were synthesized and characterized by infrared spectroscopy (IR), proton nuclear magnetic resonance (1H NMR), carbon-13 nuclear magnetic resonance (13C NMR), mass spectrometry (MS) and elemental analysis. Some of the compounds show good cytotoxic activity against cancerous cell lines.
- Saeedian Moghadam, Ebrahim,Saravani, Farhad,Ostad, Seyednasser,Tavajohi, Shohreh,Pirali Hamedani, Morteza,Amini, Mohsen
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p. 211 - 217
(2018/08/07)
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- One-pot synthesis of 2-methyl-1,5-diaromatic-1H-pyrroles from styrene, acetone and arylamines using TBHP, copper(II) trifluoromethanesulfonate and sulfamic acid
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The one-pot copper/manganese co-catalyzed heterocyclization of arylamine derivatives with styrene and acetone to produce a series of 2-methyl-1,5-diaromatic-1H-pyrroles was investigated. The described reaction combines 1,4-dicarbonyl synthesis and Paal-Knorr type condensation reactions.
- Xu, Congjun,Han, Yufei,Chen, Shaowei,Xu, Dengzhi,Zhang, Bingfu,Shan, Zhenliang,Du, Shimei,Xu, Liying,Gong, Ping
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p. 260 - 263
(2017/12/29)
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- Synthesis of 1,4-Dicarbonyl Compounds from Silyl Enol Ethers and Bromocarbonyls, Catalyzed by an Organic Dye under Visible-Light Irradiation with Perfect Selectivity for the Halide Moiety over the Carbonyl Group
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We report the visible-light-induced radical coupling reaction of silyl enol ethers with α-bromocarbonyl compounds to give 1,4-dicarbonyls. The reaction was effectively accelerated using an inexpensive organic dye (eosin Y) as a photoredox catalyst. 1,4-Dicarbonyl compounds alone were afforded, without the generation of carbonyl adducts of the α-halocarbonyls, which are usually generated in the presence of fluoride anions or Lewis acids. A variety of silyl enol ethers, α-bromoketones, α-bromoesters, and α-bromoamides were applied to this system to produce the coupling compounds.
- Esumi, Naoto,Suzuki, Kensuke,Nishimoto, Yoshihiro,Yasuda, Makoto
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supporting information
p. 5704 - 5707
(2016/11/17)
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- Copper/Manganese Cocatalyzed Oxidative Coupling of Vinylarenes with Ketones
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A novel copper/manganese cocatalyzed direct oxidative coupling of terminal vinylarenes with ketones via C(sp3)-H bond functionalization following C-C bond formation has been developed using tert-butyl hydroperoxide as the radical initiator. Various ketones underwent a free-radical addition of terminal vinylarenes to give the corresponding 1,4-dicarbonyl products with excellent regioselectivity and efficiency through one step. A possible reaction mechanism has been proposed.
- Lan, Xing-Wang,Wang, Nai-Xing,Zhang, Wei,Wen, Jia-Long,Bai, Cui-Bing,Xing, Yalan,Li, Yi-He
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supporting information
p. 4460 - 4463
(2015/09/28)
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- A regio- and stereoselective ω-transaminase/monoamine oxidase cascade for the synthesis of chiral 2,5-disubstituted pyrrolidines
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Biocatalytic approaches to the synthesis of optically pure chiral amines, starting from simple achiral building blocks, are highly desirable because such motifs are present in a wide variety of important natural products and pharmaceutical compounds. Herein, a novel one-pot ω-transaminase (TA)/monoamine oxidase (MAO-N) cascade process for the synthesis of chiral 2,5-disubstituted pyrrolidines is reported. The reactions proceeded with excellent enantio- and diastereoselectivity (>94 % ee; >98 % de) and can be performed on a preparative scale. This methodology exploits the complementary regio- and stereoselectivity displayed by both enzymes, which ensures that the stereogenic center established by the transaminase is not affected by the monoamine oxidase, and highlights the potential of this multienzyme cascade for the efficient synthesis of chiral building blocks. Mirror mirror on the wall: A ω-transaminase (ω-TA)/monoamine oxidase (MAO-N) cascade process for the asymmetric synthesis of chiral 2,5-disubstituted pyrrolidines is reported. The methodology exploits the complementary regio- and stereoselectivity displayed by both enzymes, which ensures that the stereogenic center established by the TA reaction is not affected by the MAO-N catalyzed step. Copyright
- O'Reilly, Elaine,Iglesias, Cesar,Ghislieri, Diego,Hopwood, Jennifer,Galman, James L.,Lloyd, Richard C.,Turner, Nicholas J.
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supporting information
p. 2447 - 2450
(2014/03/21)
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- Benzoyl radicals from (hetero)aromatic aldehydes. Decatungstate photocatalyzed synthesis of substituted aromatic ketones
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Benzoyl radicals are generated directly from (hetero)aromatic aldehydes upon tetrabutylammonium decatungstate ((n-Bu4N)4W 10O32), TBADT) photocatalysis under mild conditions. In the presence of α,β-unsaturated e
- Ravelli, Davide,Zema, Michele,Mella, Mariella,Fagnoni, Maurizio,Albini, Angelo
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experimental part
p. 4158 - 4164
(2010/11/02)
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- Carbonylative 1,4-addition of potassium aryltrifluoroborates to vinyl ketones
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Potassium aryltrifluoroborates have proven to be useful reagents for the carbonylative aroylation of vinyl ketones; this study broadens the scope of potassium aryltrifluoroborates in homogeneous catalysis and shows that the solvent can act as the proton s
- Sauthier, Mathieu,Lamotte, Nicolas,Dheur, Julien,Castanet, Yves,Mortreux, Andre
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experimental part
p. 969 - 971
(2010/08/21)
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- Synthesis of furans, pyrroles and pyridazines by a ruthenium-catalysed isomerisation of alkynediols and in situ cyclisation
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Alkyne-1,4-diols are readily available substrates which are isomerised to 1,4-diketones using Ru(PPh3)3(CO)H2/xantphos as a catalyst. In situ cyclisation into furans, pyrroles and pyridazines has been achieved under suitable conditions.
- Pridmore, Simon J.,Slatford, Paul A.,Taylor, James E.,Whittlesey, Michael K.,Williams, Jonathan M.J.
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supporting information; experimental part
p. 8981 - 8986
(2009/12/27)
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- Highly selective synthesis of 1-phenylpentane-1, 4-diones, and (E)-5-hydroxy-5-phenylpent-3-en-2-ones catalyzed by organophosphorus compounds
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1-Phenylpentane-1, 4-diones, and (E)- 5-hydroxy-5-phenylpent-3-en-2-ones were synthesized via organophosphine-catalyzed addition reaction of but-3-en-2-one with aldehydes. The features of the present protocols include high selectivity, operational simplicity, atom economy, and mild reaction conditions without transition metals.
- Zhang, Qing,Qiao, Yan-Fei,Huang, Min,Liang, Hong-Dong,Zhou, Ru-Jin
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experimental part
p. 425 - 430
(2010/07/16)
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- PYRROLE DERIVATIVES AND THEIR METHODS OF USE
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The invention relates to a series of substituted pyrrole derivatives, compositions comprising the same, and methods of treating conditions and disorders using such compounds and compositions.
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Page/Page column 68-69; 76-77
(2008/06/13)
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- 1,5-Diphenylpyrrole derivatives as antimycobacterial agents. Probing the influence on antimycobacterial activity of lipophilic substituents at the phenyl rings
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Synthesis and biological evaluation of new derivatives of 1,5-bis(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM 212, 16) are reported. Variously substituted phenyl rings with different substitution pattern and lipophilicity were
- Biava, Mariangela,Porretta, Giulio Cesare,Poce, Giovanna,De Logu, Alessandro,Saddi, Manuela,Meleddu, Rita,Manetti, Fabrizio,De Rossi, Edda,Botta, Maurizio
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supporting information; experimental part
p. 3644 - 3648
(2009/04/07)
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- Ruthenium-catalysed conversion of 1,4-alkynediols into pyrroles
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Various 1,2,5-substituted pyrroles have been synthesised from 1,4-alkynediols using a ruthenium catalysed isomerisation to give the corresponding 1,4-dicarbonyl compounds, which undergo in situ cyclisation to pyrroles in the presence of amine.
- Pridmore, Simon J.,Slatford, Paul A.,Daniel, Aurélie,Whittlesey, Michael K.,Williams, Jonathan M.J.
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p. 5115 - 5120
(2008/02/09)
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- 1,4-Carbonylative addition of arylboronic acids to methyl vinyl ketone: a new synthetic tool for rapid furan and pyrrole synthesis
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The rhodium catalysed 1,4-carbonylative addition of arylboronic acids to methyl vinyl ketone under carbon monoxide pressure was studied. High yields of 1,4-diketones were obtained using a catalytic system formed from Rh(COD)2BF4 (COD=1,5-cyclooctadiene) and triphenylphosphine even at very low catalyst loading (0.02 mol %). A short synthetic procedure combining this carbonylation reaction with a subsequent cyclisation step affords pyrroles or furans.
- Chochois, Hélène,Sauthier, Mathieu,Maerten, Eddy,Castanet, Yves,Mortreux, André
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p. 11740 - 11746
(2007/10/03)
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- Zinc-mediated chain extension reaction of 1,3-diketones to 1,4-diketones and diastereoselective synthesis of trans-1,2-disubstituted cyclopropanols
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A variety of 1,3-diketones can be efficiently converted into the corresponding 1,4-diketones and trans-1,2-disubstituted cyclopropanols by using organozinc species in one-pot reactions. It was found that 2.3 equiv of CF 3CO2ZnCH2I was effective to give the corresponding chain-extended products in 44-85% yields, while a mixture of organozinc species formed from 4.0 equiv of Et2Zn, 2.0 equiv of CF3CO2H, and 4.0 equiv of CH2I2 resulted in the formation of trans-1,2-disubstituted cyclopropanols with quite good yields and diastereoselectivity.
- Xue, Song,Li, Le-Zhen,Liu, Yong-Kang,Guo, Qing-Xiang
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p. 215 - 218
(2007/10/03)
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- Antimycobacterial pharmaceutical composition
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An antimycobacterial combination and composition for treating tuberculosis are described. The compounds used are N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2-methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide of formula (I) or a pharmaceutically ac
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Page/Page column 11
(2008/06/13)
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- PYRROLE DERIVATIVES AS ANTIMYCOBACTERIAL COMPOUNDS
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Novel pyrrole derivatives of formula (I), and their pharmaceutically acceptable acid addition salts having superior antimycobacterial activity against clinically sensitive as well as resistant strains of Mycobacterium tuberculosis as well as having lesser
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- New synthesis of 1,4-diketones via rhodium-catalysed 1,4 carbonylative addition of arylboronic acids to α,β-unsaturated ketones
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The reaction of various arylboronic acids with α,β-unsaturated ketones under CO pressure and in the presence of rhodium catalyst yields 1,4-diketones.
- Sauthier, Mathieu,Castanet, Yves,Mortreux, Andre
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p. 1520 - 1521
(2007/10/03)
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- Carbon-carbon bond cleavage of α-substituted benzoins by retro-benzoin condensation; A new method of synthesizing ketones
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When α-benzylbenzoin (3a, α-benzyl-α-hydroxybenzyl phenyl ketone) was treated with potassium cyanide (1) in N,N-dimethylformamide at 80°C for 1h, the carbon-carbon bond was cleaved, resulting in the formation of deoxybenzoin (4a, benzyl phenyl ketone) and benzaldehyde (2a). This carbon- carbon bond cleavage proceeds through a retro-benzoin condensation mechanism. This method of synthesizing ketones was applied to several α-substituted benzoins (3), and the corresponding ketones (4) were formed in good yields. Further, we found that the cyanide ion-donating ability of tetrabutylammonium cyanide (6, Bu4NCN) is more effective than that of potassium cyanide (1, KCN). As expected from the chemical analogy between cyanide ion and azolium ylide, several azolium salts (7) can also be employed in the retro-benzoin condensation as catalysts. The benzoin derivatives 3 were synthesized in the following three ways; reaction of alkyl halide (9) with benzoin (5), Michael addition of benzoin (5) with acceptors (10), and Grignard reaction of benzils (8). Alkylation of the benzoins without isolation, followed by carbon-carbon bond cleavage, readily afforded the corresponding ketones (4).
- Miyashita, Akira,Suzuki, Yumiko,Okumura, Yoko,Iwamoto, Ken-Ichi,Higashino, Takeo
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- Synthesis of ketones by retro-benzoin condensation catalyzed by potassium cyanide
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The treatment of 2-benzyl-1,2-diphenyl-2-hydroxyethanone (3a, benzylbenzoin) with potassium cyanide in DMF gave deoxybenzoin (4a). The formation of deoxybenzoin (4a) proceeds through retro-benzoin condensation by catalytic action of cyanide ion. Similarly, retro-benzoin condensation applied to several substituted benzoins 3 resulted in the formation of the corresponding ketones 4 in excellent yields.
- Miyashita,Suzuki,Okumura,Higashino
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p. 252 - 254
(2007/10/03)
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- Facile Control of Regioselectivity in the Reaction of Tin Enolates with α-Halogeno Carbonyls by Additives
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Tin enolates 1 reacted with α-halogeno ketones 2 and esters 10 to give a variety of 1,4-diketones 3 and γ-keto esters 11, respectively, in the presence of appropriate additives such as hexamethylphosphoric triamide (HMPT), tributylphosphine oxide and tetrabutylammonium bromide, while complexation of these additives with tributyltin bromide allowed catalytic production of β-keto oxiranes 4 instead of 3.The reaction mechanism for the preparation of 1,4-diketone 3 is discussed.
- Yasuda, Makoto,Oh-hata, Tatsuhiro,Shibata, Ikuya,Baba, Akio,Matsuda, Haruo
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p. 859 - 866
(2007/10/02)
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- Manganese(II and III)-Mediated Synthesis of Cyclic Peroxides from Alkenes, Active Methylene Compounds, and Molecular Oxygen
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The reaction of 1,1-diphenylethene, 1,1-bis(4-chlorophenyl)ethene, 1,1-bis(4-methylphenyl)ethene, 1,1-bis(4-methoxyphenyl)ethene, and 1,1-bis(4-fluorophenyl)ethene with 2-methyl-1,3-cyclohexanedione, 2-methyl-1,3-cyclopentanedione, 2-acetylcyclohexanone, ethyl 2-acetyl-3-oxobutanoate, 3-methyl-2,4-pentanedione, 1,3-cyclohexanedione, and 2,4-pentanedione in the presence of Mn(OAc)2 and molecular oxygen yielded the corresponding cyclic peroxides in moderate-to-good yields.Similar reaction of 1,1-disubstituted alkenes with 1,3-cyclopentanedione in the presence of Mn(OAc)3 and molecular oxygen gave 2,2,9,9-tetraphenyloctahydro-3,4,7,8-tetraoxabenzindene-4a,6a-diols.Acid-catalyzed decomposition of 4-acetyl-6,6-diaryl-3-methyl-1,2-dioxan-3-ols yielded 3-acetyl-5-aryl-2-methylfurans in moderate yields.Treatment of the 4-acetyl-6,6-diaryl-3-methyl-1,2-dioxan-3-ols with alkali gave 6,6-diaryl-3-methyl-1,2-dioxan-3-ols which gave 1-aryl-1,4-pentanediones upon treatment with hydrochloric acid in acetic acid.The synthetic utility and mechanism of the reactions are discussed.
- Qian, Chang-Yi,Yamada, Takashi,Nishino, Hiroshi,Kurosawa, Kazu
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p. 1371 - 1378
(2007/10/02)
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- Formation of 1,2-Dioxanes by the Use of Tris(2,4-pentanedionato)manganese(III) or Manganese(III) Acetate
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The reactions of 1,1-diphenylethene, 1,1-bis(4-chlorophenyl)ethene, 1,1-bis(4-methoxyphenyl)ethene, 1,1-bis(4-methylphenyl)ethene, 1,1-bis(4-fluorophenyl)ethene, styrene, 1-octene, cyclohexene, and cyclooctene with tris(2,4-pentanedionato)manganese(III) () in acetic acid at room temperature give 4-acetyl-3-methyl-1,2-dioxan-3-ol in 8-92percent yields, together with 3-acetyl-4-hydroxy-3-hexene-2,5-dione.The similar reactions of 1,1-diphenylethene with 2,4-pentanedione, 3-methyl-2,4-pentanedione, 3-ethyl-2,4-pentanedione, 1-phenyl-1,3-butanedione, acetoacetanilide, and 1,3-cyclohexanedione in the presence of manganese(III) acetate also give the corresponding cyclic peroxide in good to moderate yields.The mechanisms of manganese(III)-induced 1,2-dioxane ring formation and concomitant radical side reaction are discussed.
- Nishino, Hiroshi,Tategami, Shin-ichi,Yamada, Takashi,Korp, James D.,Kurosawa, Kazu
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p. 1800 - 1809
(2007/10/02)
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- Inhibitors of Cholesterol Biosynthesis. 1. trans-6-(2-Pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a Novel Series of HMG-CoA Reductase Inhibitors. 1. Effects of Structural Modifications at the 2- and 5-Positions of the Pyrrole Nucleus
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A novel series of trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones and their dihydroxy acid derivatives were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro.A systematic study of substitution at the 2- and 5-positions of the pyrrole ring revealed that optimum potency was realized with the 2-(4-fluorophenyl)-5-isopropyl derivative 8x (Table III), which possessed 30percent of the in vitro activity of the potent fungal metabolite compactin (I).A molecular modeling analysis led to the description of a pharmacophore model characterized by (A) length limits of 5.9 and 3.3 Angstroem for the 2- and 5-substituents, respectively, as well as an overall width limit of 10.6 Angstroem across the pyrrole ring from the 2- to the 5-substituent and (B) an orientation of the ethyl(ene) bridge to the 4-hydroxypyran-2-one ring nearly perpendicular to the planes of the parent pyrrole, hexahydronaphthalene, and phenyl rings of the structures examined (Figure 3, θ = 80-110 deg).Attempts to more closely mimic compactin's polar isobutyric ester side chain with the synthesis of 2-phenylpyrroles containing polar phenyl substituents resulted in analogues (Table III, 8m-p) with equal or slightly reduced potencies when compared to the 2-pyrroles, supporting the hypothesis that inhibitory potency is relatively insensitive to side-chain polarity or charge distribution in this area.
- Roth, B. D.,Ortwine, D. F.,Hoefle, M. L.,Stratton, C. D.,Sliskovic, D. R.,et al.
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