- Naked-eye fluorescent sensor for Cu(II) based on indole conjugate BODIPY dye
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Graphical abstract A novel indole mono-styryl BODIPY was synthesised and characterized for the colorimetric recognition of Cu2+. It was also revealed from this study 3 can passively diffuse through cell membrane and stain both bacterial and mammalian cells even in very low concentrations. BODIPY-indole 3 retains inside the cells in cytometry and can be further modified for other applications.
- Tümay, Sureyya O.,Okutan, Elif,Sengul, Ibrahim F.,?zcan, Emrah,Kandemir, Hakan,Doruk, Tu?rul,?etin, Metin,?o?ut, Bünyemin
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- Synthesis, spectroscopic, computational and drug docking studies of 1-(benzenesulfonyl)-2-methyl-1H-indole-3-carbaldehyde
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An N-Substituted 1H-indole derivative having an empirical formula C16H13NO3S was synthesized by the condensation of 2-Methyl-1H-Indole-3-carbaldehyde and benzene sulfonyl chloride in presence of a phase transfer catalyst of type quaternary ammonium salt in basic conditions. Then the compound was characterized by using FT-IR, UV–Visible and NMR spectroscopic methods. Thus the obtained experimental results were effectively compared with DFT studies in arriving the structural characteristics of the title compound. From vibrational analysis, it was observed that carbonyl frequency is somewhat lower than a typical aldehydic stretching frequency and it could be possible only when the formyl group is coplanar with the ring and subsequent resonance conjugation reduces its force constant. Similarly, the optical absorption behavior of a typical indole ring suffered from a bathochromic shift due to the presence of ring substituents. Finally, the molecular drug docking studies of the title compound were performed using AutoDock 4.2 tools to ascertain its binding mode, efficiency and the nature of chemical interactions with the target proteins and it has been predicted theoretically that the binding efficiency of the ligand on the target receptor surface was found to be better in the case of Gram positive bacteria S. Aureus than the Gram negative N. Meningitidis.
- Bellamkonda, Yagna Narayana,Vijaya Chamundeeswari
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Read Online
- Triphenylphosphine/1,2-Diiodoethane-Promoted Formylation of Indoles with N, N -Dimethylformamide
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Despite intensive studies on the synthesis of 3-formylindoles, it is still highly desirable to develop efficient methods for the formylation of indoles, due to the shortcomings of the reported methods, such as inconvenient operations and/or harsh reaction conditions. Here, we describe a Ph3P/ICH2CH2I-promoted formylation of indoles with DMF under mild conditions. A Vilsmeier-type intermediate is readily formed from DMF promoted by the Ph3P/ICH2CH2I system. A onestep formylation process can be applied to various electron-rich indoles, but a hydrolysis needs to be carried out as a second step in the case of electron-deficient indoles. Convenient operations make this protocol attractive.
- Lin, Jin-Hong,Xiao, Ji-Chang,Zhu, Yu-Rong
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supporting information
(2021/11/22)
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- Palladium-catalysed annulative allylic alkylation for the synthesis of benzannulated heteroarenes
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A conceptually novel intramolecular allylic alkylation strategy is developed for the synthesis of carbazoles and dibenzothiophenes. In an unusual event, palladium catalyses the formation of π-allylpalladium complexes of the respective (2-methylindol-3-yl)allyl acetates and subsequently facilitates the benzannulation process. This journal is
- Yadav, Sonu,Ramasastry
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supporting information
p. 77 - 80
(2021/01/13)
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- First discovery of pimprinine derivatives and analogs as novel potential herbicidal, insecticidal and nematicidal agents
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Pimprinine and streptochlorin are indole natural products produced by many species of organisms, and they are reported to possess a wide range of biological activities, such as anticancer, antiviral, antifungal activity and so on. In this study, three series of pimprinine derivatives or analogs were efficiently synthesized under the optimized methods. Biological assays conducted at Syngenta firstly indicated the pimprinine derivatives or analogs possessed potential herbicidal and insecticidal activity, and this is highlighted by compounds 21g, 21h, 21i, 21j, 21l, 22h, 22i and 23h, they possessed significant biological activity as well as broad spectrum. Meanwhile, compounds with benzothiophene-oxazole core (21h, 22h and 23h), showed effective nematicidal activity in primary screening. Compounds 21g and 21i were identified as the most promising lead structures for further study.
- Zhang, Ming-Zhi,Mulholland, Nick,Seville, Anne,Hough, Gemma,Smith, Nicholas,Dong, Hong-Qiang,Zhang, Wei-Hua,Gu, Yu-Cheng
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supporting information
(2020/12/21)
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- Synthesis of Chiral Polycyclic Tetrahydrocarbazoles by Enantioselective Aminocatalytic Double Activation of 2-Hydroxycinnamaldehydes with Dienals
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An efficient aminocatalytic enantioselective double-activation strategy has been developed that combines several different aminocatalytic modes in a cascade process, such as iminium ion, vinylogous iminium ion, trienamine, and dienamine activations. By using this strategy, 2-hydroxycinnamaldehydes worked well with various dienals via [4 + 2] cycloaddition and the oxa-Michael reaction-initiated cascade, respectively, leading to chiral polycyclic tetrahydrocarbazole and chromane derivatives with excellent diastereo- and enantioselectivities.
- Ming, Yong-Chao,Lv, Xue-Jiao,Liu, Ming,Liu, Yan-Kai
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supporting information
p. 6515 - 6519
(2021/09/02)
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- Copper-catalyzed synthesis and anticancer activity evaluation of indolo[1,2-a]quinoline derivatives
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A simple and effective one-pot synthesis of substituted indolo[1,2-a]quinolines has been developed. The desired products were obtained in up to 98% yield when substituted 2-methyindoles were treated with 2-iodobenzaldehyde in the presence of Cs2CO3, CuI and L-proline. Our mechanistic study confirmed that the reaction sequence involved an intermolecular Knoevenagel reaction followed by an intramolecular Ullmann-type coupling reaction. Moreover, some of the synthesized compounds were found to be active against human breast (MCF-7) and colorectal (HCT-116) cancer cells with IC50 values of 27.96 μM and in the range of 6.21–46.91 μM, respectively.
- Borwornpinyo, Suparerk,Chuanopparat, Nutthawat,Jearawuttanakul, Kedchin,Kanjanasirirat, Phongthon,Ngernmeesri, Paiboon,Rattanarat, Hassayaporn,Seemakhan, Sawinee,Thanetchaiyakup, Adisak
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- Access to Polycyclic Thienoindolines via Formal [2+2+1] Cyclization of Alkynyl Indoles with S8and K2S
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The syntheses of polycyclic thienoindolines bearing a dihydrothiophene or tetrahydrothiophene subunit have not been reported, despite the fact that such compounds may have interesting medicinal properties. Herein, we report a protocol for accessing polycyclic dihydrothiophenes by means of formal [2+2+1] intramolecular dearomatizing cyclization of alkynyl indoles with K2S and S8 as the sources of sulfide. In addition, tetrahydrothienoindolines were stereoselectively synthesized via a one-pot, two-step protocol involving AgNO3-catalyzed alkenyl dearomatization followed by two nucleophilic addition reactions involving K2S.
- Ma, Jinhui,Luo, Jiajun,Jiang, Kai,Zhang, Guangwen,Liu, Shubin,Yin, Biaolin
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supporting information
p. 8033 - 8038
(2021/10/25)
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- Molecular iodine mediated oxidative cleavage of the C-N bond of aryl and heteroaryl (dimethylamino)methyl groups into aldehydes
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The oxidative cleavage of the C-N bond of aryl and heteroaryl (dimethylamino)methyl groups is achieved by employing molecular iodine as a mild oxidizing agent under ambient conditions in the presence of a mild base. The important reaction of C3 formylation of free NH and substituted indoles containing various substituents is accomplished from the corresponding Mannich bases. This methodology can also be extended for the synthesis of aryl and other heteroaryl aldehydes and ketones. Furthermore, the usefulness of the method is successfully demonstrated on a gram scale.
- Mandrekar, Ketan S.,Tilve, Santosh G.
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supporting information
p. 4152 - 4155
(2021/03/15)
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- C3-Formylation of Indoles in Continuous Flow
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We have developed a continuous flow C3-formylation technique for indoles using hexamethylenetetramine (HMTA) and iodine. A mixed solvent system of DMF–H2O (1:1, vol/vol) completely dissolves reagents and prevents clogging of microchannels during fluid flow. The continuous flow technique provides maximized mixing and excellent heat transfer efficiency. Thus, flow chemistry accelerates the rate of C3-formylation of indoles in the absence of a strong acid, base, or metal catalyst. We show that high yields of C3-formylated indoles (up to 83%) can be obtained at 150°C when the residence time is as low as 8 min.
- Sung, Ha Kyoung,Kim, Dong Hyun,Kim, Joon Seok,Park, Chan Pil
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supporting information
p. 388 - 392
(2020/12/30)
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- Anti-tumor compound NY and series of derivatives thereof
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The invention relates to an anti-tumor compound NY and a series of derivatives thereof, and an application of the anti-tumor compound NY and the series of derivatives of the anti-tumor compound NY inmedicines. According to the invention, ADAM17 is used as a target spot to design and completely synthesize 15 compounds of NY series; and the antitumor activity of the 15 compounds of the NY series isverified; thus, a potential antitumor activity drug is provided clinically.
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Paragraph 0058-0061; 0087-0089
(2020/05/02)
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- Access to Polycyclic Sulfonyl Indolines via Fe(II)-Catalyzed or UV-Driven Formal [2 + 2 + 1] Cyclization Reactions of N-((1H-indol-3-yl)methyl)propiolamides with NaHSO3
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A variety of structurally novel polycyclic sulfonyl indolines have been synthesized via FeCl2-catalyzed or UV-driven intramolecular formal [2 + 2 + 1] dearomatizing cyclization reactions of N-(1H-indol-3-yl)methyl)propiolamides with NaHSO3 in an aqueous medium. The reactions involve the formation of one C-C bond and two C-S bonds in a single step.
- Lu, Lin,Luo, Chenguang,Peng, Hui,Jiang, Huanfeng,Lei, Ming,Yin, Biaolin
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supporting information
p. 2602 - 2605
(2019/04/30)
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- Direct construction of carbazoles from 2-methyl-indole-3-carbaldehydes and enals
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The direct and rapid construction of carbazoles was achieved via the reaction of 2-methyl-indole-3-carbaldehydes with enals promoted by LiCl/DBU in a single operation. This mild and green reaction proceeds through a [4 + 2] cycloaddition/dehydration/oxidative aromatization cascade to generate carbazoles in good to excellent yields. The reaction features mild reaction conditions, a broad substrate scope, and excellent functional group tolerance, using O2 (1 atm) as the sole oxidant and affording H2O as the only by-product. More importantly, 4-fluoroquinocarbazole, a significant bioactive compound, was generated in 80% yield in only one step from the obtained carbazole.
- Liu, Dehai,Huang, Jie,Fu, Zhenqian,Huang, Wei
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supporting information
p. 968 - 972
(2019/04/17)
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- Synthesis, Antiviral Activity, and Induction of Plant Resistance of Indole Analogues Bearing Dithioacetal Moiety
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A series of compounds with potential activity to induce plant resistance was synthesized from indole and thiol compounds and methodically evaluated for antiviral activity. The results indicated that some of the synthesized compounds had high antipotato virus Y (PVY), anticucumber mosaic virus, and antitobacco mosaic virus activities. Notably, compound D21 exhibited the best activity against PVY among these compounds in vivo, and the 50% effective concentrations (EC50) of protection activity is 122 μg/mL, which was distinctively better than the corresponding values for ribavirin (653 μg/mL), Ningnanmycin (464 μg/mL), and Xiangcaoliusuobingmi (279 μg/mL). Interestingly, we found that the protection activity of D21 was associated with improvement of chlorophyll content and defense-related enzyme activities. Moreover, D21 could trigger the malate dehydrogenase (MDH) signaling pathway, as further confirmed by the MDH activity evaluation. Hence, D21 can protect plants against viral activity and has potential as a novel activator for plant resistance induction.
- Wei, Chunle,Zhang, Jian,Shi, Jing,Gan, Xiuhai,Hu, Deyu,Song, Baoan
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p. 13882 - 13891
(2019/12/04)
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- Synthesis of 3-Formylindoles via Electrochemical Decarboxylation of Glyoxylic Acid with an Amine as a Dual Function Organocatalyst
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A new method for 3-formalytion of indoles has been developed through electrochemical decarboxylation of glyoxylic acid with the amine as a dual function organocatalyst. The amine facilitated both the electrochemical decarboxylation and the nucleophilic reaction efficiently, whose loading can be as low as 1 mol %. This protocol has a broad range of functional group tolerance under ambient conditions. The gram-scale experiment has shown great potential in the synthetic application of this strategy.
- Lin, Dian-Zhao,Huang, Jing-Mei
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supporting information
p. 5862 - 5866
(2019/08/26)
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- One-pot synthesis of substituted indolo[1,2-a]quinolines under transition-metal-free conditions
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A simple and efficient one-pot synthesis of substituted indolo[1,2-a]quinolines under transition-metal-free conditions has been developed. When 2-fluorobenzaldehyde was treated with substituted 2-methylindoles in the presence of Cs2CO3, the desired products were typically obtained in good to excellent yields. This reaction sequence involves a nucleophilic aromatic substitution and a Knoevenagel condensation reaction. Our mechanistic investigation revealed that both reactions could proceed as an intermolecular reaction in the first step.
- Thanetchaiyakup, Adisak,Rattanarat, Hassayaporn,Chuanopparat, Nutthawat,Ngernmeesri, Paiboon
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supporting information
p. 1014 - 1018
(2018/02/23)
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- Discovery of the cancer cell selective dual acting anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131)
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Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound 4a was first identified in a phenotypic screen in which HeLa cells treated with 4a manifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that 4a causes an increase in mitotic marker pH3 and autophagy marker LC3. Importantly 4a induces cell death in cancer cells while sparing normal cells which regrow after 4a is removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed 4a as the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI50 1.5 μM). In a mouse model of paclitaxel-resistant colon cancer, 4a showed 74% tumor growth inhibition when administered at a dose of 20 mg/kg IP twice a day.
- See, Cheng Shang,Kitagawa, Mayumi,Liao, Pei-Ju,Lee, Kyung Hee,Wong, Jasmine,Lee, Sang Hyun,Dymock, Brian W.
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p. 344 - 367
(2018/07/25)
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- Selective and Efficient Formylation of Indoles (C3) and Pyrroles (C2) Using 2,4,6-Trichloro-1,3,5-Triazine/Dimethylformamide (TCT/DMF) Mixed Reagent
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This study introduces an efficient method for the selective formylation of indoles and pyrroles at the positions of C(3) and C(2), respectively. The mixture of three equivalents of N,N-dimethylformamide and one equivalent of 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) generates an easy handling formylating agent for the efficient formylation of these classes of compounds to give the corresponding aldehydes under mild reaction conditions. This procedure was highly efficient, and a range of formylated indoles and pyrroles were obtained in good to excellent yields.
- Iranpoor, Nasser,Panahi, Farhad,Erfan, Soodabeh,Roozbin, Fatemeh
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p. 904 - 910
(2017/03/27)
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- An environmentally friendly protocol for oxidative halocyclization of tryptamine and tryptophol derivatives
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An environmentally friendly and efficient protocol (KX/oxone) for oxidative halocyclization of tryptamine/tryptophol derivatives was developed and demonstrated with 28 examples and concise total synthesis of cyclotryptamine alkaloid protubonines A and B. The distinct advantage of this protocol over all previous methods is that no organic byproduct is generated from a halogenating agent or oxidant, thus greatly reducing the environmental impact of halocyclization and facilitating the post-reaction purification.
- Xu, Jun,Tong, Rongbiao
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supporting information
p. 2952 - 2956
(2017/07/24)
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- NOVEL TUBULIN POLYMERIZATION INHIBITOR AND METHOD FOR SYNTHESIZING SAME
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The present invention relates to (E)-ethyl 2-(2-methyl-3-((2-(naphtho[2,1-b]furan-2-carbonyl)hydrazono)methyl)-1H-indol-1-yl)acetate as a novel tubulin polymerization inhibitor and a method for synthesizing the same. The compound of the present invention can inhibit mitosis and induce apoptosis and thus be used as an anticancer agent, by binding to tubulin to inhibit microtube polymerization. According to the synthesis method of the present invention, the reaction is simplified and the efficiency is 60%, or higher, leading to a very high yield, thereby providing an effective synthesis method.
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Paragraph 0072-0075
(2016/05/10)
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- Cyclopenta[b]annulation of Heteroarenes by Organocatalytic γ′[C(sp3)?H] Functionalization of Ynones
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A new approach for the cyclopenta[b]annulation of heteroarenes through metal-free and directing-group-free γ′[C(sp3)?H] functionalization and intramolecular hydroalkylation of ynones has been developed. In an unprecedented event, nucleophilic addition of an organophosphine to the designed ynones triggers γ′[C(sp3)?H] functionalization, leading to the formation of heteroaryl-based ortho-quinodimethane (oQDM) intermediates that undergo carbocyclization to provide cyclopentannulated heteroarenes in good yields and excellent stereoselectivities. Deuterium-labeling experiments substantiated the proposed reaction mechanism as well as the speculated epimerization.
- Raghu, Moluguri,Grover, Jagdeep,Ramasastry
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supporting information
p. 18316 - 18321
(2016/12/16)
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- Design and synthesis of novel indole-chalcone fibrates as lipid lowering agents
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A series of novel indole-chalcone fibrates were synthesized and their hypolipidemic activity was evaluated in triton WR-1339 induced hyperlipidemic rat model. Preliminary studies indicated that the hybrids 19, 24 and 29 exhibited potent in vitro antioxidant and significant in vivo antidyslipidemic effects. Our results suggest that these new hybrid architectures may serve as promising leads for the development of next generation lipid lowering agents.
- Sashidhara, Koneni V.,Dodda, Ranga Prasad,Sonkar, Ravi,Palnati, Gopala Reddy,Bhatia, Gitika
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p. 499 - 509
(2014/06/10)
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- I2-mediated C3-formylation of indoles by tertiary amine and H2O
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An I2-promoted 3-formylation of free (N-H) and N-substituted indoles with tetramethylethylenediamine (TMEDA) and H2O as the carbonyl source is achieved, providing 3-formylindole in moderate to excellent yields with good functional gr
- Zhang, Bo,Liu, Bin,Chen, Jianbin,Wang, Jiehui,Liu, Miaochang
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supporting information
p. 5618 - 5621
(2014/12/11)
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- Elaboration of thorough simplified vinca alkaloids as antimitotic agents based on pharmacophore similarity
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Thorough simplification of vinca alkaloids based on pharmacophore similarity has been conducted. A concise process for the syntheses of target compounds was successfully developed with yields from poor to excellent (19-98%). Cell growth inhibitory activities of these synthesized compounds were evaluated in five cancer cell lines including MCF-7, MDA-MB-231, HepG2, HepG2/ADM and K562. Almost all compounds exhibited moderate antitumor activity with optimal IC50 value of 0.89 ± 0.07 μM in MCF-7 cells. Investigation of structure-activity relationship (SAR) indicates that electron-withdraw substituents on the ring contribute to the enhancement of the antitumor activities. The simplified vinca alkaloids are confirmed as antimitotic agents, which inhibit the polymerization of tubulin just like vinblastine.
- Zheng, Jing,Deng, Lijuan,Chen, Minfeng,Xiao, Xuzhi,Xiao, Shengwei,Guo, Cuiping,Xiao, Gaokeng,Bai, Liangliang,Ye, Wencai,Zhang, Dongmei,Chen, Heru
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p. 158 - 167
(2013/10/01)
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- Highly enantioselective Friedel-Crafts alkylation/N-hemiacetalization cascade reaction with indoles
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A new ring for your indole: An unprecedented copper-catalyzed enantioselective Friedel-Crafts alkylation/N-hemiacetalization cascade reaction with indoles and β,γ-unsaturated α-ketoesters is reported. This mild strategy provides new access to various synthetically and biologically important 2,3-dihydro-1H-pyrrolo[1,2-a]indoles in a highly enantioselective manner.
- Cheng, Hong-Gang,Lu, Liang-Qiu,Wang, Tao,Yang, Qing-Qing,Liu, Xiao-Peng,Li, Yang,Deng, Qiao-Hui,Chen, Jia-Rong,Xiao, Wen-Jing
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supporting information
p. 3250 - 3254
(2013/04/10)
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- Organocatalytic asymmetric Michael addition of aliphatic aldehydes to indolylnitroalkenes: Access to contiguous stereogenic tryptamine precursors
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Because of the importance of the indole framework and the versatile transformation of nitro and formyl groups, the efficient synthesis of optically pure 2-alkyl-3-(1H-indol-3-yl)-4-nitrobutanals, one type of tryptamine precursors are of great interest for pharmaceutical and biological research. Herein, the Michael addition of aliphatic aldehydes to indolylnitroalkenes has been developed using (S)-diphenylprolinol trimethylsilyl ether as an organocatalyst, which provides the desired optically pure syn 2-alkyl-3-(1H-indol-3-yl)-4-nitrobutanal derivatives in up to 98% yield with up to >99:1 dr and >99% ee. To show the synthetic usefulness of this methodology, optically active 2-alkyl-4-nitro-3-(1-tosyl-1H-indol-3-yl)butan-1- ol and tryptamine derivatives are readily obtained by stepwise systematic transformations.
- Chen, Jian,Geng, Zhi-Cong,Li, Ning,Huang, Xiao-Fei,Pan, Feng-Feng,Wang, Xing-Wang
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p. 2362 - 2372
(2013/05/21)
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- Regioselective synthesis of 4-substituted indoles via C-H activation: A ruthenium catalyzed novel directing group strategy
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A highly regioselective functionalization of indole at the C-4 position by employing an aldehyde functional group as a directing group, and Ru as a catalyst, under mild reaction conditions (open flask) has been uncovered. This strategy to synthesize 4-substituted indoles is important, as this class of privileged molecules serves as a precursor for ergot alkaloids and related heterocyclic compounds.
- Lanke, Veeranjaneyulu,Ramaiah Prabhu, Kandikere
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supporting information
p. 6262 - 6265
(2014/01/17)
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- Unconventional stereoselective one-pot synthesis of Knoevenagel-type indoles via in situ condensation of iminium salts with active methylene reagents in memory of Professor Angelo Ranise
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A simple one-pot procedure for the stereoselective synthesis of Knoevenagel-type indoles is described. The method is based on the in situ reaction of indole iminium salts (four of them are fully characterized) with acyclic symmetrical and unsymmetrical active methylene reagents in the presence of triethylamine. In general, the overall yields are moderate to good. Some of relevant reaction parameters and steric effects affecting stereoselectivity are discussed.
- Ranise, Angelo,Lucchesini, Francesco,Caviglia, Matteo,Alfei, Silvana,Spallarossa, Andrea,Caneva, Chiara
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p. 10858 - 10868
(2014/01/06)
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- Synthesis and evaluation of indole-based chalcones as inducers of methuosis, a novel type of nonapoptotic cell death
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Methuosis is a novel caspase-independent form of cell death in which massive accumulation of vacuoles derived from macropinosomes ultimately causes cells to detach from the substratum and rupture. We recently described a chalcone-like compound, 3-(2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1- one (i.e., MIPP), which can induce methuosis in glioblastoma and other types of cancer cells. Herein, we describe the synthesis and structure-activity relationships of a directed library of related compounds, providing insights into the contributions of the two aryl ring systems and highlighting a potent derivative, 3-(5-methoxy, 2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (i.e., MOMIPP) that can induce methuosis at low micromolar concentrations. We have also generated biologically active azide derivatives that may be useful for future studies aimed at identifying the protein targets of MOMIPP by photoaffinity labeling techniques. The potential significance of these studies is underscored by the finding that MOMIPP effectively reduces the growth and viability of Temozolomide-resistant glioblastoma and doxorubicin-resistant breast cancer cells. Thus, it may serve as a prototype for drugs that could be used to trigger death by methuosis in cancers that are resistant to conventional forms of cell death (e.g., apoptosis).
- Robinson, Michael W.,Overmeyer, Jean H.,Young, Ashley M.,Erhardt, Paul W.,Maltese, William A.
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experimental part
p. 1940 - 1956
(2012/05/20)
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- Integrated structure-based activity prediction model of benzothiadiazines on various genotypes of HCV NS5b polymerase (1a, 1b and 4) and its application in the discovery of new derivatives
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This work presents the first structure-based activity prediction model for benzothiadiazines against various genotypes of HCV NS5b polymerase (1a, 1b and 4).The model is a comprehensive workflow of structure-based field template followed by guided docking. The field template was used as a pre-filter and a tool to provide hits in good orientation and position. It was created based on detailed molecular interaction field analysis which includes Topomer CoMFA, grid independent analysis and Superstar. On the other hand, Guided docking was used as a refinement and assessment tool. It was actively directed by two scores: Moldock score as an interaction descriptor (r2 = 0.65) and a template similarity score as a measure for accurate binding-mode compliance. The docking template was based on energy-based pharmacophore analysis. The whole procedure was formulated and tweaked for both screening (ROC of AUC = 0.91) and activity prediction (r2 of 0.8) for the genotype 1a. In order to widen the model scope, linear interaction energy was used as a tool for predicting activities of other genotypes based on the docked ligand poses while mutation binding energy was used to investigate the effect of each amino acid mutation in genotype 4. The model was applied for structure-based fragment hopping by screening a library designed by reaction enumeration. A top scoring hit was used to generate a focused library such that it has lower TPSA than the original class ligands and thus better pharmacokinetic properties. After that, experimental validation was carried out by the synthesis of this library and its biological evaluation which yielded compounds that exhibit EC50 ranging from 1.86 to 23 μM.
- Ismail, Mohamed A.H.,Abou El Ella, Dalal A.,Abouzid, Khaled A.M.,Mahmoud, Amr H.
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experimental part
p. 2455 - 2478
(2012/05/05)
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- Design, synthesis and biological evaluation of thiazole- and indole-based derivatives for the treatment of type II diabetes
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Present studies have shown that the lipid carrier has a significant role in several aspects of metabolic syndrome in A-FABP/ap2-deficient mice, including type 2 diabetes and atherosclerosis. 38 Thiazole- and indole-based derivatives were synthesized and investigated for their inhibitory effects on the production of LPS-stimulated TNF-α. Among them, 12b exhibited an excellent inhibitory efficiency compared to BMS309403 (95% vs. 85%) at the concentration of 10 μM and a binding affinity for ap2 with the apparent Ki values 33 nM. Oral administration of 12b at a dosage of 50 mg/kg effectively reduced the levels of plasma blood glucose, triglycerides, insulin, total cholesterol and alanine aminotransferase in high-fat/diet-induced obesity model. The results highlighted that 12b was a potent anti-diabetic agent.
- Xu, Qinyuan,Huang, Li,Liu, Juan,Ma, Liang,Chen, Tao,Chen, Jinying,Peng, Fei,Cao, Dong,Yang, Zhuang,Qiu, Neng,Qiu, Jingxiang,Wang, Guangcheng,Liang, Xiaolin,Peng, Aihua,Xiang, Mingli,Wei, Yuquan,Chen, Lijuan
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experimental part
p. 70 - 81
(2012/07/30)
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- NBu4NI-catalyzed C3-formylation of indoles with N-methylaniline
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nBu4NI-catalyzed C3-selective formylation of N-H and N-substituted indoles by using N-methylaniline as a formylating reagent was first successfully demonstrated.
- Li, Lan-Tao,Huang, Juan,Li, Hong-Ying,Wen, Li-Juan,Wang, Peng,Wang, Bin
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supporting information; experimental part
p. 5187 - 5189
(2012/06/01)
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- Structural Characterization and Computer-Aided Optimization of a Small-Molecule Inhibitor of the Arp2/3 Complex, a Key Regulator of the Actin Cytoskeleton
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CK-666 (1) is a recently discovered small-molecule inhibitor of the actin-related protein 2/3 (Arp2/3) complex, a key actin cytoskeleton regulator with roles in bacterial pathogenesis and cancer cell motility. Although 1 is commercially available, the crystal structure of Arp2/3 complex with 1 bound has not been reported, making its mechanism of action uncertain. Furthermore, its relatively low potency increases its potential for off-target effects invivo, complicating interpretation of its influence in cell biological studies and precluding its clinical use. Herein we report the crystal structure of 1 bound to Arp2/3 complex, which reveals that 1 binds between the Arp2 and Arp3 subunits to stabilize the inactive conformation of the complex. Based on the crystal structure, we used computational docking and free-energy perturbation calculations of monosubstituted derivatives of 1 to guide optimization efforts. Biochemical assays of ten newly synthesized compounds led to the identification of compound 2, which exhibits a threefold increase in inhibitory activity invitro relative to 1. In addition, our computational analyses unveiled a surface groove at the interface of the Arp2 and Arp3 subunits that can be exploited for additional structure-based optimization.
- Baggett, Andrew W.,Cournia, Zoe,Han, Min Suk,Patargias, George,Glass, Adam C.,Liu, Shih-Yuan,Nolen, Brad J.
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scheme or table
p. 1286 - 1294
(2012/07/17)
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- Antifungal agents. Part 3: Synthesis and antifungal activities of 3-acylindole analogs against phytopathogenic fungi in vitro
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To find more potent antifungal compounds, twenty 3-acylindole analogs were synthesized and bio-evaluated for their antifungal activities against seven phytopathogenic fungi. Structure-activity relationships investigations revealed that 4- or 6-methyl and 3-acetyl or propionyl groups were the important structural properties of 3-acylindoles for the activities. Especially 4-methyl-3-propionylindole, 12, displayed the more potent activities than hymexazol, a commercially available agricultural fungicide, and might be considered as a new promising lead candidate for further design and synthesis of agricultural fungicides.
- Xu, Hui,Bin Yang, Wen,Wang, Qin
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experimental part
p. 864 - 868
(2012/06/29)
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- Mild and selective Ru-catalyzed formylation and Fe-catalyzed acylation of free (N-H) indoles using anilines as the carbonyl source
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C3-selective formylation and acylation of free (N-H) indoles under mild conditions can be achieved by using Ru- and Fe-catalyzed oxidative coupling of free (N-H) indoles with anilines, respectively. Both processes are operationally simple, compatible with a variety of functional groups and generally provide the desired products in good yields. 13C-labeling experiments unambiguously established that the carbonylic carbon in the formylation products originated from methyl group of N-methyl aniline.
- Wu, Wenliang,Su, Weiping
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supporting information; experimental part
p. 11924 - 11927
(2011/09/19)
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- Novel benzofuran-3-one indole inhibitors of PI3 kinase-α and the mammalian target of rapamycin: Hit to lead studies
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A series of benzofuran-3-one indole phosphatidylinositol-3-kinases (PI3K) inhibitors identified via HTS has been prepared. The optimized inhibitors possess single digit nanomolar activity against p110α (PI3K-α), good pharmaceutical properties, selectivity versus p110γ (PI3K-γ), and tunable selectivity versus the mammalian target of rapamycin (mTOR). Modeling of compounds 9 and 32 in homology models of PI3K-α and mTOR supports the proposed rationale for selectivity. Compounds show activity in multiple cellular proliferation assays with signaling through the PI3K pathway confirmed via phospho-Akt inhibition in PC-3 cells.
- Bursavich, Matthew G.,Brooijmans, Natasja,Feldberg, Lawrence,Hollander, Irwin,Kim, Stephen,Lombardi, Sabrina,Park, Kaapjoo,Mallon, Robert,Gilbert, Adam M.
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scheme or table
p. 2586 - 2590
(2010/06/19)
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- A thermal cascade route to pyrroloisoindolone and pyrroloimidazolones
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(Chemical Equation Presented) Flash vacuum pyrolysis (FVP) of indol-1-ylacrylate derivatives 11 and 15 or the isomeric indol-3-ylacrylates 21, 22, and 24 at 925°C (0.05 Torr) provides pyrrolo[1,2-a]indol-3-ones 2, 18, 28, and 29 in 53-90% yield by a cascade mechanism that involves a sigmatropic migration, elimination, electrocyclization sequence. Pyrrolo[1,2-a]imidazol-5- ones 3 and pyrrolo[1,2-c]imidazol-5-ones 4 were similarly obtained by FVP of corresponding 2,5-unsubstituted imidazol-1-ylacrylates (e.g., 33), with the former isomer predominating in ca. 80:20 ratio. Migration to the 2-position is therefore favored in the initial sigmatropic shift. FVP of 2-substituted imidazol-1-ylacrylates 35, 37, and 51 (825-875°C) instead give pyrrolo[1,2-c]imidazol-5-ones 56-58 only (88-91%), and that of 4,5-disubstituted imidazol-1-ylacrylates 39 and 41 (825-850°C) provide pyrrolo[1,2-a] imidazol-5-ones 59 and 60 exclusively (93-95%), and thus the selectivity of the initial shift can be controlled by the presence of substituents on the imidazole 2- and 5-positions. FVP of the benzimidazole analogues 61 and 62 at 950°C gave the pyrrolo[1,2-a]benzimidazol-1-ones 6 (71%) and 63 (36%), respectively.
- McNab, Hamish,Tyas, Richard G.
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p. 8760 - 8769
(2008/03/13)
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- Creation of new promoters for plant's root growth: its application for the syntheses of vulcanine and borreline, and for combating desertification at gobi desert in inner mongolia 1#
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Abstract - Various new 2-substituted indole-3-carbaldehydes are prepared. Structurally related alkaloids, vulcanine and borreline, are synthesized as well. Among the compounds, 2-haloindole-3-carbaldehydes are found to be potent promoters of plant's root growth. Its successful preliminary application is reported for making Gobi desert in Inner Mongolia full of plant.
- Somei, Masanori,Sayama, Shinsuke,Naka, Katsumi,Shinmoto, Kotaro,Yamada, Fumio
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experimental part
p. 537 - 554
(2009/09/25)
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- Synthesis and antifungal activity of new 1-halogenobenzyl-3-imidazolylmethylindole derivatives
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A series of 1-benzyl-3-(imidazol-1-ylmethyl)indole derivatives 35-46 were prepared under mild reaction conditions and tested for their antifungal activity. Pharmacomodulation at N1, C2 and C5 of the indole ring and at the level of the alkyl chain (R1) was carried out starting from the corresponding 3-acylindoles 6, 7 or 3-formylindoles 11-22. Target imidazolyl compounds 35-46 were obtained in satisfactory yields by CO2 elimination from the intermediate carbamates. All of the compounds were evaluated in vitro against two human fungal pathogens, Candida albicans (CA980001) and Aspergillus fumigatus (AF980003); amphotericin B, fluconazole and itraconazole were used as references. Seven out of 27 compounds (35b, 35e, 35g, 35h, 36a, 38a and especially 40a) exerted significant antifungal activity against C. albicans, with MIC in the range of 1-6 μg mL-1. As regards inhibitory activity against A. fumigatus, the MIC figures of most of our compounds were in excess of 20 μg mL-1 in contrast to the reference drugs, amphotericin B and itraconazole, whose MIC90 and MIC80 values were 0.14 and 0.50 μg mL-1, respectively. The most potent compound, 45a, exhibited MIC value (8±1 μg mL-1) 16-fold higher than that of itraconazole.
- Na, Young-Min,Le Borgne, Marc,Pagniez, Fabrice,Le Baut, Guillaume,Le Pape, Patrice
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- Novel and potent human and rat β3-adrenergic receptor agonists containing substituted 3-indolylalkylamines
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A novel series of 2-(3-indolyl)alkylamino-1-(3-chlorophenyl)ethanols was prepared and evaluated for in vitro ability to stimulate cAMP production in Chinese hamster ovary cells expressing cloned human β3-AR. The optically active 30a was found to be the most potent and selective human β3-AR agonist in this series with an EC50 value of 0.062 nM. In addition, 30a selectivity for human β3-AR was 210-fold and 103-fold that for human β2-AR and β1-AR, respectively. Furthermore, 30a showed potent agonistic activity at rat β3-AR.
- Harada, Hiroshi,Hirokawa, Yoshimi,Suzuki, Kenji,Hiyama, Yoichi,Oue, Mayumi,Kawashima, Hitoshi,Yoshida, Naoyuki,Furutani, Yasuji,Kato, Shiro
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p. 1301 - 1305
(2007/10/03)
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- An unusual oxidation of gramine methiodides under NaNO2/DMF conditions
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Gramine methiodides of a few indoles undergo an unusual oxidation under NaNO2/DMF conditions to produce the corresponding indole-3-aldehydes.
- Sridar,Maheswari,Reddy
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p. 1253 - 1254
(2007/10/03)
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- Vilsmeier Formylation and Glyoxylation Reactions of Nucleophilic Aromatic Compounds Using Pyrophosphoryl Chloride
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Reactions of N,N-dimethylformamide and N-methylformanilide with pyrophosphoryl chloride lead to the formation of reagents that undergo reactions with a wide range of nucleophilic aromatic substrates, including indoles, pyrroles, thiophenes, furans, and methoxy-substituted carbocyclic arenes to afford, after hydrolysis of the initial products, good to excellent yields of the expected aldehydes; reactions with methyl oxamates allow the preparation of methyl arylglyoxylates. Key words: pyrophosphoryl chloride, N,N-dimethylformamide, methoxyarene, heterocyle, formylation
- Downie, Ian M.,Earle, Martyn J.,Heaney, Harry,Shuhaibar, Khamis F.
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p. 4015 - 4034
(2007/10/02)
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- Indanediones-1,3 VIII. Hydroxy-2 indolyl-2 indanediones-1,3, (indolyl-3 methylene)-2 indanediones-1,3 et derives: recherche d'une activite anti-inflammatoire
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1,3-Indandiones VIII. 2-Hydroxy-2-indolyl-1,3-indandiones, 2-(indol-3-ylmethylene indandione and derivatives: search for anti-inflammatory activity.A series of 2-hydroxy-2-indolyl-1,3-indandiones, diversely substituted on the heterocycle were synthetized in order to study their anti-inflammatory activity.Catalytic hydrogenation gave 2,3-dihydroxy-1 indanones 6 and NaBH4 reduction of 3i led to the corresponding indanetriol 7i.Base-catalyzed isomerization of hydroxy-β-diketones 3 furnished 3-indololylcarbonyl phthalides 9.Only compound 3d exhibited a significant inhibition of mouse paw edema.Experimentation in the rat paw edema test confirmed the anti-inflammatory effect of 3d, but it was associated with an anti-coagulant activity. ω-Amino-alkylation of the indole nitrogen of 3d led to loss of anti-inflammatory activity.Introduction of a double bond between the indandione and indole nuclei, leading to 2-(indol-3-ylmethylene)-1,3 indandiones 12, proved ineffective in raising this activity. 2-hydroxy-2-indolyl-1,3-indandiones/ 2,3-dihydroxyindanones/ 1,2,3-indantriols/ 3-indolylcarbonyl-phthalides/ 2-(indol-3-ylmethylene)-1,3-indandiones/ anti-inflammatory activity/ anti-coagulant activity
- Courant, Jacqueline,Leblois, Danielle,Tandon, Manju,Robert-Piessard, Sylvie,le Baut, Guillaume,et al.
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p. 145 - 154
(2007/10/02)
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- A CONVENIENT SYNTHETIC METHOD OF 2-SUBSTITUTED INDOLES AND ITS APPLICATION FOR THE SYNTHESIS OF NATURAL ALKALOID, BORRERINE
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A simple synthetic method of 2-substituted indoles is developed.Total synthesis of natural alkaloid, borrerine, is also reported
- Somei, Masanori,Sayama, Shinsuke,Naka, Katsumi,Yamada, Fumio
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p. 1585 - 1588
(2007/10/02)
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- Structural study of Nitrovinylindoles: (I) 2-methyl-3-(2'-methyl-2'-nitrovinyl)indole and (II) 3-(2'-nitrovinyl)indole
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Compound (I) is 2-methyl-3-(2'-methyl-2'-nitrovinyl)indole, C12H12N2O2, Mr =216,24, monoclinic, P21/n, a = 16.710(1), b = 7.627(1), c = 17.646(1) Angstroem, β = 104.8(1) deg, V = 2174.7(1) Angstroem3, Z = 8, Dx = 1.321 g cm-3, Mo Kα, λ = 0.71073 Angstroem, μ = 0.858 ca-1, F(000) = 912, room temperature, R = 0.061 for 1956 observed reflections.Compound (II) is 3-(2'-nitrovinyl)indole, C10H8N2O2, Mr = 188.18, monoclinic, P21/n, a = 10.178(1), b = 10.608(1), c = 8.411(1) Angstroem, β = 105.5(2) deg, V = 875.0(1) Angstroem3, Z = 4, Dx = 1.4284 g cm-3, Cu Kα, λ = 1.5418 Angstroem, μ = 8.068 cm-1, F(000) = 392, room temperature, R = 0.040 for 1330 observed reflections.Compounds (I) and (II) have a similar geometry, the only significant difference lying in the rotation of the nitrovinyl chain.This feature could be responsible for the difference in biological activity.In both compounds, the molecules are associated, forming chargetransfer complexes.
- Fonseca, I.,Martinez-Crrera, S.,Garcia-Blanco, S.,Rodriguez, J. G.,Subirats, J. B.
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p. 265 - 276
(2007/10/02)
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- NEW (4+2)-CYCLOADDITIONS OF IN SITU GENERATED INDOLYL ENOL ETHERS AS HETEROCYCLIC DONOR-ACTIVATED 1,3-DIENES TO CARBAZOLE DERIVATIVES
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The ambident alkoxy-indolyl-methylcarbenium ions 1a-c are deprotonated by NaH to give in situ generated enol ethers which can be easily trapped by a dienophile such as, a.g., dimethyl acetylenedicarboxylate to form the carbazole derivatives 3, 4, and I.On reaction with the ethoxy-2-methylindolylcarbenium ion 1 d under the same conditions, a stereoselective Michael-type addition with formation of 6 takes place.
- Pindur, Ulf,Pfeuffer, Ludwig
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p. 3079 - 3082
(2007/10/02)
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- Regioselective, Mild Acylation of 2-Methylindole with Di- and Trialkoxycarbenium Tetrafluoroborates - A Simple Procedure for Deriving 3-Acyl-2-methyl-indoles and 3-Methoxycarbonyl-2-methylindole. Reactions of Electron-rich Heterocycles with Derivatives of Carboxylic Ortho Acids, VII.
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The regioselective acylation of 2-methylindole (2) with acyclic di- and trialkoxycarbenium tetrafluoroborates 1 produces, by way of the stable indolyl-alkoxycarbenium ions 4, the 3-acylated indoles 5a-5c, and the 3-methoxycarbonylindole 5d.The ambident electrophilic cations 1 all react as a1-electrophiles with the very nucleophilic indole 2.In the reaction of 2 with trimethoxycarbenium tetrafluoroborate (2d) methylated products are formed additionally. - Keywords: 3-Acylated 2-methylindoles; Synthesis with di- and trialkoxycarbenium tetrafluoroborates
- Pindur, Ulf,Flo, Camran
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p. 375 - 384
(2007/10/02)
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- Fused Indoles. Synthesis of β-Carbolines and Azerinoindoles from 3-(2-Alkylindol-3-yl)-2-azidoacrylates
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Decomposition of the azidoacrylates (6) derived from 2-substituted indole-3-carbaldehydes gives pharmacologically important β-carbolines , azepinoindoles (13), or enamines (14) depending on the conditions.The formation of azepinoindoles, shown to proceed by cyclisation of the initially formed enamines, represents a new reaction of vinyl azides which is particularly favoured in the indole series.
- Moody, Christopher J.,Ward, John G.
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p. 2895 - 2901
(2007/10/02)
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