- Synthesis and anti-tuberculosis activity of the marine natural product caulerpin and its analogues
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Caulerpin (1a), a bis-indole alkaloid from the marine algal Caulerpa sp., was synthesized in three reaction steps with an overall yield of 11%. The caulerpin analogues (1b-1g) were prepared using the same synthetic pathway with overall yields between 3% and 8%. The key reaction involved a radical oxidative aromatic substitution involving xanthate (3) and 3-formylindole compounds (4a-4g). All bis-indole compounds synthesized were evaluated against the Mycobacterium tuberculosis strain H37Rv, and 1a was found to display excellent activity (IC50 0.24 μM).
- Canche Chay, Cristina I.,Cansino, Rocio Gomez,Espitia Pinzon, Clara I.,Torres-Ochoa, Ruben O.,Martinez, Roberto
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- A facile approach to tryptophan derivatives for the total synthesis of argyrin analogues
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A facile route has been established for the synthesis of indole-substituted (S)-tryptophans from corresponding indoles, which utilizes a chiral auxiliary-facilitated Strecker amino acid synthesis strategy. The chiral auxiliary reagents evaluated were (S)-methylbenzylamine and related derivatives. To illustrate the robustness of the method, eight optically pure (S)-tryptophan analogues were synthesized, which were subsequently used for the convergent synthesis of a potent antibacterial agent, argyrin A and its analogues.
- Chen, Chou-Hsiung,Genapathy, Sivaneswary,Fischer, Peter M.,Chan, Weng C.
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- Intramolecular Diels-Alder reaction for the synthesis of tetracyclic carbazoles and isocanthines
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One pot intramolecular Diels-Alder reaction has been efficiently used as a new route for the synthesis of four tetracyclic carbazoles and four isocanthine analogues where a dialdehyde is utilised as a common intermediate for both the scaffolds. Biological activity was evaluated for some molecules, which demonstrated moderate activity against HeLa cervical cancer cell lines.
- Naik, Prajakta N.,Khan, Ayesha,Kusurkar, Radhika S.
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- Mapping the melatonin receptor. 7. Subtype selective ligands based on β-substituted N-acyl-5-methoxytryptamines and β-Substituted N-acyl-5-methoxy-1-methyltryptamines
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A series of β-substituted and β,β-disubstituted N-acyl 5-methoxy-1-methyltryptamines and 5-methoxytryptamines have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human MT1 and MT2 receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency of all analogues was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores, β-Methylmelatonin (17a) and β,β-dimethylmelatonin (17b), though showing a slight decrease in binding at human receptors, show an increase in potency on Xenopus, N-Butanoyl 5-methoxy-1-methyl-β,β-trimethylenetryptamine (12c) is an antagonist at human MT1 receptors but an agonist at MT2, while N-butanoyl 5-methoxy-1-methyl-β,β-tetramethylenetryptamine (13c) is an antagonist at MT1 but had no action at MT2 and is one of the first examples of an MT1 selective antagonist.
- Tsotinis, Andrew,Vlachou, Margarita,Papahatjis, Demetris P.,Calogeropoulou, Theodora,Nikas, Spyros P.,Garratt, Peter J.,Piccio, Vincent,Vonhoff, Stefan,Davidson, Kathryn,Teh, Muy-Teck,Sugden, David
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- Synthesis of polycyclic spirooxindoles via an asymmetric catalytic one-pot stepwise Aldol/chloroetherification/aromatization procedure
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A general method for the synthesis of chiral pentacyclic spirooxindoles containing a tetrahydropyrano[2,3-b]indole scaffold through a one-pot stepwise sequence from 3-(3-indolomethyl)oxindole, paraformaldehyde and NCS is reported. Furthermore, the pentacyclic spirooxindoles could be transformed to bispirooxindole and other structurally diverse spirocyclic oxindoles.
- Jiang, Yan,Yu, Shuo-Wen,Yang, Yi,Liu, Ying-Le,Xu, Xiao-Ying,Zhang, Xiao-Mei,Yuan, Wei-Cheng
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- Synthesis, biological evaluation and mechanism study of chalcone analogues as novel anti-cancer agents
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A series of novel chalcone analogues were designed, synthesized and evaluated as anticancer agents. The results of antiproliferative activity tests showed that most of the analogues exhibited moderate to very good antiproliferative activities with GI50 values in the micromol to sub-micromol range. Especially compound 10a gave 0.026 μM to 0.035 μM GI50 for five cancer cell lines. The mechanistic studies including tubulin polymerization inhibition, disruption of microtubule dynamics and cell cycle arrest assay demonstrated that compound 10a could effectively inhibit in vitro cellular tubulin polymerization, interfere with the mitosis, resulting in a prolonged G2/M cell cycle arrest and ultimately lead to cell apoptosis of cancer cells. Taken together, these results suggested that 10a may became a promising lead compound for development of new anticancer drugs.
- Chen, Jie,Yan, Jun,Hu, Jinhui,Pang, Yanqing,Huang, Ling,Li, Xingshu
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- Design, synthesis and biological evaluation of pyridine-chalcone derivatives as novel microtubule-destabilizing agents
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Further optimization of the trimethoxyphenyl scaffold of parent chalcone compound (2a) by introducing a pyridine ring afforded a series of novel pyridine-chalcone derivatives as potential anti-tubulin agents. All the target compounds were evaluated for their antiproliferative activities. Among them, representative compound 16f exhibited the most potent activity with the IC50 values ranging from 0.023 to 0.045 μM against a panel of cancer cell lines. Further mechanism study results demonstrated that compound 16f effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Moreover, cellular mechanism studies disclosed that 16f caused G2/M phase arrest, induced cell apoptosis and disrupted the intracellular microtubule network. Also, 16f reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 16f significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, which was stronger than the reference compound CA-4, indicating that it is worthy to investigate 16f as a potent microtubule-destabilizing agent for cancer therapy.
- Xu, Feijie,Li, Wenlong,Shuai, Wen,Yang, Limei,Bi, Yi,Ma, Cong,Yao, Hequan,Xu, Shengtao,Zhu, Zheying,Xu, Jinyi
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- Design, synthesis, and biological evaluation of NAD(P)H: Quinone oxidoreductase (NQO1)-targeted oridonin prodrugs possessing indolequinone moiety for hypoxia-selective activation
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The enzyme NQO1 is a potential target for selective cancer therapy due to its overexpression in certain hypoxic tumors. A series of prodrugs possessing a variety of cytotoxic diterpenoids (oridonin and its analogues) as the leaving groups activated by NQO1 were synthesized by functionalization of 3-(hydroxymethyl)indolequinone, which is a good substrate of NQO1. The target compounds (29a-m) exhibited relatively higher antiproliferative activities against NQO1-rich human colon carcinoma cells (HT-29) and human lung carcinoma (A549) cells (IC50?=?0.263–2.904?μM), while NQO1-defficient lung adenosquamous carcinoma cells (H596) were less sensitive to these compounds, among which, compound 29h exhibited the most potent antiproliferative activity against both A549 and HT-29?cells, with IC50 values of 0.386 and 0.263?μM, respectively. Further HPLC and docking studies demonstrated that 29h is a good substrate of NQO1. Moreover, the investigation of anticancer mechanism showed that the representative compound 29h affected cell cycle and induced NQO1 dependent apoptosis through an oxidative stress triggered mitochondria-related pathway in A549?cells. Besides, the antitumor activity of 29h was also verified in a liver cancer xenograft mouse model. Biological evaluation of these compounds concludes that there is a strong correlation between NQO1 enzyme and induction of cancer cell death. Thus, this suggests that some of the target compounds activated by NQO1 are novel prodrug candidates potential for selective anticancer therapy.
- Xu, Shengtao,Yao, Hong,Pei, Lingling,Hu, Mei,Li, Dahong,Qiu, Yangyi,Wang, Guangyu,Wu, Liang,Yao, Hequan,Zhu, Zheying,Xu, Jinyi
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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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- Synthesis, anticancer activities and molecular modeling studies of novel indole retinoid derivatives
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In this study, novel (E)-3-(5-substituted-1H-indol-3-yl)-1-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-2-en-1-one (5(a-e)) derivatives were synthesized and their anticancer effects were determined in vitro. Novel indole retinoid compounds except 5e have anti-proliferative capacity in liver, breast and colon cancer cell lines. This anti-proliferative effect was further analyzed in breast cancer cell line panel by using the most potent compound 5a. It was determined that 5a can inhibit proliferation at very low IC50 concentrations in all of the breast cancer cell lines. Here, we present some evidence on apoptotic termination of cancer cell proliferation which may be primarily driven by the inhibition of RXRα and, to a lesser extent, RXRγ.
- Selen Gurkan-Alp,Mumcuoglu, Mine,Andac, Cenk A.,Dayanc, Emre,Cetin-Atalay, Rengul,Buyukbingol, Erdem
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- Combined Molecular Docking, 3D-QSAR, and Pharmacophore Model: Design of Novel Tubulin Polymerization Inhibitors by Binding to Colchicine-binding Site
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Interference with dynamic equilibrium of microtubule-tubulin has proven to be a useful tactics in the clinic. Based on investigation into the structure-activity relationship (SAR) studies of tubulin polymerization inhibitors obtained from several worldwide groups, we attempted to design 691 compounds covering several main heterocyclic scaffolds as novel colchicine-site inhibitors (CSIs). Evaluated by a series of combination of commonly used computer methods such as molecular docking, 3D-QSAR, and pharmacophore model, we can obtain the ultimate 16 target compounds derived from five important basic scaffolds in the field of medicinal chemistry. Among these compounds, compound A-132 with in silico moderate activity was synthesized, and subsequently validated for preliminary inhibition of tubulin polymerization by immunofluorescence assay. In additional, the work of synthesis and validation of biological activity for other 15 various structure compounds will be completed in our laboratory. This study not only developed a hierarchical strategy to screen novel tubulin inhibitors effectively, but also widened the spectrum of chemical structures of canonical CSIs.
- Li, Dong-Dong,Qin, Ya-Juan,Zhang, Xin,Yin, Yong,Zhu, Hai-Liang,Zhao, Lin-Guo
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- Synthesis and Antiproliferative Activity of New N-Acylhydrazone Derivatives Containing Benzothiazole and Indole Based Moiety
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Through a structure-based molecular hybridization strategy, a series of new N-acylhydrazone derivatives containing the benzothiazole and indole based moiety were designed, synthesized and screened for in vitro antiproliferative activity against Hep G2 cancer cell line. One compound (7a) exhibited excellent antiproliferative activity with IC50 values of 0.78 μM against Hep G2. In addition, C-5 substitutions of the indole ring of target compounds might be crucial for their cytotoxic activities. Additionally, the relative configuration of target compounds was confirmed as the E isomer. Further chemical manipulation of derivative 7a can make it possible to obtain new potential antitumor agents.
- Ding, Yangyang,Kang, Congmin,Liu, Kai
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- INDQ/NO, a bioreductively activated nitric oxide prodrug
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The design, synthesis, and development of INDQ/NO, a novel nitric oxide (NO) prodrug targeted by a bioreductive trigger, are described. INDQ/NO, an indolequinone-diazeniumdiolate is found to be metabolized to produce NO by DT-diaphorase, a bioreductive enzyme that is overexpressed in certain cancers and hypoxic tumors. Cell-based assays revealed that INDQ/NO induces DNA damage and is a potent inhibitor of cancer cell proliferation.
- Sharma, Kavita,Iyer, Aishwarya,Sengupta, Kundan,Chakrapani, Harinath
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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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- Revision of the Structure and Total Synthesis of Topsentin C
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An efficient synthetic approach to access (indol-3-yl)ethane-1,2-diamines with a protecting group at the indole N atom from readily available 3-(2-nitrovinyl)indoles is reported. This approach includes solvent-free conjugate addition of O-pivaloylhydroxylamines to 1-Boc-3-(2-nitrovinyl)indoles followed by mild reduction of the adducts. The obtained (indol-3-yl)ethane-1,2-diamines are convenient synthetic precursors for several classes of marine alkaloids. The first total synthesis of racemic topsentin C, a secondary metabolite from Hexadella sp., based on this approach is reported. The initially proposed structure for topsentin C has been revised.
- Golantsov, Nikita E.,Festa, Alexey A.,Varlamov, Alexey V.,Voskressensky, Leonid G.
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- First total synthesis of marine alkaloid hyrtiosulawesine
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Hyrtiosulawesine was isolated from Indonesian specimens of the marine sponges Hyrtios erectus and H. reticulatu in 2002. We report here the first total synthesis of hyrtiosulawesine using an efficient and convenient synthetic strategy which could be widely used in the synthesis of other β-caboline compounds. All structures of new compounds were confirmed by 1H NMR, 13C NMR and HRMS.
- Zhang, Pu Yong,Wan, Sheng Biao,Ren, Su Mei,Jiang, Tao
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- Development of Novel Bis(indolyl)-hydrazide-Hydrazone Derivatives as Potent Microtubule-Targeting Cytotoxic Agents against A549 Lung Cancer Cells
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The biological significance of microtubules makes them a validated target of cancer therapy. In this study, we have utilized indole, an important pharmacological scaffold, to synthesize novel bis(indolyl)-hydrazide-hydrazone derivatives (NMK-BH compounds) and recognized NMK-BH3 as the most effective one in inhibiting A549 cell proliferation and assembly of tissue-purified tubulin. Cell viability experiments showed that NMK-BH3 inhibited proliferation of human lung adenocarcinoma (A549) cells, normal human lung fibroblasts (WI38) and peripheral blood mononuclear cells (PBMC) with IC50 values of -2, 48.5, and 62 μM, respectively. Thus, the relatively high cytotoxicity of NMK-BH3 toward lung carcinoma (A549) cells over normal lung fibroblasts (WI38) and PBMC confers a therapeutic advantage of reduced host toxicity. Flow cytometry, Western blot, and immunofluorescence studies in the A549 cell line revealed that NMK-BH3 induced G2/M arrest, mitochondrial depolarization, and apoptosis by depolymerizing the cellular interphase and spindle microtubules. Consistent with these observations, study in cell free system revealed that NMK-BH3 inhibited the microtubule assembly with an IC50 value of -7.5 μM. The tubulin-ligand interaction study using fluorescence spectroscopy indicated that NMK-BH3 exhibited strong and specific tubulin binding with a dissociation constant of -1.4 μM at a single site, very close to colchicine site, on β-tubulin. Collectively, these findings explore the cytotoxic potential of NMK-BH3 by targeting the microtubules and inspire its development as a potential candidate for lung cancer chemotherapy.
- Das Mukherjee, Dipanwita,Kumar, N. Maruthi,Tantak, Mukund P.,Das, Amlan,Ganguli, Arnab,Datta, Satabdi,Kumar, Dalip,Chakrabarti, Gopal
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- Cu-mediated oxidative dimerization of skatole to tryptanthrin, an indolo[2,1-b]quinazolone alkaloid
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A one-pot conversion of skatole to tryptanthrin, an indolo[2,1-b]quinazoline alkaloid, was achieved by Cu-mediated oxidation.
- Itoh, Tomoki,Abe, Takumi,Nakamura, Shuhei,Ishikura, Minoru
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- Extended Multicomponent Reactions with Indole Aldehydes: Access to Unprecedented Polyheterocyclic Scaffolds, Ligands of the Aryl Hydrocarbon Receptor
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The participation of reactants undergoing a polarity inversion along a multicomponent reaction allows the continuation of the transformation with productive domino processes. Thus, indole aldehydes in Groebke–Blackburn–Bienaymé reactions lead to an initial adduct which spontaneously triggers a series of events leading to the discovery of novel reaction pathways together with direct access to a variety of linked, fused, and bridged polyheterocyclic scaffolds. Indole 3- and 4-carbaldehydes with suitable isocyanides and aminoazines afford fused adducts through oxidative Pictet–Spengler processes, whereas indole 2-carbaldehyde yields linked indolocarbazoles under mild conditions, and a bridged macrocycle at high temperature. These novel structures are potent activators of the human aryl hydrocarbon receptor signaling pathway.
- Ghashghaei, Ouldouz,Pedrola, Marina,Seghetti, Francesca,Martin, Victor V.,Zavarce, Ricardo,Babiak, Michal,Novacek, Jiri,Hartung, Frederick,Rolfes, Katharina M.,Haarmann-Stemmann, Thomas,Lavilla, Rodolfo
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supporting information
p. 2603 - 2608
(2020/11/30)
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- 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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- Design, synthesis, anticancer activity, molecular docking and ADME studies of novel methylsulfonyl indole-benzimidazoles in comparison with ethylsulfonyl counterparts
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Cancer poses a world-wide healthcare problem, demanding selective and effective therapy protocols. To address that, a vast amount of therapeutic candidates are being investigated in the field of medicinal chemistry. Accordingly, indole-benzimidazole structures have recently gained considerable interest because of their anticancer properties and estrogen receptor (ER) modulatory actions. In this study, novel methylsulfonyl indole-benzimidazole derivatives have been synthesized upon substitution of respectively the first (R1) and fifth (R2) positions of benzimidazole and indole groups. Structure and activity relationships were then studied via1H NMR, 13C NMR, mass spectral and in silico docking analyses, as well as cell viability measurements. We found that the compounds exhibited substantial affinity levels towards ER alpha (ERα). In addition, the correlation analysis of cytotoxicity profiles between ethyl- and methyl-sulfonyl indole-benzimidazoles revealed a collection of effective and consistent R1 and R2 substitutions. However, for some candidate derivatives, distinctive cytotoxicity levels and varying viability versus ERα affinity correlations were observable across the studies, suggesting that the sulfonyl side chain modifications themselves can also influence the ERα binding levels. These results demonstrated that our novel methylsulfonyl indole-benzimidazole derivatives, similar to their ethylsulfonyl counterparts, exhibit anticancer effects with potential estrogen receptor modulatory actions. This journal is
- Karadayi, Fikriye Zengin,Yaman, Murat,Kisla, Mehmet Murat,Konu, Ozlen,Ates-Alagoz, Zeynep
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p. 9010 - 9019
(2021/06/06)
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- Design and Synthesis of Pyrano[3,2-b]indolones Showing Antimycobacterial Activity
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Latent Mycobacterium tuberculosis infection presents one of the largest challenges for tuberculosis control and novel antimycobacterial drug development. A series of pyrano[3,2-b]indolone-based compounds was designed and synthesized via an original eight-step scheme. The synthesized compounds were evaluated for their in vitro activity against M. tuberculosis strains H37Rv and streptomycin-starved 18b (SS18b), representing models for replicating and nonreplicating mycobacteria, respectively. Compound 10a exhibited good activity with MIC99 values of 0.3 and 0.4 μg/mL against H37Rv and SS18b, respectively, as well as low toxicity, acceptable intracellular activity, and satisfactory metabolic stability and was selected as the lead compound for further studies. An analysis of 10a-resistant M. bovis mutants disclosed a cross-resistance with pretomanid and altered relative amounts of different forms of cofactor F420 in these strains. Complementation experiments showed that F420-dependent glucose-6-phosphate dehydrogenase and the synthesis of mature F420 were important for 10a activity. Overall these studies revealed 10a to be a prodrug that is activated by an unknown F420-dependent enzyme in mycobacteria.
- Monakhova, Natalia,Korduláková, Jana,Vocat, Anthony,Egorova, Anna,Lepioshkin, Alexander,Salina, Elena G.,Nosek, Jozef,Repková, Eva,Zemanová, Júlia,Jurdáková, Helena,Górová, Renáta,Roh, Jaroslav,Degiacomi, Giulia,Sammartino, José Camilla,Pasca, Maria Rosalia,Cole, Stewart T.,Miku?ová, Katarína,Makarov, Vadim
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- Cu-Catalyzed Dimerization of Indole Derived Oxime Acetate for Synthesis of Biimidazo[1,2- a]indoles
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A copper-mediated cyclization and dimerization of indole derived oxime acetate was developed to generate a series of biimidazo[1,2-a]indole scaffolds with two contiguous stereogenic quaternary carbons in one step.
- Xie, Tao,Sui, Qi-Bang,Qin, Lu-Zhe,Wen, Xiaoan,Sun, Hongbin,Xu, Qing-Long,Zhen, Le
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supporting information
p. 5518 - 5529
(2021/05/04)
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- KOH-mediated stereoselective alkylation of 3-bromooxindoles for the synthesis of 3,3′-disubstituted oxindoles with two contiguous all carbon quaternary centres
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The stereoselective synthesis of 3,3′-disubstituted oxindoles having all-carbon quaternary stereocenters has been achieved using KOH as a base with an excellent diastereomeric ratio (98?:?2). The practicability of the present methodology has been validated with the synthesis of a series of substrates in good to excellent yields. The aesthetic simplicity, accessibility, and eco-friendly base (KOH) have prompted the broader application of the present methodology in organic synthesis.
- Devi, Manju,Jadhav, Amol P.,Singh, Ravi P.
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supporting information
p. 8445 - 8448
(2021/05/25)
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- Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids
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We report here a concise, collective, and asymmetric total synthesis of sarpagine alkaloids and biogenetically related koumine alkaloids, which structurally feature a rigid cage scaffold, with L-tryptophan as the starting material. Two key bridged skeleton-forming reactions, namely tandem sequential oxidative cyclopropanol ring-opening cyclization and ketone α-allenylation, ensure concurrent assembly of the caged sarpagine scaffold and installation of requisite derivative handles. With a common caged intermediate as the branch point, by taking advantage of ketone and allene groups therein, total synthesis of five sarpagine alkaloids (affinisine, normacusine B, trinervine, Na-methyl-16-epipericyclivine, and vellosimine) with various substituents and three koumine alkaloids (koumine, koumimine, and N-demethylkoumine) with more complex cage scaffolds has been accomplished.
- He, Ling,Jiang, Yan,Qiao, Zhen,Qiu, Hanyue,Su, Xiaojiao,Tan, Qiuyuan,Yang, Jiaojiao,Yang, Zhao,Zhang, Min,Zhou, Wenqiang
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supporting information
p. 13105 - 13111
(2021/05/10)
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- Design, synthesis, molecular docking and ADME studies of novel indole-thiazolidinedione derivatives and their antineoplastic activity as CDK6 inhibitors
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Several 5-((5-substituted-1H-indole-3-yl)methylene)-3-(2-oxo-2-(3/4-substituted-phenylethyl)-thiazolidine-2,4-dione derivatives (9-24) were designed and synthesized as CDK6 inhibitors, and their anticancer activity was probed on the MCF-7 breast cancer cell line and their effects on gene expression profiles were elucidated. According to biological activity assays, compounds10,15, and18were found to possess favorable cytotoxicity on this cell line. For a better understanding of their activity rationale, genomic studies were conducted. Changes in gene expression levels occurring in MCF-7 cells were studied on 48 genes selected among genes associated with the estrogen receptor, tumor suppressor and oncogenes, microtubule formation, apoptosis, the cell cycle, drug resistance and inflammation. It was determined that there are significant differences in gene expression levels in 21 of these genes. Comparing to other genes, these compounds inhibited gene expression of CDK6 much more. For a more thorough evaluation of their mechanism of action involving this pathway, docking analysis was performed with a corresponding enzyme that is synthesized by the CDK6 gene. By doing so, the binding profiles of these derivatives were compared to the reference study. In the end, the impact of the indole-thiazolidinediones on CDK6 and their mechanisms of action were elucidated. Compounds15and18possess higher affinity with better binding interactions relative to that of compound10. These two compounds were highlighted as possible candidates for upcoming design studies of CDK6 inhibitors. Moreover, the druglikeness of the indole-thiazolidinediones was calculated and compared to commercial anticancer drugs.
- Ates-Alagoz, Zeynep,Baran, Sercan,Karadayi, Fikriye Zengin,Kisla, Mehmet Murat,Mutlu, Pelin,Do?an, Tu?ba Somay
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p. 18025 - 18038
(2021/10/12)
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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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- Recyclable and reusablen-Bu4NBF4/PEG-400/H2O system for electrochemical C-3 formylation of indoles with Me3N as a carbonyl source
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A safe, practical and eco-friendly electrochemical methodology for the synthesis of 3-formylated indoles has been developed by the utilization of Me3N as a novel formylating reagent. Stoichiometric oxidants, metal catalysts, and activating agents were avoided in this method, and an aqueous biphasic system ofn-Bu4NBF4/PEG-400/H2O was used as a recyclable and reusable reaction medium, which made this electrosynthesis approach more sustainable and environmentally friendly. This process expanded the substrate scope and functional group tolerance for bothN-EDG andN-EWG indoles. Furthermore, late-stage functionalization and total/formal synthesis of drugs and natural products were realized by means of this route.
- Cheng, Didi,Li, Jingyi,Li, Yujin,Ling, Fei,Liu, Lei,Liu, Tao,Zhong, Weihui
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supporting information
p. 4107 - 4113
(2021/06/17)
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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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- Method for synthesizing melatonin intermediate by taking methoxyphenamine as raw material
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The invention belongs to the technical field of compound synthesis, and aims to solve the problem that expensive reducing agents are needed in the present method for synthesizing melatonin, and the cost is high. The invention provides a method for synthesizing melatonin intermediate by taking methoxyphenamine as a raw material, and the like. Pt / Al with supported catalyst by taking methoxyaniline and ethylene glycol as raw materials2 O3 One-step hydrothermal method synthesizes 5 - methoxyindole and then obtains melatonin precursor 3 methoxytryptamine by 5 -step hydrothermal reaction. 5 - Methoxyindole is firstly synthesized by taking ethylene glycol and paramethoxyaniline as raw materials, then 3 methoxytryptamine is obtained through 5 - steps, and the total yield of the reaction is 14.0%. final synthesis of melatonin. A new melatonin synthesis route is designed, and the melatonin precursor 5 - methoxytryptamine is synthesized by using a raw material aniline derivative and ethylene glycol which are simple in application structure and low in cost.
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Paragraph 0023; 0025; 0029
(2021/11/10)
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- Discovery and synthesis of novel indole derivatives-containing 3-methylenedihydrofuran-2(3H)-one as irreversible LSD1 inhibitors
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Lysine-specific demethylase 1 (LSD1), demethylase against mono- and di - methylated histone3 lysine 4, has emerged as a promising target in oncology. More specifically, it has been demonstrated as a key promoter in acute myeloid leukemia (AML), and several LSD1 inhibitors have already entered into clinical trials for the treatment of AML. In this paper, a series of new indole derivatives were designed and synthesized based on a lead compound obtained by a high-throughput screening with our in-house compound library. Among the synthetic compounds, 9e was characterized as a potent LSD1 inhibitor with an IC50 of 1.230 μM and can inhibit the proliferation of THP-1 cells effectively. And most importantly, this is the first irreversible LSD1 inhibitor that is not derived from monoamine oxidase inhibitors. Hence, the discovery of 9e may serve as a proof of concept work for AML treatment.
- Liu, Hong-Min,Suo, Feng-Zhi,Li, Xiao-Bo,You, Ying-Hua,Lv, Chun-Tao,Zheng, Chen-Xing,Zhang, Guo-Chen,Liu, Yue-Jiao,Kang, Wen-Ting,Zheng, Yi-Chao,Xu, Hai-Wei
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p. 357 - 372
(2019/05/17)
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- Discovery of certain benzyl/phenethyl thiazolidinone-indole hybrids as potential anti-proliferative agents: Synthesis, molecular modeling and tubulin polymerization inhibition study
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A series of certain benzyl/phenethyl thiazolidinone-indole hybrids were synthesized for the study of anti-proliferative activity against A549, NCI-H460 (lung cancer), MDA-MB-231 (breast cancer), HCT-29 and HCT-15 (colon cancer) cell lines by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). We found that compound G37 displayed highest cytotoxicity with IC50 value of 0.92 ± 0.12 μM towards HCT-15 cancer cell line among all the synthesized compounds. Moreover, compound G37 was also tested on normal human lung epithelial cells (L132) and was found to be safe in contrast to HCT-15 cells. The lead compound G37 showed significant G2/M phase arrest in HCT-15 cells. Additionally, compound G37 significantly inhibited tubulin polymerization with IC50 value of 2.92 ± 0.23 μM. Mechanistic studies such as acridine orange/ethidium bromide (AO/EB) dual staining, DAPI nuclear staining, annexinV/propidium iodide dual staining, clonogenic growth inhibition assays inferred that compound G37 induced apoptotic cell death in HCT-15 cells. Moreover, loss of mitochondrial membrane potential with elevated intracellular ROS levels was observed by compound G37. These compounds bind at the active pocket of the α/β-tubulin with higher number of stable hydrogen bonds, hydrophobic and arene-cation interactions confirmed by molecular modeling studies.
- Sigalapalli, Dilep Kumar,Pooladanda, Venkatesh,Singh, Priti,Kadagathur, Manasa,Guggilapu, Sravanthi Devi,Uppu, Jaya Lakshmi,Tangellamudi, Neelima D.,Gangireddy, Pavan Kumar,Godugu, Chandraiah,Bathini, Nagendra Babu
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supporting information
(2019/08/26)
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- Synthesis, characterization, and biological evaluation of indole aldehydes containing N-benzyl moiety
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The present study describes the synthesis, characterization and biological evaluation of N-benzyl indole aldehydes. The biological activities of the newly synthesized compounds were examined by investigating their antioxidant and anti-inflammatory activities. The potential of these compounds as an antioxidant was determined by 2,2-diphenylpicrylhydrazyl, Nitric oxide, Superoxide, peroxide radical scavenging methods. We found that aldehydes 4a, 4b, 4c, and 4e and shows promising in vitro DPPH scavenging antioxidant activity while aldehyde 4b and 4e show good in vitro anti-inflammatory activity.
- Survase, Dattatray N.,Karhale, Shrikrishna S.,Khedkar, Vijay M.,Helavi, Vasant B.
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p. 3486 - 3497
(2019/11/11)
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- N-Alkylation-Initiated Redox-Neutral [5 + 2] Annulation of 3-Alkylindoles with o-Aminobenzaldehydes: Access to Indole-1,2-Fused 1,4-Benzodiazepines
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Described herein is an unprecedented N-Alkylation-initiated redox-neutral [5 + 2] annulation of 3-Alkylindoles with o-Aminobenzaldehydes via a cascade N-Alkylation/dehydration/[1,5]-hydride transfer/Friedel-Crafts alkylation sequence. A series of indole-1,2-fused 1,4-benzodiazepines are facilely constructed in moderate to good yields in one step. This protocol features excellent regioselectivity, metal-free conditions, high step economy, and wide substrate scope.
- Wang, Shuai,Shen, Yao-Bin,Li, Long-Fei,Qiu, Bin,Yu, Liping,Liu, Qing,Xiao, Jian
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supporting information
p. 8904 - 8908
(2019/11/19)
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- Method for synthesizing indole -3 - formaldehyde compounds (by machine translation)
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The invention relates to a synthetic indole - 3 - formaldehyde compounds, which belongs to the technical field of organic synthesis. The invention will be indole compound, hexamethylene tetramine, crystalline aluminum trichloride, N, N - dimethyl formamide in proportion in 120 °C reaction under the condition of 1 - 20 the H, then filtered, washing, filtering, concentrating, column chromatography purification and other after-treatment technology, make the refined indole - 3 - formaldehyde compound. The invention overcomes the indole - 3 - benzaldehyde compound of preparation need to use not stabilized peroxide, and for a long time under the high temperature reaction of the defect. And the invention uses the advantages of simple equipment, product yield is high, the resulting yield of a target product can be up to 94%. In addition, the invention relates to a low reaction conditions, less catalyst levels, low energy consumption, the post treatment process is simple and easy to use, without the need of using a high dosage of acid or alkali, post-processing the solvent can be recovered and recycled, industrial "three wastes" is discharged little, suitable for large-scale production. (by machine translation)
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Paragraph 0041-0044; 0071-0074
(2018/08/28)
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- IMIDAZOLYL-SUBSTITUTED INDOLE DERIVATIVES BINDING 5-HT7 SEROTONIN RECEPTOR AND PHARMACEUTICAL COMPOSITIONS THEREOF
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The invention relates to a new class of substituted indole derivatives that are able to activate 5-HT7 serotonin receptor. These compounds bind 5-HT7 serotonin receptor with high affinity and selectivity, while possessing favourable physicochemical properties. The compounds of the invention are the first described low-basicity 5-HT7 receptor agonists. The invention also relates to use of such compounds in the treatment or prevention of 5-HT7 receptor-related disorders, especially of the central nervous system. The invention also relates to the isotopically labelled compounds for use in the in vivo diagnostics or imaging of a 5-HT7 serotonin receptor.
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Page/Page column 15; 29
(2018/02/28)
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- Chalcone analogue containing sulfones substitute, preparation method thereof and medical application thereof
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The invention relates to the field of the medicinal chemistry, and specifically relates to a novel chalcone analogue containing sulfones substitute and a preparation method thereof. The invention further discloses a medicinal composition containing the belonged compound and application of the compound for treating tumor or treating other diseases or symptoms by inhibiting microtubule protein activity.
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Paragraph 0252
(2018/07/30)
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- Novel nicotinoyl pyrazoline derivates bearing N-methyl indole moiety as antitumor agents: Design, synthesis and evaluation
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In the present work, twenty-five nicotinoyl pyrazoline derivates bearing N-methyl indole moiety have been designed and synthesized. The biological evaluation of these compounds as tubulin assembly inhibitors revealed that most of them were potential antitumor agents. Among them, compound 28 exhibited most potency against cancer cell line panels (GI50 = 29–90 nM for HeLa, HepG2 and MCF-7 cells) without toxicity to non-tumor cells (CC50 > 300 μM for 293 T cell), bound to the colchicine site of tubulin and displayed excellent inhibitory activity in tubulin assembly assay (IC50 = 1.6 μM, better than CA-4). Molecular dynamics simulation was carried out to validate the docking pose of compound 28 with tubulin crystalline. Further investigation on HepG2 and HeLa cells demonstrated that compound 28 could cause mitosis arrest to G2/M phase, and subsequently induced cell apoptosis. The efficiency in vivo of compound 28 was also evaluated on HeLa-Xenograft nude mice, and the relative tumor inhibition ration was up to 61.52% without noticeable weight loss and tissue damage (examined by H&E staining), which was comparable to CA-4 (inhibited 59.92%). In brief, compound 28 is a promising candidate for tumor therapy as tubulin assembly inhibitor.
- Chen, Kun,Zhang, Ya-Liang,Fan, Jing,Ma, Xiang,Qin, Ya-Juan,Zhu, Hai-Liang
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p. 722 - 737
(2018/07/29)
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- Efficient Synthesis and Biological Activity of Novel Indole Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors
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A series of novel indole derivatives were synthesized as potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase. Among those, compound 10b demonstrated the highest growth inhibition rate of 66.7% against the VEGFR-2 tyrosine kinase at 10 μM which indicates that indole-benzothiazole might be the favorable structure. The binding mode of compound 10b with VEGFR-2 tyrosine kinase was evaluated by molecular docking.
- Zhang,Xu,Wang,Kang
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p. 3006 - 3016
(2018/02/21)
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- Method for recovering and utilizing byproduct of chlorination of phosphorus pentachloride
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The invention relates to a technology for comprehensively utilizing the byproduct of chlorination of phosphorus pentachloride, and mainly relates to a post treatment, which scientifically utilizes the excess phosphorus pentachloride reagent. The byproduct is converted into an organic synthesis reagent with a wide application range. The wastes are converted into a valuable resource. The discharge of waste water, waste gas, and waste solid is reduced. The obtained reagent is an excellent active reagent, which is widely used in the chemical industry, pharmacy industry, and material industry. The production cost is reduced, and the environment is protected.
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Paragraph 0036-0037
(2017/08/28)
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- Design and synthesis of bis(indolyl)ketohydrazide-hydrazones: Identification of potent and selective novel tubulin inhibitors
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A novel series of ketohydrazide-hydrazones as analogues of naturally occurring coscinamides has been synthesized and evaluated for their anticancer activity against five cancer cell lines. Of the twenty-synthesized ketohydrazide-hydrazones, compounds, 21c, 21f, 21g, 21k and 21o showed cytotoxic effects (less than 50% cell survival) against multiple cancer cell lines when tested at a final concentration of 10?μM. IC50 of three compounds 21f, 21k and 21o was determined to be less than 5?μM for all tested cancer cell lines. Compound 21k exhibited significant anticancer activity against MCF-7, MDA-MB-231, HCT-116 and JURKAT cancer cell lines with IC50 values of 0.8?μM, 0.50?μM, 0.15?μM, and 0.22?μM, respectively. Also, 21k was found to be more selectively cytotoxic against tumor cells when compared to normal cells. Preliminary mechanism of action studies indicated that the most active compound 21k induced caspase-dependent apoptosis in cells. 21k arrests cell cycle in G2/M phase by inhibiting of tubulin polymerization (IC50?=?0.6?μM).
- Tantak, Mukund P.,Klingler, Linus,Arun,Kumar, Anil,Sadana, Rachna,Kumar, Dalip
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p. 184 - 194
(2017/05/12)
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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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- Synthesis and evaluation of selenium-containing indole chalcone and diarylketone derivatives as tubulin polymerization inhibition agents
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Sixteen new selenium-containing indole chalcone and diarylketone derivatives were synthesized and evaluated as tubulin polymerization inhibitors. Among them, compound 25b exhibited the most potent antiproliferative activities against six human cancer cell lines with IC50 values of 0.004-0.022 μM. A microtubule dynamics assay and an immunofluorescence assay confirmed that 25b could effectively inhibit tubulin polymerization (IC50 = 2.1 ± 0.27 μM). Further cellular mechanism studies revealed that 25b induced G2/M phase arrest, which was further evidenced by the decrease in the mitochondrial membrane potential (MMP).
- Zhang, Shun,An, Baijiao,Li, Jiayan,Hu, Jinhui,Huang, Ling,Li, Xingshu,Chan, Albert S. C.
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p. 7404 - 7410
(2017/09/25)
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- Iodine-catalyzed C3-formylation of indoles using hexamethylenetetramine and air
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An efficient iodine-catalyzed chemoselective 3-formylation of free (N–H) and N-substituted indoles was achieved by using hexamethylenetetramine (HMTA) in the presence of activated carbon under air atmosphere. This new method could provide 3-formylindoles in moderate to excellent yields with fairly short reaction times. Moreover, this catalytic formylation of indoles procedure can be applied to gram-scale synthesis.
- Wang, Qing-Dong,Yang, Jin-Ming,Fang, Dong,Ren, Jiangmeng,Zeng, Bu-Bing
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supporting information
p. 2877 - 2880
(2017/07/11)
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- Iron-Catalyzed C3-Formylation of Indoles with Formaldehyde and Aqueous Ammonia under Air
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An efficient iron-catalyzed C3-selective formylation of free (N-H) or N-substituted indoles was developed by employing formaldehyde and aqueous ammonia, with air as the oxidant. This new method gave 3-formylindoles in moderate to excellent yields with fairly short reaction times. Moreover, this procedure for catalytic formylation of indoles can be applied to gram-scale syntheses.
- Wang, Qing-Dong,Zhou, Bin,Yang, Jin-Ming,Fang, Dong,Ren, Jiangmeng,Zeng, Bu-Bing
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supporting information
p. 2670 - 2674
(2017/10/06)
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- Synthesis, Evaluation, and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity Through Microtubule Destabilization in Vitro and in Vivo
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Twenty-nine novel indole-chalcone derivatives were synthesized and evaluated for antiproliferative activity. Among them, 14k exhibited most potent activity, with IC50 values of 3-9 nM against six cancer cells, which displayed a 3.8-8.7-fold increase in activity when compare with compound 2. Further investigation revealed 14k was a novel tubulin polymerization inhibitor binding to the colchicine site. Its low cytotoxicity toward normal human cells and nearly equally potent activity against drug-resistant cells revealed the possibility for cancer therapy. Cellular mechanism studies elucidated 14k arrests cell cycle at G2/M phase and induces apoptosis along with the decrease of mitochondrial membrane potential. Furthermore, good metabolic stability of 14k was observed in mouse liver microsomes. Importantly, 14k and its phosphate salt 14k-P inhibited tumor growth in xenograft models in vivo without apparent toxicity, which was better than the reference compound CA-4P and 2. In summary, 14k deserves consideration for cancer therapy.
- Yan, Jun,Chen, Jie,Zhang, Shun,Hu, Jinhui,Huang, Ling,Li, Xingshu
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p. 5264 - 5283
(2016/07/06)
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- Synthesis and Biological Evaluation of 1-Methyl-1H-indole–Pyrazoline Hybrids as Potential Tubulin Polymerization Inhibitors
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A series of 1-methyl-1H-indole–pyrazoline hybrids were designed, synthesized, and biologically evaluated as potential tubulin polymerization inhibitors. Among them, compound e19 [5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide] showed the most potent inhibitory effect on tubulin assembly (IC50=2.12 μm) and in vitro growth inhibitory activity against a panel of four human cancer cell lines (IC50values of 0.21–0.31 μm). Further studies confirmed that compound e19 can induce HeLa cell apoptosis, cause cell-cycle arrest in G2/M phase, and disrupt the cellular microtubule network. These studies, along with molecular docking and 3D-QSAR modeling, provide an important basis for further optimization of compound e19 as a potential anticancer agent.
- Zhang, Ya-Liang,Qin, Ya-Juan,Tang, Dan-Jie,Yang, Meng-Ru,Li, Bo-Yan,Wang, Yan-Ting,Cai, Hong-Yu,Wang, Bao-Zhong,Zhu, Hai-Liang
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p. 1446 - 1458
(2016/07/16)
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- Organocatalytic enantioselective synthesis of C3 functionalized indole derivatives
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A highly enantioselective Michael addition reaction of indolylnitroalkenes with 1,3-dicarbonyl compounds has been developed to obtain enantiomerically enriched 3-(2-nitro-1-(1-tosyl-1H-indol-3-yl)ethyl)pentane-2,4-dione derivatives in up to 98% ee using BnCPN as an organocatalyst. The transition state structure has been predicted using DFT calculation.
- Kaur, Jasneet,Islam, Nasarul,Kumar, Akshay,Bhardwaj, Vimal K.,Chimni, Swapandeep Singh
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p. 8042 - 8049
(2016/11/22)
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- Synthesis, biological evaluation and molecular docking studies of novel 1-(4,5-dihydro-1Hpyrazol-1-yl)ethanone-containing 1-methylindol derivatives as potential tubulin assembling inhibitors
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A series of novel compounds (6a-6v) containing 1-methylindol and 1-(4,5-dihydro-1H-pyrazol-1-yl) ethanone skeletons were designed, synthesized and biologically evaluated as potential tubulin polymerization inhibitors and anticancer agents. Among them, compound 6q showed the most potent tubulin polymerization inhibitory activity (IC50 = 1.98 mM) and in vitro growth inhibitory activity against A549, MCF-7 and HepG2 cell lines, with IC50 values of 0.15 mM, 0.17 mM, and 0.25 mM respectively, comparable to the positive control. Furthermore, compound 6q was a potent inducer of apoptosis in A549 cells and it had typical cellular effects for microtubule interacting agents, causing arrest of the cell cycle in the G2/M phase. Confocal microscopy assay and molecular docking results further demonstrated that 6q could bind tightly to the colchicine site of tubulin and act as an anti-tubulin agent. These studies, along with 3D-QSAR modeling provided an important basis for further optimization of compound 6q as a potential anticancer agent.
- Yang, Meng-Ru,Qin, Ya-Juan,Chen, Chen,Zhang, Ya-Liang,Li, Bo-Yan,Liu, Tian-Bao,Gong, Hai-Bin,Wang, Bao-Zhong,Zhu, Hai-Liang
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p. 30412 - 30424
(2017/07/12)
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- Synthesis, biological evaluation, and molecular docking studies of novel 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives as potential tubulin polymerization inhibitors
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A series of 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives were designed, synthesized and evaluated as potential tubulin polymerization inhibitors and for the cytotoxicity against anthropic cancer cell lines. Among the novel compounds, compound 11f was demonstrated the most potent tubulin polymerization inhibitory activity (IC50 = 1.5 μM) and antiproliferative activity against A549, HepG2 and MCF-7 (GI50 = 2.4, 3.8 and 5.1 μM, respectively), which was compared with the positive control colchicine and CA-4. We also evaluated that compound 11f could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Docking simulation and 3D-QSAR model in these studies provided more information that could be applied to design new molecules with more potent tubulin inhibitory activity.
- Wang, Yan-Ting,Qin, Ya-Juan,Yang, Na,Zhang, Ya-Liang,Liu, Chang-Hong,Zhu, Hai-Liang
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p. 125 - 137
(2015/06/22)
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- Asymmetric Synthesis of Furo[3,4-b]indoles by Catalytic [3+2] Cycloaddition of Indoles with Epoxides
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A highly efficient N,N′-dioxide-NiII catalyst system for the catalytic [3+2] cycloaddition of indoles with epoxides through C-C cleavage of oxiranes was accomplished under mild conditions. It provided a promising approach for chiral furo[3,4-b]indoles in up to 98 % yield with up to 91 % enantiomeric excess (ee) and >95:5 diastereomeric ratio (d.r.). A promising approach: Catalytic de-aromatic [3+2] cycloaddition of indoles with epoxides by C-C cleavage of oxiranes is accomplished by using a highly efficient N,N′-dioxide-NiII catalyst system. A range of chiral furo[3,4-b]indoles is obtained with high enantiomeric excesses and diastereomeric ratios.
- Chen, Weiliang,Xia, Yong,Lin, Lili,Yuan, Xiao,Guo, Songsong,Liu, Xiaohua,Feng, Xiaoming
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supporting information
p. 15104 - 15107
(2015/11/02)
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- Palladium-catalyzed C-H ethoxycarbonyldifluoromethylation of electron-rich heteroarenes
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The first Pd-catalyzed C-H ethoxycarbonyldifluoromethylation with BrCF2CO2Et has been developed. The use of a bidentate phosphine ligand (Xantphos) is critical for the reaction to occur. A variety of electron-rich heteroarenes, including indoles, furans, thiophenes, and pyrroles, can be ethoxycarbonyldifluoromethylated in moderate to excellent yields. The reactions take place at the C-H bonds adjacent to the heteroatoms with high regioselectivity. This method provides a new protocol for the introduction of difuoroalkyl groups into electron-rich heteroarenes.
- Shao, Changdong,Shi, Guangfa,Zhang, Yanghui,Pan, Shulei,Guan, Xiaohong
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supporting information
p. 2652 - 2655
(2015/06/16)
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- Chiral anion phase transfer of aryldiazonium cations: An enantioselective synthesis of C3-diazenated pyrroloindolines
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Herein is reported the first asymmetric utilization of aryldiazonium cations as a source of electrophilic nitrogen. This is achieved through a chiral anion phase-transfer pyrroloindolinization reaction that forms C3-diazenated pyrroloindolines from simple tryptamines and aryldiazonium tetrafluoroborates. The title compounds are obtained in up to 99% yield and 96% ee. The air- and water-tolerant reaction allows electronic and steric diversity of the aryldiazonium electrophile and the tryptamine core. Live and let diazene: Chiral anion phase transfer of aryldiazonium cations has been utilized to prepare C3-diazenated pyrroloindolines. The air- and water-tolerant reaction allows electronic and steric diversity in the aryldiazonium electrophile and the tryptamine core, with the products being obtained in up to 99% yield and 96% ee (MTBE=methyl tert-butyl ether).
- Nelson, Hosea M.,Reisberg, Solomon H.,Shunatona, Hunter P.,Patel, Jigar S.,Toste, F. Dean
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supporting information
p. 5600 - 5603
(2014/06/10)
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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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