- Tuning Molecular Vibrational Energy Flow within an Aromatic Scaffold via Anharmonic Coupling
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From guiding chemical reactivity in synthesis or protein folding to the design of energy diodes, intramolecular vibrational energy redistribution harnesses the power to influence the underlying fundamental principles of chemistry. To evaluate the ability
- Schmitz, Andrew J.,Pandey, Hari Datt,Chalyavi, Farzaneh,Shi, Tianjiao,Fenlon, Edward E.,Brewer, Scott H.,Leitner, David M.,Tucker, Matthew J.
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- 2-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives: Simplification and modification of aconitine scaffold for the discovery of novel anticancer agents
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The molecular chaperone heat shock protein 90 (Hsp90) is a promising target for cancer therapy. Natural product aconitine is a potential Hsp90 inhibitor reported in our previous work. In this study, we designed and synthesized a series of 2-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives as potent Hsp90 inhibitors by simplifying and modifying aconitine scaffold. Among these compounds, 14t exhibited an excellent antiproliferative activity against LoVo cells with an IC50 value of 0.02 μM and a significant Hsp90α inhibitory activity with an IC50 value of 0.71 nM. Molecular docking studies provided a rational binding model of 14t in complex with Hsp90α. The following cell cycle and apoptosis assays revealed that compound 14t could arrest cell cycle at G1/S phase and induce cell apoptosis via up-regulation of bax and cleaved-caspase 3 protein expressions while inhibiting the expressions of bcl-2. Moreover, 14t could inhibit cell migration in LoVo and SW620 cell lines. Consistent with in vitro results, 14t significantly repressed tumor growth in the SW620 xenograft mouse model.
- Zhang, Yi,Zhang, Ting-jian,Li, Xin-yang,Liang, Jing-wei,Tu, Shun,Xu, Hai-li,Xue, Wen-han,Qian, Xin-hua,Zhang, Zhen-hao,Zhang, Xu,Meng, Fan-hao
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Read Online
- Nickel Boride Catalyzed Reductions of Nitro Compounds and Azides: Nanocellulose-Supported Catalysts in Tandem Reactions
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Nickel boride catalyst prepared in situ from NiCl2 and sodium borohydride allowed, in the presence of an aqueous solution of TEMPO-oxidized nanocellulose (0.01 wt%), the reduction of a wide range of nitroarenes and aliphatic nitro compounds. Here we describe how the modified nanocellulose has a stabilizing effect on the catalyst that enables low loading of the nickel salt pre-catalyst. Ni-B prepared in situ from a methanolic solution was also used to develop a greener and facile reduction of organic azides, offering a substantially lowered catalyst loading with respect to reported methods in the literature. Both aromatic and aliphatic azides were reduced, and the protocol is compatible with a one-pot Boc-protection of the obtained amine yielding the corresponding carbamates. Finally, bacterial crystalline nanocellulose was chosen as a support for the Ni-B catalyst to allow an easy recovery step of the catalyst and its recyclability for new reduction cycles.
- Proietti, Giampiero,Prathap, Kaniraj Jeya,Ye, Xinchen,Olsson, Richard T.,Dinér, Peter
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supporting information
p. 133 - 146
(2021/11/04)
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- Quinazoline substituted 1, 2, 3-triazole derivative as well as pharmaceutical composition, preparation method and application thereof
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The invention discloses a quinazoline substituted 1, 2, 3-triazole derivative, the derivative is shown as a general formula (I), and the definition of each substituent group is shown in the specification. In addition, the invention also discloses a preparation method of the compound. The compound shown in the general formula (I) has an inhibiting effect on proliferation of tumor cells, also has an inhibiting effect on proliferation of human colon cancer (HCT-116) and human lung cancer cell strain (A549) cells, and can be used as an antitumor drug.
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Paragraph 0068-0072
(2022/03/31)
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- A general procedure for carbon isotope labeling of linear urea derivatives with carbon dioxide
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Carbon isotope labeling is a traceless technology, which allows tracking the fate of organic compounds either in the environment or in living organisms. This article reports on a general approach to label urea derivatives with all carbon isotopes, including14C and11C, based on a Staudinger aza-Wittig sequence. It provides access to all aliphatic/aromatic urea combinations.
- Babin, Victor,Sallustrau, Antoine,Loreau, Olivier,Caillé, Fabien,Goudet, Amélie,Cahuzac, Hélo?se,Del Vecchio, Antonio,Taran, Frédéric,Audisio, Davide
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supporting information
p. 6680 - 6683
(2021/07/12)
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- Design, synthesis, and in vitro and in vivo anti-angiogenesis study of a novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor based on 1,2,3-triazole scaffold
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In the past five years, our team had been committed to click chemistry research, exploring the biological activity of 1,2,3-triazole by synthesizing different target inhibitors. In this study, a series of novel indole-2-one derivatives based on 1,2,3-triazole scaffolds were synthesized for the first time, and their inhibitory activity on vascular endothelial growth factor receptor-2 (VEGFR-2) was tested. Most of the compounds had shown promising activity in the VEGFR-2 kinase assay and had low toxicity to human umbilical vein endothelial cells (HUVECs). The compound 13d (IC50 = 26.38 nM) had better kinase activity inhibition ability than sunitinib (IC50 = 83.20 nM) and was less toxic to HUVECs. Moreover, it had an excellent inhibitory effect on HT-29 and MKN-45 cells. On the one hand, by tube formation assay, transwell, and Western blot analysis, compound 13d could inhibit VEGFR-2 protein phosphorylate on HUVECs, thereby inhibiting HUVECs migration and tube formation. In vivo study, the zebrafish model with VEGFR-2 labeling also verified that compound 13d had more anti-angiogenesis ability than sunitinib. On the other hand, molecular docking and molecular dynamics (MD) simulation results showed that compound 13d could stably bind to the active site of VEGFR-2. Based on the above findings, compound 13d could be considered an effective anti-angiogenesis drug and has more development value than sunitinib.
- Wang, De-pu,Liu, Kai-li,Li, Xin-yang,Lu, Guo-qing,Xue, Wen-han,Qian, Xin-hua,Mohamed O, Kamara,Meng, Fan-hao
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- Synthesis of new derivatives of alepterolic acid via click chemistry
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Alepterolic acid is a natural diterpenoid isolated from Aleuritopteris argentea (S. G. Gmél.) Fée, a fern with potential medicinal activity, used in China as a folk medicine to regulate menstruation and prevent cancer. Nevertheless, there are few reports
- Aisa, Haji Akber,Cao, Jianguo,Guo, Hongmei,Huang, Guozheng,Jin, Xin,Wang, Qi,Zhao, Qingjie
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p. 917 - 925
(2021/11/16)
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- Visible-Light-Mediated Strategies to Assemble Alkyl 2-Carboxylate-2,3,3-Trisubstituted β-Lactams and 5-Alkoxy-2,2,4-Trisubstituted Furan-3(2H)-ones Using Aryldiazoacetates and Aryldiazoketones
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Two new visible-light-mediated strategies are described starting from aryldiazoacetates. The first approach describes their reaction with azides to afford the corresponding imines, and then reaction with aryldiazoketones produces alkyl 2-carboxylate-2,3,3
- Deflon, Victor M.,Dos Santos, Caio Y.,Gallo, Rafael D. C.,Jurberg, Igor D.,Munaretto, Laiéli S.,Okada, Celso Y.
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supporting information
p. 9292 - 9296
(2021/12/06)
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- Design and synthesis of novel diosgenin-triazole hybrids targeting inflammation as potential neuroprotective agents
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Alzheimer's disease is a progressive neurodegenerative disease, and its incidence is expected to increase as the global population ages. Recent studies provide increasing evidence that inflammation plays a key role in the pathogenesis and progression of AD. Diosgenin, an active ingredient in Dioscorea nipponica Makino, is a promising bioactive lead compound in the treatment of Alzheimer's disease, which exhibited anti-inflammatory activity. To search for more efficient anti-Alzheimer agents, a series of novel diosgenin-triazolyl hybrids were designed, synthesized, and their neuroprotective effects against oxygen-glucose deprivation-induced neurotoxicity and LPS-induced NO production were evaluated. Most of these new hybrids displayed better activities than DIO. In particular, the promising compound L6 not only demonstrated an excellent neuroprotective effect but also showed the best anti-inflammatory activity. The structure-activity relationship study illustrated that the introduction of benzyl or phenyl triazole did improve the activity, and the introduction of benzyl triazole was better than that of phenyl triazole. The results we obtained showed that the diosgenin skeleton could be a promising structural template for the development of new anti-Alzheimer drug candidates, and compound L6 has the potential to be an important lead compound for further research.
- Huang, Yi,Huang, Weiwei,Yang, Guixiang,Wang, Rui,Ma, Lei
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supporting information
(2021/05/21)
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- Synthesis and antitumor activity of 1-substituted 1,2,3-triazole-mollugin derivatives
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A new series of mollugin-1,2,3-triazole derivatives were synthesized using a copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of corresponding O-propargylated mollugin with aryl azides. All the compounds were evaluated for their cytotoxicity on five human cancer cell lines (HL-60, A549, SMMC-7721, SW480, and MCF-7) using MTS assays. Among the synthesized series, most of them showed cytotoxicity and most of all, compounds 14 and 17 exhibited significant cytotoxicity of all five cancer cell lines.
- Hu, Jiang-Miao,Li, Hong-Mei,Liu, Shou-Jin,Luo, Han,Lv, Yong-Feng,Zhang, Hong
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- Triazole [5, 4-d] pyrimidone tricyclic compounds as well as preparation method and application thereof
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The invention relates to triazole [5, 4-d] pyrimidone tricyclic compounds as well as a preparation method and application thereof.The triazole [5, 4-d] pyrimidone tricyclic compounds are prepared by following steps: taking different substituted anilines a
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Paragraph 0064; 0067-0070; 0074
(2021/07/09)
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- Cycloaddition Reactions of Azides and Electron-Deficient Alkenes in Deep Eutectic Solvents: Pyrazolines, Aziridines and Other Surprises
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The reaction of organic azides and electron-deficient alkenes was investigated in a deep eutectic solvents. A series of highly substituted 2-pyrazolines was successfully isolated and their formation rationalised by DFT calculations. The critical effect of substitution was also explored; even relatively small changes in the cycloaddition partners led to completely different reaction outcomes and triazolines, triazoles or enaminones can be formed as major products depending on the alkene employed. (Figure presented.).
- Casarrubios, Luis,Díez-González, Silvia,Lachhani, Kushal,Pimpasri, Chaleena,Rzepa, Henry S.,Sebest, Filip,White, Andrew J. P.
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supporting information
(2020/05/19)
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- Metal-Free 1,2,3-Triazole Synthesis in Deep Eutectic Solvents
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The metal-free regioselective preparation of 1,5- and 1,4-disubstituted triazoles is reported through a cycloaddition-elimination sequence. Reactions were carried out in environmentally friendly deep eutectic solvent (DES) and pure products were isolated
- Díez-González, Silvia,Haselgrove, Samuel,Sebest, Filip,White, Andrew J. P.
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p. 605 - 609
(2020/04/08)
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- Regioselective synthesis of 4-fluoro-1,5-disubstituted-1,2,3-triazoles from synthetic surrogates of α-fluoroalkynes
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α-Fluoroalkynes are elusive molecules due to their instability and inaccessibility. Here, we show that α-fluoronitroalkenes can serve as synthetic surrogates of α-fluoroalkynes in [3+2] cycloaddition reactions with organic azides facilitated by a catalytic amount of trifluoroacetic acid (TFA). This work provides the first regioselective method to access 4-fluoro-1,5-disubstituted-1,2,3-triazoles.
- Jana, Sampad,Adhikari, Sweta,Cox, Michael R.,Roy, Sudeshna
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supporting information
p. 1871 - 1874
(2020/02/20)
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- Design, synthesis and biological evaluation of homoerythrina alkaloid derivatives bearing a triazole moiety as PARP-1 inhibitors and as potential antitumor drugs
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A series of homoerythrina alkaloid derivatives containing a 1,2,3-triazole moiety as PARP-1 inhibitors were designed and synthesized. And their anti-proliferative activity was further evaluated. Compound 10n had excellent activity to inhibit proliferation of A549 cells (IC50 = 1.89 μM), which was higher than harringtonine (IC50 = 10.55 μM), pemetrexed (IC50 = 3.39 μM), and rucaparib (IC50 = 4.91 μM). Furthermore, the selectivity index of compound 10n was higher than rucaparib and pemetrexed for lung cancer cells. Flow cytometry analysis showed that compound 10n significantly arrested the cell cycle in the S phase, then induced apoptosis of A549 cells (apoptosis rate is 46%), which effectively inhibited cell proliferation. Simultaneously, western blot analysis revealed that compound 10n could prevent the biosynthesis of PAR. Further analysis results revealed that compound 10n could inhibit the expression of cyclin A, down-regulate the expression of bcl-2/bax, activate caspase-3, and ultimately induce apoptosis of A549 cells. All the results indicated that compound 10n had potential research value as a novel PARP-1 inhibitor in antitumor, and it provided a new reference for further development of PARP-1 inhibitors.
- Li, Shuai,Li, Xin-yang,Zhang, Ting-jian,Kamara, Mohamed Olounfeh,Liang, Jing-wei,Zhu, Ju,Meng, Fan-hao
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- Design, synthesis and biological evaluation of erythrina derivatives bearing a 1,2,3-triazole moiety as PARP-1 inhibitors
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Inhibitors of poly (ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer, and many researchers are interested in the development of new PARP-1 inhibitors. Herein, we designed and synthesized 44 novel erythrina derivatives bearing a 1,2,3-triazole moiety as PARP-1 inhibitors. MTT assay results indicated that compound 10b had the most potent anti-proliferative activity against A549 cells among five cancer cells. The enzyme inhibitory activity in vitro of compound 10b was also significantly better than rucaparib. Furthermore, the selectivity index of compound 10b was higher than rucaparib for lung cancer cells. Flow cytometry analysis showed that compound 10b induced apoptosis of A549 cells by the mitochondrial pathway. Western blot analysis indicated that compound 10b was able to inhibit the biosynthesis of PAR effectively, and it was more potent than rucaparib. Also, compound 10b was able to up-regulate the ratio of bax/bcl-2, activate caspase-3, and ultimately induced apoptosis of A549 cells. The combined results revealed that the discovery of novel non-amide based PARP-1 inhibitors have great research significance and provide a better choice for the future development of drugs.
- Li, Shuai,Li, Xin-yang,Meng, Fan-hao,Qian, Xin-hua,Xue, Wen-han,Zhang, Ting-jian,Zhu, Ju
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supporting information
(2020/01/21)
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- Methyl-2,2-difluoro-2-(fluorosulfonyl) acetate (MDFA)/copper (I) iodide mediated and tetrabutylammonium iodide promoted trifluoromethylation of 1-aryl-4-iodo-1,2,3-triazoles
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While several methods are available for the synthesis of a host of trifluoromethylated heterocycles, very few of them have been applied to access 4-trifluoromethylated 1,2,3-triazoles. We report herein a general methodology for the trifluoromethylation of 1-aryl-4-iodo-1, 2, 3-triazoles. Tetrabutylammonium iodide (TBAI) has been shown to provide enhanced conversion in these CuI-mediated reaction using methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MDFA). The method exhibited broad functional group tolerance and was applied to the synthesis of a library of 1-aryl-4-trifluoromethyl-1,2,3-triazoles on the multi-gram scale.
- Arunachalam, Pirama Nayagam,Chandran, Thirumurugan Kothandarama,Corte, James R.,Gupta, Anuradha,Kumar, Hemantha,Mathur, Arvind,Nimje, Roshan Y.,Panja, Chiradeep,Puttaramu, Jayashankara Vaderapura
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supporting information
(2020/06/08)
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- Optimizing the aryl-triazole of cjoc42 for enhanced gankyrin binding and anti-cancer activity
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Gankyrin is an oncoprotein overexpressed in numerous cancer types and appears to play a key role in regulating cell proliferation, cell growth, and cell migration. These roles are largely due to gankyrin's protein-protein interaction with the 26S proteaso
- Almasri, Joseph,D'Souza, Amber,Dukhande, Vikas V.,Farrales, Pamela,Gnanmony, Manu,Gupta, Vivek,Juang, Daniel,Kabir, Abbas,Kanabar, Dipti,Muth, Aaron,Shukla, Snehal,Torrents, Nicolas
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supporting information
(2020/07/10)
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- Discovery and structure-activity relationship studies of 1-aryl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives as potent dual inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and trytophan 2,3-dioxygenase (TDO)
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Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), which mediate kynurenine pathway of tryptophan degradation, have emerged as potential new targets in immunotherapy for treatment of cancer because of their critical role in immunosuppression in the tumor microenvironment. In this investigation, we report the structural optimization and structure-activity relationship studies of 1-phenyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives as a new class of IDO1/TDO dual inhibitors. Among all the obtained dual inhibitors, 1-(3-chloro-4-fluorophenyl)-6-fluoro-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione (38) displayed the most potent IDO1 and TDO inhibitory activities with IC50 (half-maximal inhibitory concentration) values of 5 nM for IDO1 and 4 nM for TDO. It turned out that compound 38 was not a PAINS compound. Compound 38 could efficiently inhibit the biofunction of IDO1 and TDO in intact cells. In LL2 (Lewis lung cancer) and Hepa1-6 (hepatic carcinoma) allograft mouse models, this compound also showed considerable in vivo anti-tumor activity and no obvious toxicity was observed. Therefore, 38 could be a good lead compound for cancer immunotherapy and deserving further investigation.
- Pan, Shulei,Zhou, Yangli,Wang, Qiusheng,Wang, Yanlin,Tian, Chenyu,Wang, Tianqi,Huang, Luyi,Nan, Jinshan,Li, Linli,Yang, Shengyong
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- Synthesis and Antitrypanosomal Activity of 1,4-Disubstituted Triazole Compounds Based on a 2-Nitroimidazole Scaffold: a Structure-Activity Relationship Study
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Chagas disease affects 6–8 million people worldwide, remaining a public health concern. Toxicity, several adverse effects and inefficiency in the chronic stage of the disease are the major challenges regarding the available treatment protocols. This work involved the synthesis of twenty-two 1,4-disubstituted-1,2,3-triazole analogues of benznidazole (BZN), by using a click chemistry strategy. Analogues were obtained in moderate to good yields (40-97 %). Antitrypanosomal activity was evaluated against the amastigote forms of Trypanosoma cruzi. Compound 8 a (4-(2-nitro-1H-imidazol-1-yl)methyl)-1-phenyl-1H-1,2,3-triazole) without substituents on phenyl ring showed similar biological activity to BZN (IC50=3.0 μM, SI>65.3), with an IC50=3.1 μM and SI>64.5. Compound 8 o (3,4-di-OCH3?Ph) with IC50 = 0.65 μM was five-fold more active than BZN, and showed an excellent selectivity index (SI>307.7). Compound 8 v (3-NO2, 4-CH3?Ph) with IC50=1.2 μM and relevant SI>166.7, also exhibited higher activity than BZN. SAR analysis exhibited a pattern regarding antitrypanosomal activity relative to BZN, in compounds with electron-withdrawing groups (Hammett σ+) at position 3, and electron-donating groups (Hammett σ-) at position 4, as observed in 8 o and 8 v. Further research might explore in vivo antitrypanosomal activity of promising analogues 8 a, 8 o, and 8 v. Overall, this study indicates that approaches such as the bioisosteric replacement of amide group by 1,2,3-triazole ring, the use of click chemistry as a synthesis strategy, and design tools like Craig-plot and Topliss tree are promising alternatives to drug discovery.
- Assun??o, Elvis L. F.,Carvalho, Diego B.,das Neves, Amarith R.,Kawasoko Shiguemotto, Cristiane Y.,Portapilla, Gisele B.,de Albuquerque, Sergio,Baroni, Adriano C. M.
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p. 2019 - 2028
(2020/09/21)
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- Synthesis of azido-substituted benzaldehydes via SNAr chemistry
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Conditions for the formation of azidobenzaldehydes and azidobenzonitriles using sodium azide in DMSO under typical SNAr conditions are described. This simplifies access to these valuable building blocks compared to the more common sequences reported in the literature. Interestingly, fluorosubstituted aryl ketones and esters do not afford azides, but instead amine products.
- Kafle, Arjun,Yossef, Sandy,Handy, Scott T.
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supporting information
(2020/04/21)
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- Nucleophilic Iron Complexes in Proton-Transfer Catalysis: An Iron-Catalyzed Dimroth Cyclocondensation
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The nucleophilic iron complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]) is an active catalyst in C?H-amination but also in proton-transfer catalysis. Herein, we describe the successful use of this complex as a proton-transfer catalyst in the cyclocondensation reaction between azides and ketones to the corresponding 1,2,3-triazoles. Cross-experiments indicate that the proton-transfer catalysis is significantly faster than the nitrene-transfer catalysis, which would lead to the C?H amination product. An example of a successful sequential Dimroth triazole–indoline synthesis to the corresponding triazole-substituted indolines is presented.
- Baykal, Aslihan,Zhang, Dihan,Knelles, Jakob,Alt, Isabel T.,Plietker, Bernd
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supporting information
p. 3003 - 3010
(2019/08/21)
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- Investigating the Impact of Conformational Molecular Engineering on the Crystal Packing of Cavity Forming Porphyrins
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Herein we report the synthesis of 5,10,15,20-tetraaryl-(X)-substituted-2,3,7,8,12,13,17,18-octaethylporphyrins (OETArXPs) and a structural investigation of their solid-state properties via small molecule X-ray diffraction. A series of halogen (fluorine to iodine), nitrogenous (azido, cyano), alkyl (TMS-acetylene and acetylene), and chained (benzyloxy) porphyrins were chosen as the initial target molecules. Following this, a selection of tetravalent metal complexes [Cu(II), Ni(II), and Pd(II)] based on these porphyrins were synthesized to allow for an investigation of the effects of metal complexes on the structural properties of these highly substituted porphyrins. The size of the halogen atom affects the potential of intermolecular interactions and the resulting crystal packing in these 4-halo-OETArXP complexes. The fluorine series have an equal preference for alkyl or aryl groups (ortho-hydrogen), the chlorine series favor interactions between the alkyl groups, and the bromine appears to favor the aryl (ortho- and meta-hydrogens). This results in an extensive cupping pattern in the unit cell. For the 2,6-halo-OETArXP it was established that the change in position alters the types of the intermolecular contacts toward face-to-edge or face-to-face interactions and alters the packing patterns observed. Within the 4-benzyloxy-OETArXP series the meso-substituent favors interacting with the core of the porphyrin macrocycle. The 4-cyano-OETArXP is a suitable hydrogen-bond acceptor and results in an interesting Z-shape network. Additionally, it was highlighted that solvent effects play a much larger role in crystal packing than intermolecular/intramolecular interaction or metal(II) center substitution. This is accompanied by a study using both the azide- and acetylene-OETArXPs as a base molecule to allow for a quick one-step reaction for the generation of a variety of functionalized compounds. Using a copper(I)-catalyzed azide-alkyne cycloaddition reaction, we were able to append hydrogen bonding functionalities to the OETArXPs framework in high yields. The crystal packing images included in this work shows the potential to create selective and functional receptor sites based on free base porphyrins. However, insofar as analytical measurements indicate, the design of such a free base porphyrin through crystal engineering has not yet been realized. The variety of porphyrin packing arrangements herein indicates the need for further studies.
- Flanagan, Keith J.,Twamley, Brendan,Senge, Mathias O.
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p. 15769 - 15787
(2019/12/11)
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- INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE AND/OR TRYPTOPHAN 2,3-DIOXYGENASE
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The present invention relates to compounds of Formula (I) inhibiting indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) enzymes. Further, their synthesis and their use as medicaments in inter alia the treatment of cancer is disclosed. Formula (I)
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Page/Page column 97-98
(2019/08/20)
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- Thermal azide-Alkene cycloaddition reactions: straightforward multi-gram access to Δ2-1,2,3-Triazolines in deep eutectic solvents
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The multi-gram synthesis of a wide range of 1,2,3-Triazolines via azide-Alkene cycloaddition reactions in a Deep Eutectic Solvent (DES) is reported. The role of DES in this transformation as well as the origin of the full product distribution was studied with an experimental/computational-DFT approach.
- Sebest, Filip,Casarrubios, Luis,Rzepa, Henry S.,White, Andrew J. P.,Díez-González, Silvia
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supporting information
p. 4023 - 4035
(2018/09/11)
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- Tuning the biological activity of cationic anthraquinone analogues specifically toward Staphylococcus aureus
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Development of new antibacterial agents against drug resistant bacteria is an imminent task, especially against methicillin-resistant Staphylococcus aureus (MRSA). While MRSA can still be treated with broad spectrum antibiotics, the use of which often leads to the disruption of normal microbial flora leading to Clostridium difficile infection (CDI). Herein, a new class of antibacterial agent, cationic anthraquinone analogues specifically against MRSA, has been developed. Through the variation and optimization of substituents, these agents are selective toward MRSA, and not Gram negative bacteria which may avoid the problem of CDI. In addition, newly discovered lead compounds also show significantly reduced cytotoxicity against normal mammalian cells than cancerous cells. This interesting finding can alleviate the toxicity and side effect problems often associate with the use of antibiotics.
- Subedi, Yagya Prasad,Alfindee, Madher N.,Shrestha, Jaya P.,Chang, Cheng-Wei Tom
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p. 683 - 690
(2018/08/23)
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- Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds
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Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) click chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives. All the synthetic compounds were evaluated for their in vitro activity against chloroquine resistant Plasmodium falciparum (W2) and for cytotoxicity to HepG2 cells. Compounds containing the naphthoquinolyl triazole moieties showed higher antimalarial activity than lapachol (IC50 123.5 μM) and selectivity index (SI) values in the range of 4.5–197.7. Molecular docking simulations of lapachol, atovaquone and all the newly synthesized compounds were carried out for interactions with PfDHODH, a mitochondrial enzyme of the parasite respiratory chain that is essential for de novo pyrimidine biosynthesis. Docking of the naphthoquinonolyl triazole derivatives to PfDHODH yielded scores between ?9.375 and ?14.55 units, compared to ?9.137 for lapachol and ?12.95 for atovaquone and disclosed the derivative 17 as a lead compound. Therefore, the study results show the enhancement of DHODH binding affinity correlated with improvement of SI values and in vitro activities of the lapachol derivatives.
- Brand?o, Geraldo Célio,Rocha Missias, Franciele C.,Pereira, Guilherme Rocha,Arantes, Lucas Miquéias,Soares, Luciana Ferreira,Braga de Oliveira, Alaide,Roy, Kuldeep K.,Doerksen, Robert J.
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p. 191 - 205
(2018/05/02)
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- Synthesis of novel 1,2,3-triazole based artemisinin derivatives and their antiproliferative activity
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Two series of novel 1,2,3-triazole based artemisinin derivatives were designed, synthesized via a copper(i)-catalyzed azide alkyne cycloaddition (CuAAC) reaction and investigated for their antiproliferative activity by MTT assay against various human canc
- Kapkoti, Deepak Singh,Singh, Shilpi,Luqman, Suaib,Bhakuni, Rajendra Singh
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p. 5978 - 5995
(2018/04/23)
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- Design of "click" Fluorescent Labeled 2′-deoxyuridines via C5-[4-(2-Propynyl(methyl)amino)]phenyl Acetylene as a Universal Linker: Synthesis, Photophysical Properties, and Interaction with BSA
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Microenvironment-sensitive fluorescent nucleosides present attractive advantages over single-emitting dyes for sensing inter-biomolecular interactions involving DNA. Herein, we report the rational design and synthesis of triazolyl push-pull fluorophore-la
- Bag, Subhendu Sekhar,Gogoi, Hiranya
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p. 7606 - 7621
(2018/06/18)
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- Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors
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It is now known that “gain of function” mutations of RET (REarranged during Transfection) kinase are specific and key oncogenic events in the onset of thyroid gland cancers such as the Medullary Thyroid Carcinoma (MTC). Although a number of RET inhibitors exist and are capable of inhibiting RET variants, in which mutations are outside the enzyme active site, the majority becomes dramatically ineffective when mutations are within the protein active site (V804L and V804M). Pursuing a receptor-based virtual screening against the kinase domain of RET, we found that compound 5 is able to inhibit efficiently both wild type and V804L mutant RET. Compound 5 was able to significantly reduce proliferation of both commercially available TT cell lines and surgical thyroid tissues obtained from patients with MTC and displayed a suitable drug-like profile, thus standing out as a promising candidate for further development towards the treatment of clinically unresponsive MTC.
- La Pietra, Valeria,Sartini, Stefania,Botta, Lorenzo,Antonelli, Alessandro,Ferrari, Silvia Martina,Fallahi, Poupak,Moriconi, Alessio,Coviello, Vito,Quattrini, Luca,Ke, Yi-Yu,Hsing-Pang, Hsieh,Da Settimo, Federico,Novellino, Ettore,La Motta, Concettina,Marinelli, Luciana
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supporting information
p. 491 - 505
(2018/03/21)
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- Dual roles of substituted thiourea as reductant and ligand in CuAAC reaction
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A highly efficient catalytic system, CuSO4·5H2O/1-(4-methoxyphenyl)-3-phenylthiourea, for the copper(I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC) was discovered. In the above catalytic system, substituted thiourea acts both as a reductant and a ligand. CuSO4·5H2O/1-(4-methoxyphenyl)-3-phenylthiourea is both an economical and efficient catalyst for the CuAAC reaction. In addition, the new catalytic system has advantageous features including mild and green reaction conditions, and broad substrate compatibility. A variety of 1,4-disubstituted 1,2,3-triazoles have been prepared with good to excellent yields with the CuSO4·5H2O/1-(4-methoxyphenyl)-3-phenylthiourea catalytic system in aqueous solution.
- Wang, Siyu,Jia, Kai,Cheng, Jiajia,Chen, Yu,Yuan, Yaofeng
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supporting information
p. 3717 - 3721
(2017/09/01)
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- A reliable one-pot synthesis of aryl azides from aryl amines using organotin azides as effective and recoverable reagents
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A mild and mass-efficient procedure based on the one-pot diazotization-azidodediazoniation of aromatic amines is described. A wide range of aryl azides are obtained in moderate to high yields by using tributyltin azide as an effective and reusable azide source in the presence of p-toluenesulfonic acid at room temperature. The method was also successfully applied employing an insoluble polymer-supported organotin azide.
- Godoy Prieto, Leonela,Lo Fiego, Marcos J.,Chopa, Alicia B.,Lockhart, María T.
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supporting information
p. 26 - 32
(2016/12/18)
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- PURINONES AS UBIQUITIN-SPECIFIC PROTEASE 1 INHIBITORS
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The application relates to inhibitors of USP1 useful in the treatment of cancers, and other USP1 associated diseases and disorders, having the Formula: (I), where R1, R2, R3, R3', R4, R5, X1, X2, X3, X4, and n are described herein.
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Paragraph 00358
(2017/06/12)
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- Synthesis and biological evaluation of novel 3-O-tethered triazoles of diosgenin as potent antiproliferative agents
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Diosgenin, a promising anticancer steroidal sapogenin, was isolated from Dioscorea deltoidea. Keeping its stereochemistry rich architecture intact, a scheme for the synthesis of novel diosgenin analogues was designed using Cu (I)-catalysed alkyne-azide cy
- Masood-ur-Rahman,Mohammad, Younis,Fazili, Khalid Majid,Bhat, Khursheed Ahmad,Ara, Tabassum
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- Synthesis of Gallic-Acid-1-Phenyl-1H-[1,2,3]Triazol-4-yl Methyl Esters as Effective Antioxidants
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Using a click chemistry approach, a series of gallic-acid-1-phenyl-1H-[1,2,3]triazol-4-ylmethyl esters was synthesized to develop more effective antioxidants. The results of DPPH screening indicate that few of the synthesized analogs display better antioxidant effect compared to the standards. Among all, compounds, 9 and 20 displayed highest DPPH radical scavenging effect with IC50 values as low as 6.4±0.2 and 7.9±0.4 μM respectively, compared to the standard ascorbic acid (IC50=12±0.8 μM) and gallic acid (IC50=9.0±0.6 μM). Compound 10 also displayed a potent antioxidant effect with IC50 of 10.80±0.4 μM. This study provides an important aspect with regard to the use of these gallic-acid based synthetic antioxidants in food industry as dietary supplements.
- Lone, Shabir H.,Rehman, Shakeel U,Bhat, Khursheed A.
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p. 111 - 118
(2017/02/15)
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- Glucose promoted facile reduction of azides to amines under aqueous alkaline conditions
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A quick and efficient method for the reduction of azides to amines in water using d-glucose and KOH as green reagents is reported. The protocol is simple, inexpensive, scalable, and can be applied to different aromatic, heteroaromatic and sulphonyl azides. A high level of chemoselectivity is observed for azide reduction in the presence of other reducible functionalities like cyano, nitro, ether, ketone, amide and acid. The reaction gets completed in a short time (5-20 minutes), and furnishes the amines in high yield (85-99%). Unlike conventional hydrogenations, this reduction protocol does not require any metal catalyst, elaborate experimental setup or use of high-pressure equipment.
- Chandna, Nisha,Kaur, Fatehjeet,Kumar, Shobhna,Jain, Nidhi
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supporting information
p. 4268 - 4271
(2017/09/29)
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- General Method for the Synthesis of 1,4-Disubstituted 5-Halo-1,2,3-triazoles
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A general method for the synthesis of 1,4-disubstituted 5-halo-1,2,3-triazoles has been developed. The one-pot two-step process consists of a CuAAC reaction of a copper(I) acetylide with an organic azide catalyzed by (aNHC)CuCl, followed by halogenation with N-chlorosuccinimide, N-bromosuccinimide, or I2.
- Gribanov, Pavel S.,Topchiy, Maxim A.,Karsakova, Iuliia V.,Chesnokov, Gleb A.,Smirnov, Alexander Yu.,Minaeva, Lidiya I.,Asachenko, Andrey F.,Nechaev, Mikhail S.
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supporting information
p. 5225 - 5230
(2017/09/29)
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- Selective C(sp2)-H Halogenation of "click" 4-Aryl-1,2,3-triazoles
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Selective bromination reactions of "click compounds" are described. Electron-neutral and electron-deficient arenes selectively undergo unprecedented Pd-catalyzed C-H ortho-halogenations assisted by simple triazoles as modular directing groups, whereas electron-rich arenes are regioselectively halogenated following an electrophilic aromatic substitution reaction pathway. These C-H halogenation procedures exhibit a wide group tolerance, complement existing bromination procedures, and represent versatile synthetic tools of utmost importance for the late-stage diversification of "click compounds". The characterization of a triazole-containing palladacycle and density functional theory studies supported the mechanism proposal.
- Goitia, Asier,Gómez-Bengoa, Enrique,Correa, Arkaitz
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supporting information
p. 962 - 965
(2017/02/26)
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- A comparison of novel organoiridium(III) complexes and their ligands as a potential treatment for prostate cancer
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A range of 1,4-substituted 2-pyridyl-N-phenyl triazoles were synthesised and evaluated for their antiproliferative properties against lymph node cancer of the prostate (LNCaP) and bone metastasis of prostate cancer (PC-3) cells. Excellent-to-low IC50 values were determined (5.6-250 μM), and a representative group of 4 ligands were then complexed to iridium(III) giving highly luminescent species. Reevaluation of these compounds against both cell lines was then undertaken and improved potency (up to 72-fold) was observed, giving IC50 values of 0.36-11 μM for LNCaP and 0.85-5.9 μM for PC-3. Preliminary screens for in vivo toxicity were conducted using a zebrafish model showing a wide range of induced toxicity depending of the compound evaluated. Apoptosis and Caspase-3 levels were also determined and showed no statistical difference between some of the treated specimens and the controls. This study may identify novel therapeutic agents for advanced stage of prostate cancer in humans.
- Hockey, Samantha C.,Barbante, Gregory J.,Francis, Paul S.,Altimari, Jarrad M.,Yoganantharajah, Prusothman,Gibert, Yann,Henderson, Luke C.
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p. 305 - 313
(2016/01/28)
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- Synthesis of novel 1,2,3-triazole-containing pyridinepyrazole amide derivatives based on one-pot click reaction and their evaluation for potent nematicidal activity against Meloidogyne incognita
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In order to find a novel, leading nematicide compound, a series of pyridinepyrazole amide derivatives containing 1,2,3-triazoles were synthesized via click chemistry in a one-pot reaction. Their structures were characterized by proton nuclear magnetic res
- Chen, Xiulei,Xiao, Youxin,Wang, Gaolei,Li, Zhong,Xu, Xiaoyong
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p. 5495 - 5508
(2016/06/01)
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- Synthesis of α-santonin derived acetyl santonous acid triazole derivatives and their bioevaluation for T and B-cell proliferation
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A new series of α-santonin derived acetyl santonous acid 1,2,3-triazole derivatives were synthesised using Huisgen 1,3-dipolar cyclo-addition reaction (click chemistry approach) and evaluated for their in vitro inhibition activity on concanavalin A (ConA) induced T cell proliferation and lipopolysaccharide (LPS) induced B cell proliferation. Among the synthesised series, compounds 2-10 and 19 exhibited significant inhibition against ConA and LPS stimulated T-cell and B-cell proliferation in a dose dependent manner. More significantly compounds 4, 9-10 and 19 exhibited potent inhibition activity with remarkably lower cytotoxicity on the mitogen-induced T cell and B cell proliferation at 1 μM concentration. The compound 6 displayed potent immunosuppressive effects with ~89% against LPS induced B-cell and ~83% against ConA stimulated T-cell proliferation at 100 μM concentration without cytotoxicity. Compound 10 was more selective against B cell proliferation and exhibited 81% and 69% suppression at 100 and 1 μM concentration respectively. The present study led to the identification of several santonin analogs with reduced cytotoxicity and strong inhibition activity against the cell proliferation induced by the mitogens.
- Dangroo, Nisar A.,Singh, Jasvinder,Dar, Alamgir A.,Gupta, Nidhi,Chinthakindi, Praveen K.,Kaul, Anpurna,Khuroo, Mohmmed A.,Sangwan, Payare L.
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p. 160 - 169
(2016/05/24)
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- An unprecedentedly simple method of synthesis of aryl azides and 3-hydroxytriazenes
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Fischer's approach towards the synthesis of aryl azides and triazinoles from diazonium salts and hydroxylammonium chloride (phenylhydraxylamine) was reinvestigated and optimized. The new methodology enables the preparation of aryl azides and triazinoles in high yields in water at room temperature. The procedure is very simple, robust, easily scalable, reproducible, and "green".
- Gribanov, Pavel S.,Topchiy, Maxim A.,Golenko, Yulia D.,Lichtenstein, Yana I.,Eshtukov, Artur V.,Terekhov, Vladimir E.,Asachenko, Andrey F.,Nechaev, Mikhail S.
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p. 5984 - 5988
(2018/06/06)
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- A novel triazole derivative of betulinic acid induces extrinsic and intrinsic apoptosis in human leukemia HL-60 cells
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In an attempt to arrive at more potent cytotoxic agent than the bioactive natural product betulinic acid, influence of small structural modifications of its 1, 2, 3 triazole derivatives tethered at C-28 and both C3, C-28 using click chemistry approach has been studied. The chemically characterized triazoles have been screened for in vitro cytotoxicity against four human cancer cell lines HL-60, MiaPaCa-2, PC-3 and A549 which has allowed to identify triazole derivative 28{1N (4-fluoro phenyl)-1H-1, 2, 3-triazol-4-yl} methyloxy betulinic ester having better potency profile than the parent compound with IC50 values in the range of 5-7 μM. It caused disruption of mitochondrial membrane potential, rendered Bcl-2 cleavage, Bax translocation and decrease Bcl-2/Bax ratio. These events are accompanied by activation of caspases -9, -3, which cleave the PARP-1. It also induces caspase-8, which is involved in extrinsic apoptotic pathway. Therefore, it induces apoptosis through both intrinsic and extrinsic pathways in human leukemia HL-60 cells.
- Khan, Imran,Guru, Santosh K.,Rath, Santosh K.,Chinthakindi, Praveen K.,Singh, Buddh,Koul, Surrinder,Bhushan, Shashi,Sangwan, Payare L.
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p. 104 - 116
(2015/12/04)
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- Copper-Mediated Functionalization of Aryl Trifluoroborates
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This paper describes the Cu(OTf)2-mediated coupling of aryl and heteroaryl trifluoroborates with tetrabutylammonium or alkali metal salts to form C-O, C-N, and C-halogen bonds. The reactions proceed under mild conditions (often room temperature over 16 hours) with carboxylate, halide, and azide salts, all nucleophiles that have been underrepresented in the copper cross-coupling literature. Preliminary results show that copper salts bearing weakly coordinating X-type ligands are essential for enabling these transformations to proceed under mild conditions.
- Schimler, Sydonie D.,Sanford, Melanie S.
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supporting information
p. 2279 - 2284
(2016/10/06)
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- A library of 1,2,3-triazole-substituted oleanolic acid derivatives as anticancer agents: Design, synthesis, and biological evaluation
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A series of novel oleanolic acid coupled 1,2,3-triazole derivatives have been designed and synthesized by employing a Cu(i) catalyzed Huisgen 1,3-dipolar cycloaddition reaction. The anti-proliferative evaluation indicated that some compounds exhibited exc
- Wei, Gaofei,Luan, Weijing,Wang, Shuai,Cui, Shanshan,Li, Fengran,Liu, Yongxiang,Liu, Yang,Cheng, Maosheng
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p. 1507 - 1514
(2015/01/30)
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- Palladium-catalyzed cross-coupling reaction of azides with isocyanides
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An efficient palladium-catalyzed cross-coupling reaction of azides with isocyanides is developed, providing a general synthetic route to unsymmetric carbodiimides with excellent yields. This method shows a broad substrate scope, including not only aryl azides, but also unactivated benzyl and alkyl azides. Furthermore, from readily available substrates, Pd-catalyzed coupling with a tandem amine insertion cascade to obtain unsymmetric trisubstituted guanidines has been achieved in a one-pot fashion.
- Zhang, Zhen,Li, Zongyang,Fu, Bin,Zhang, Zhenhua
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supporting information
p. 16312 - 16315
(2015/11/16)
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- Synthetic modification of hydroxychavicol by Mannich reaction and alkyne-azide cycloaddition derivatives depicting cytotoxic potential
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Here we report the design, synthesis and lead optimization of hydroxychavicol (1) a high yielding metabolite ubiquitously present in the Piper betel leaves with the significant cytotoxic activity. This is the first report to describe the synthetic strateg
- Kumar, Sunil,Pathania, Anoop S.,Satti, Naresh K.,Dutt, Parbhu,Sharma, Neha,Mallik, Fayaz A.,Ali, Asif
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p. 236 - 245
(2015/05/27)
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- An Efficient Copper-Catalyzed One-Pot Synthesis of 1-Aryl-1,2,3-triazoles from Arylboronic Acids in Water under Mild Conditions
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A convenient method for one-pot two-step 1,3-dipolar cycloadditon reaction of arylboronic acid, sodium azide followed with terminal alkynes in the presence of 2-pyrrolecarbaldiminato-Cu(II) complexes catalyst is reported. Various 1-aryl-1,2,3-triazoles were prepared in 63%-97% yields in water at 30C without any additives and avoiding the isolation of unstable aryl azides.
- Hao, Changbo,Zhou, Changjian,Xie, Jianwei,Zhang, Jie,Liu, Ping,Dai, Bin
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supporting information
p. 1317 - 1320
(2015/11/27)
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- Click chemistry inspired facile synthesis and bioevaluation of novel triazolyl analogs of Ludartin
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A convenient and modular synthesis involving diastereoselective Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reaction was carried out to furnish 1,4-disubstituted-1,2,3-triazoles of Ludartin. This reaction scheme involving Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reaction leading to the formation of triazolyl analogs is being reported for the first time. All the triazolyl products were characterised using spectral data analysis. Sulphorhodamine B cytotoxicity screening of the resulting products against a panel of five human cancerous cell-lines revealed that few of the analogs display promising broad spectrum cytotoxic effect. Among all the synthesized compounds, only 3q displayed the best cytotoxic effect with IC50 values of 12, 11, 38, 39 and 8.5 μM but less than the standard Ludartin (1) with IC50 values of 6.3, 7.4, 7.5, 6.9 and 0.5 μM against human neuroblastoma (T98G), lung (A-549), prostate (PC-3), colon (HCT-116) and breast (MCF-7) cancer cell lines, respectively. The present synthesis was designed based on the previous literature reports of Ludartin as an aromatase inhibitor. Our work provides an initial study on structure-activity relationship of triazolyl analogs of sesquiterpene lactones in general and Ludartin (1) in particular.
- Lone, Shabir H.,Bhat, Khursheed A.,Majeed, Rabiya,Hamid, Abid,Khuroo, Mohd A.
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p. 1047 - 1051
(2014/03/21)
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