- Cobalt-Catalyzed Dearomatization of Indoles via Transfer Hydrogenation to Afford Polycyclic Indolines
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A cobalt-catalyzed dearomatization of indoles via transfer hydrogenation with HBpin and H2O has been developed. This reaction offered a straightforward platform to access hexahydropyrido[1,2-a]indoles in high regio- and chemoselectivity. A preliminary reaction mechanism was proposed on the basis of deuterium-labeling experiments, and a cobalt hydride species was involved in the reaction.
- Chen, Siwei,Cai, Min,Huang, Junru,Yao, Hequan,Lin, Aijun
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supporting information
p. 2212 - 2216
(2021/04/05)
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- PYRIDINYL AND PYRAZINYL-(AZA)INDOLSULFONAMIDES
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The present invention relates to pyridinyl and pyrazinyl-(aza)indolsulfonamides having GPR17 modulator activity. The compounds have utility in the treatment of a variety of GPR17-associated disorders.
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Page/Page column 92; 102
(2020/01/11)
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- N - benzenesulfonyl - 3 - (2 - base - acetyl) - 6 - methyl indole derivatives of use
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The invention discloses application for N-benzenesulfonyl-3-(2-yl-ethanoyl)-6-methylindole derivatives, belonging to the technical field of biological prevention and treatment of crop diseases. The N-benzenesulfonyl-3-(2-yl-ethanoyl)-6-methylindole deriva
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Paragraph 0064-0069
(2017/08/14)
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- Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)
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The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin-proteasome system (UPS) mediated protein degradation, endoplasmic reticulum-associated degradation (ERAD), and autophagy. Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083. Treatment of tumor cells with 71 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell death. In tumor bearing mice, oral administration of 71 causes rapid accumulation of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to sustained antitumor activity in in vivo xenograft models of both solid and hematological tumors. 71 has been taken into phase 1 clinical trials in patients with multiple myeloma and solid tumors.
- Zhou, Han-Jie,Wang, Jinhai,Yao, Bing,Wong, Steve,Djakovic, Stevan,Kumar, Brajesh,Rice, Julie,Valle, Eduardo,Soriano, Ferdie,Menon, Mary-Kamala,Madriaga, Antonett,Kiss Von Soly, Szerenke,Kumar, Abhinav,Parlati, Francesco,Yakes, F. Michael,Shawver, Laura,Le Moigne, Ronan,Anderson, Daniel J.,Rolfe, Mark,Wustrow, David
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p. 9480 - 9497
(2016/01/12)
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- Synthesis and quantitative structure-activity relationship (QSAR) study of novel N-arylsulfonyl-3-acylindole arylcarbonyl hydrazone derivatives as nematicidal agents
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In continuation of our program aimed at the discovery and development of natural-product-based pesticidal agents, 54 novel N-arylsulfonyl-3-acylindole arylcarbonyl hydrazone derivatives were prepared, and their structures were well characterized by 1
- Che, Zhiping,Zhang, Shaoyong,Shao, Yonghua,Fan, Lingling,Xu, Hui,Yu, Xiang,Zhi, Xiaoyan,Yao, Xiaojun,Zhang, Rui
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p. 5696 - 5705
(2013/07/26)
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- Synthesis and antiproliferative activity of novel 2-aryl-4-benzoyl- imidazole derivatives targeting tubulin polymerization
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We previously reported the discovery of 2-aryl-4-benzoyl-imidazoles (ABI-I) as potent antiproliferative agents for melanoma. To further understand the structural requirements for the potency of ABI analogs, gain insight in the structure-activity relationships (SAR), and investigate metabolic stability for these compounds, we report extensive SAR studies on the ABI-I scaffold. Compared with the previous set of ABI-I analogs, the newly synthesized ABI-II analogs have lower potency in general, but some of the new analogs have comparable potency to the most active compounds in the previous set when tested in two melanoma and four prostate cancer cell lines. These SAR studies indicated that the antiproliferative activity was very sensitive to subtle changes in the ligand. Tested compounds 3ab and 8a are equally active against highly paclitaxel resistant cancer cell lines and their parental cell lines, indicating that drugs developed based on ABI-I analogs may have therapeutic advantages over paclitaxel in treating resistant tumors. Metabolic stability studies of compound 3ab revealed that N-methyl imidazole failed to extend stability as literature reported because de-methylation was found as the major metabolic pathway in rat and mouse liver microsomes. However, this sheds light on the possibility for many modifications on imidazole ring for further lead optimization since the modification on imidazole, such as compound 3ab, did not impact the potency.
- Chen, Jianjun,Li, Chien-Ming,Wang, Jin,Ahn, Sunjoo,Wang, Zhao,Lu, Yan,Dalton, James T.,Miller, Duane D.,Li, Wei
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experimental part
p. 4782 - 4795
(2011/09/20)
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- Anti HIV-1 agents 5: Synthesis and anti-HIV-1 activity of some N-arylsulfonyl-3-acetylindoles in vitro
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In continuation of our program aimed at the discovery and development of compounds with superior anti-human immunodeficiency virus type 1 (HIV-1) activity, 21N-arylsulfonyl-3-acetylindole analogs (2a-u) were synthesized and preliminarily evaluated as HIV-
- Ran, Jun-Qiang,Huang, Ning,Xu, Hui,Yang, Liu-Meng,Lv, Min,Zheng, Yong-Tang
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supporting information; experimental part
p. 3534 - 3536
(2010/08/21)
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- Novel bis(1H-indol-2-yl)methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase
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FLT3 receptor tyrosine kinase is aberrantly active in many cases of acute myeloid leukemia (AML). Recently, bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. To optimize FLT3 activity and selectivity, 35 novel derivatives were synthesized and tested for inhibition of FLT3 and PDGFR autophosphorylation. The most potent FLT3 inhibitors 98 and 102 show IC 50 values of 0.06 and 0.04 μM, respectively, and 1 order of magnitude lower PDGFR inhibiting activity. The derivatives 76 and 82 are 20- to 40-fold PDGFR selective. Docking at the recent FLT3 structure suggests a bidentate binding mode with the backbone of Cys-694. Activity and selectivity can be related to interactions of one indole moiety with a Hydrophobic pocket including Phe-691, the only different binding site residue (PDGFR Thr-681). Compound 102 inhibited the proliferation of 32D cells expressing wildtype FLT3 or FLT3-ITD similarly as FLT3 autophosphorylation, and induced apoptosis in primary AML patient blasts.
- Mahboobi, Siavosh,Uecker, Andrea,Sellmer, Andreas,Cénac, Christophe,H?cher, Heymo,Pongratz, Herwig,Eichhorn, Emerich,Hufsky, Harald,Trümpler, Antje,Sicker, Marit,Heidel, Florian,Fischer, Thomas,Stocking, Carol,Elz, Sigurd,B?hmer, Frank-D.,Dove, Stefan
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p. 3101 - 3115
(2007/10/03)
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