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Tytuł pozycji:

Copper(I)-Catalyzed Nitrile-Addition/ N -Arylation Ring-Closure Cascade: Synthesis of 5,11-Dihydro-6 H -indolo[3,2- c ]quinolin-6-ones as Potent Topoisomerase-I Inhibitors.

Tytuł :
Copper(I)-Catalyzed Nitrile-Addition/ N -Arylation Ring-Closure Cascade: Synthesis of 5,11-Dihydro-6 H -indolo[3,2- c ]quinolin-6-ones as Potent Topoisomerase-I Inhibitors.
Autorzy :
Hsueh WY; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Lee YE; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Huang MS; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Lai CH; Department of Applied Chemistry, Chung Shan Medical University, Taichung 40201, Taiwan.
Gao YS; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Lin JC; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Chen YF; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Chang CL; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Chou SY; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Chen SF; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Lu YY; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Chang LH; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Lin SF; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Lin YH; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Hsu PC; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Wei WY; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Huang YC; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Kao YF; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Teng LW; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Liu HH; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Chen YC; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Yuan TT; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Chan YW; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Huang PH; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Chao YT; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Huang SY; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Jian BH; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Huang HY; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Yang SC; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Lo TH; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Huang GR; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Wang SY; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
Lin HS; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Chuang SH; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
Huang JJ; Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.; Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
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Źródło :
Journal of medicinal chemistry [J Med Chem] 2021 Feb 11; Vol. 64 (3), pp. 1435-1453. Date of Electronic Publication: 2021 Jan 25.
Typ publikacji :
Journal Article; Research Support, Non-U.S. Gov't
Język :
English
Imprint Name(s) :
Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
MeSH Terms :
Antineoplastic Agents/*chemical synthesis
Antineoplastic Agents/*pharmacology
Copper/*chemistry
Nitriles/*chemistry
Quinolones/*chemical synthesis
Quinolones/*pharmacology
Topoisomerase I Inhibitors/*chemical synthesis
Topoisomerase I Inhibitors/*pharmacology
Animals ; Catalysis ; DNA Topoisomerases, Type I/chemistry ; Drug Design ; Drug Screening Assays, Antitumor ; Female ; Humans ; Male ; Mice ; Mice, Nude ; Models, Molecular ; Molecular Docking Simulation ; Quinolones/pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Topoisomerase I Inhibitors/pharmacokinetics ; Xenograft Model Antitumor Assays
Substance Nomenclature :
0 (Antineoplastic Agents)
0 (Nitriles)
0 (Quinolones)
0 (Topoisomerase I Inhibitors)
789U1901C5 (Copper)
EC 5.99.1.2 (DNA Topoisomerases, Type I)
Entry Date(s) :
Date Created: 20210125 Date Completed: 20210323 Latest Revision: 20210323
Update Code :
20210324
DOI :
10.1021/acs.jmedchem.0c00727
PMID :
33492141
Czasopismo naukowe
In this paper, we present a copper(I)-catalyzed nitrile-addition/ N -arylation ring-closure cascade for the synthesis of 5,11-dihydro-6 H -indolo[3,2- c ]quinolin-6-ones from 2-(2-bromophenyl)- N -(2-cyanophenyl)acetamides. Using CuBr and t -BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis[2-(dimethylamino)ethyl]-5,12-dihydro-6 H -[1,3]dioxolo[4',5':5,6]indolo[3,2- c ]quinolin-6-one ( 2k ), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6 H -indolo[3,2- c ]quinolin-6-ones as topoisomerase-I inhibitors.

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