2. Academic Validation
  3. 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

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

  • J Med Chem. 2021 Feb 11;64(3):1435-1453. doi: 10.1021/acs.jmedchem.0c00727.
Wen-Yun Hsueh 1,  Ying-Shuan E Lee 2,  Min-Sian Huang 1,  Chin-Hung Lai 3,  Yu-Sheng Gao 1,  Jo-Chu Lin 1,  Yu-Fen Chen 1,  Chih-Lin Chang 1,  Shan-Yen Chou 2,  Shyh-Fong Chen 2,  Yann-Yu Lu 2,  Lien-Hsiang Chang 2,  Shu Fu Lin 2,  Yu-Hsiang Lin 2,  Pi-Chen Hsu 2,  Win-Yin Wei 2,  Ya-Chi Huang 2,  Yi-Feng Kao 2,  Li-Wei Teng 2,  Hung-Huang Liu 2,  Ying-Chou Chen 2,  Ta-Tung Yuan 2,  Ya-Wen Chan 1,  Po-Hsun Huang 1,  Yu-Ting Chao 1,  Shin-Yi Huang 1,  Bo-Han Jian 1,  Hsin-Yi Huang 1,  Sheng-Chuan Yang 2,  Tzu-Hao Lo 1,  Guan-Ru Huang 1,  Shao-Yun Wang 1,  Her-Sheng Lin 2,  Shih-Hsien Chuang 2,  Jiann-Jyh Huang 1 2
Affiliations

Affiliations

  • 1 Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan.
  • 2 Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 11571, Taiwan.
  • 3 Department of Applied Chemistry, Chung Shan Medical University, Taichung 40201, Taiwan.
PMID: 33492141 DOI: 10.1021/acs.jmedchem.0c00727
Abstract

In this paper, we present a copper(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6H-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-6H-[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-6H-indolo[3,2-c]quinolin-6-ones as topoisomerase-I inhibitors.

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