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
  • 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.