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

doi:10.1021/acs.jmedchem.0c00727

中山醫學大學機構典藏 CSMUIR > 中山醫學大學研究成果 > 期刊論文 > Item 310902500/23432

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/23432

Title:	Copper(I)-Catalyzed Nitrile-Addition/N-Arylation Ring-Closure Cascade: Synthesis of 5,11-Dihydro-6H-indolo[3,2-c]quinolin-6-ones as Potent Topoisomerase-I Inhibitors
Authors:	Hsueh, WY;Lee, YSE;Huang, MS;Lai, CH;Gao, YS;Lin, JC;Chen, YF;Chang, CL;Chou, SY;Chen, SF;Lu, YY;Chang, LH;Lin, SF;Lin, YH;Hsu, PC;Wei, WY;Huang, YC;Kao, YF;Teng, LW;Liu, HH;Chen, YC;Yuan, TT;Chan, YW;Huang, PH;Chao, YT;Huang, SY;Jian, BH;Huang, HY;Yang, SC;Lo, TH;Huang, GR;Wang, SY;Lin, HS;Chuang, SH;Huang, JJ
Date:	2021
Issue Date:	2022-08-05T09:37:13Z (UTC)
Publisher:	AMER CHEMICAL SOC
ISSN:	0022-2623
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.
URI:	http://dx.doi.org/10.1021/acs.jmedchem.0c00727 https://www.webofscience.com/wos/woscc/full-record/WOS:000619743200008 https://ir.csmu.edu.tw:8080/handle/310902500/23432
Relation:	JOURNAL OF MEDICINAL CHEMISTRY ,2021,v64,issue 3, P1435-1453
Appears in Collections:	[中山醫學大學研究成果] 期刊論文

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