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Discovery of indeno[1,2-\(c\)]quinoline derivatives as dual topoisomerases I/II inhibitors: Part 3

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Abstract

\((E)\)-6-Hydroxy-9-methoxy-6-(piperazin-1-yl)-11\(H\)-indeno[1,2-\(c\)]quinolin-11-one \(O\)-2-(pyrrolidin-1-yl)ethyl oxime (2c) was identified as a potential dual topo I/II inhibitor in our previous paper. In continuation for the search of more potent compounds, we describe herein the preparation of certain indeno[1,2-\(c\)]quinoline derivatives and evaluation of their antiproliferation, DNA binding affinity, and topoisomerases (topo I and topo II) inhibitory activities. Among them, \((E)\)-9-[3-(dimethylamino)propoxy]-11\(H\)-indeno[1,2-\(c\)]quinolin-11-one \(O\)-3-(dimethylamino)propyl oxime (11b) and its analog 11c exhibited approximately equal activity to the lead compound 2c against the growth of HeLa and A549 cancer cells. Both compounds 11b and 11c were more active than 2c in the inhibition of topo I and topo II. However, none of them exhibited significant DNA binding affinity while 2c was a very strong DNA binding agent. Compound 11b exhibited a high oral bioavailability of 39.8 % while the oral bioavailability of 2c and 11c was only 10.9 and 8.6 %, respectively. The in vivo anti-tumor evaluation of 11b in nude mice bearing subcutaneous breast cancer tumors revealed that treatment with low (10 mg/kg) or high (30 mg/kg) doses of 11b dramatically diminished tumor growth. Therefore, compound 11b is identified as a potential non-DNA intercalating dual topo I/II inhibitor.

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Acknowledgments

Financial support of this work by the National Science Council of the Republic of China (NSC 99-2320-B-037-011-MY3, NSC 99-2628-B-037-005-MY3, and NSC 101-2320-B-037-039-MY3) is gratefully acknowledged. We also thank the National Center for High-Performance Computing for providing computer resources and chemical database services.

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Authors and Affiliations

  1. School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung City, 807, Taiwan

    Chih-Hua Tseng

  2. Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City, 807, Taiwan

    Cherng-Chyi Tzeng, Chiao-Li Yang & Yeh-Long Chen

  3. Institute of Clinical Medicine, School of Medicine, National Cheng-Kung University, 138 Sheng-Li Road, Tainan, 704, Taiwan

    Pei-Jung Lu, Yu-Peng Liu & Hui-Ling Chen

  4. Institute of Biotechnology, National University of Kaohsiung, 700 Kaohsiung University Rd, Kaohsiung, Taiwan

    Chien-Yu Chen & Chia-Ning Yang

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Tseng, CH., Tzeng, CC., Yang, CL. et al. Discovery of indeno[1,2-\(c\)]quinoline derivatives as dual topoisomerases I/II inhibitors: Part 3. Mol Divers 17, 781–799 (2013). https://doi.org/10.1007/s11030-013-9475-5

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