Design, synthesis and biological evaluation of tetracyclic azafluorenone derivatives with topoisomerase I inhibitory properties as potential anticancer agents

Tsung-Chih Chen; Dah-Shyong Yu; Shiag-Jiun Chen; Chun-Liang Chen; Chia-Chung Lee; Ying-Yu Hsieh; Lien-Cheng Chang; Jih-Hwa Guh; Jing-Jer Lin; Hsu-Shan Huang

Arabian Journal of Chemistry (Dec 2019)

Design, synthesis and biological evaluation of tetracyclic azafluorenone derivatives with topoisomerase I inhibitory properties as potential anticancer agents

Tsung-Chih Chen,
Dah-Shyong Yu,
Shiag-Jiun Chen,
Chun-Liang Chen,
Chia-Chung Lee,
Ying-Yu Hsieh,
Lien-Cheng Chang,
Jih-Hwa Guh,
Jing-Jer Lin,
Hsu-Shan Huang

Affiliations

Tsung-Chih Chen: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan
Dah-Shyong Yu: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; Uro-Oncology Laboratory, Division of Urology, Department of Surgery, Tri-Service General Hospital and Institute of Preventive Medicine, National Defense Medical Center, Taipei 114, Taiwan
Shiag-Jiun Chen: School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan
Chun-Liang Chen: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan
Chia-Chung Lee: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan
Ying-Yu Hsieh: School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan
Lien-Cheng Chang: Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 100, Taiwan; Food and Drug Administration, Ministry of Health and Welfare, Taipei 115, Taiwan
Jih-Hwa Guh: School of Pharmacy, National Taiwan University, Taipei 100, Taiwan
Jing-Jer Lin: Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 100, Taiwan; Corresponding authors at: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan. Fax: +886 2 66387537 (H.-S. Huang). Fax: +886 2 2391 5295 (J.-J. Lin).
Hsu-Shan Huang: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan; Corresponding authors at: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan. Fax: +886 2 66387537 (H.-S. Huang). Fax: +886 2 2391 5295 (J.-J. Lin).

Journal volume & issue: Vol. 12, no. 8
pp. 4348 – 4364

Abstract

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Several 9-chloro-11H-indeno[1,2-c]quinolin-11-one derivatives have been designed which is replacing side chains with different groups containing oxygen, nitrogen or sulfur atoms. Substitution of C-6 on the starting structure, 6,9-dichloro-11H-indeno[1,2-c]quinolin-11-one, using apposite nucleophilic group with a suitable base or acid could be obtained 28 novel tetracyclic azafluorenone derivatives. The cytotoxic activity of these analogues was examined in cancer cell lines by MTT assay and compounds 4, 5, 13, and 26 were selected to evaluate in topoisomerase I drug screening assay, respectively. At the same time, 17 compounds were selected for NCI-60 anticancer drug screen to prevent the narrower concept of an in vitro screening model. Its worth to find that 9-chloro-6-(piperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one (12) showed greater cytotoxicity than another azafluorenone derivatives with an average GI50 of 10.498 μM over 60 cell lines. We also found that another analogue, 9-chloro-6-(2-methylpiperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one (13), exhibited preferential growth inhibition effect toward cancer cell lines and showed a significant inhibitory effect on topoisomerase I. Keywords: Indenoquinolinone, Topoisomerase I, Azafluorenone, Cytotoxicity, NCI-60 anticancer drug screen

Published in Arabian Journal of Chemistry

ISSN: 1878-5352 (Print)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Chemistry
Website: http://www.journals.elsevier.com/arabian-journal-of-chemistry/

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