Ring fusion strategy for the synthesis of anthra[2,3-d]oxazole-2-thione-5,10-dione homologues as DNA topoisomerase inhibitors and as antitumor agents

Chun-Liang Chen; Fei-Lan Liu; Chia-Chung Lee; Tsung-Chih Chen; Wen-Wei Chang; Jih-Hwa Guh; Ahmed Atef Ahmed Ali; Deh-Ming Chang; Hsu-Shan Huang

doi:10.1016/j.ejmech.2014.09.016

Ring fusion strategy for the synthesis of anthra[2,3-d]oxazole-2-thione-5,10-dione homologues as DNA topoisomerase inhibitors and as antitumor agents

Eur J Med Chem. 2014 Nov 24:87:30-8. doi: 10.1016/j.ejmech.2014.09.016. Epub 2014 Sep 6.

Authors

Chun-Liang Chen¹, Fei-Lan Liu², Chia-Chung Lee¹, Tsung-Chih Chen¹, Wen-Wei Chang³, Jih-Hwa Guh⁴, Ahmed Atef Ahmed Ali⁵, Deh-Ming Chang⁶, Hsu-Shan Huang⁷

Affiliations

¹ 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.
² Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; Rheumatology/Immunology/Allergy, Taipei Veterans General Hospital, Taipei 112, Taiwan.
³ School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan.
⁴ School of Pharmacy, National Taiwan University, Taipei 100, Taiwan.
⁵ Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
⁶ Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; Rheumatology/Immunology/Allergy, Taipei Veterans General Hospital, Taipei 112, Taiwan. Electronic address: ming0503@ms3.hinet.net.
⁷ 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. Electronic address: huanghs99@tmu.edu.tw.

PMID: 25240093
DOI: 10.1016/j.ejmech.2014.09.016

Abstract

The efficient synthesis of mono-substituted anthraquinones and ring fusion into anthra[2,3-d]oxazole-2-thione-5,10-dione derivatives were developed, and all the compounds were tested for their cytotoxicity against PC-3 cancer cell lines. Compounds 8, 14, 17 and 23 were selected by the NCI and 12, 17 and 19 were evaluated for topoisomerase I-mediated DNA relaxation. Among them, 17 appeared to be the most active compound of this series and not only showed higher inhibition when indicated from the low IC50 values against PC-3 cancer cell line but also attenuated the in vitro topoisomerase I-mediated DNA relaxation at low micromolar concentrations. All test compounds exhibited different cytostatic and cytotoxic activities for further developing potential anticancer drugs.

Keywords: Anthra[2,3-d]oxazole-2-thione-5,10-dione; NCI 60-cell panel assay; Topoisomerase I-mediated DNA relaxation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anthraquinones / chemistry*
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
DNA Topoisomerases, Type I / chemistry*
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
Humans
Male
Molecular Structure
Oxazoles / chemistry*
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / pathology
Structure-Activity Relationship
Topoisomerase Inhibitors / chemical synthesis*
Topoisomerase Inhibitors / pharmacology*
Tumor Cells, Cultured

Substances

Anthraquinones
Antineoplastic Agents
Oxazoles
Topoisomerase Inhibitors
DNA Topoisomerases, Type I