Structure-based hybridization, synthesis and biological evaluation of novel tetracyclic heterocyclic azathioxanthone analogues as potential antitumor agents

Tsung-Chih Chen; Chia-Lun Wu; Chia-Chung Lee; Chun-Liang Chen; Dah-Shyong Yu; Hsu-Shan Huang

doi:10.1016/j.ejmech.2014.09.050

Structure-based hybridization, synthesis and biological evaluation of novel tetracyclic heterocyclic azathioxanthone analogues as potential antitumor agents

Eur J Med Chem. 2015 Oct 20:103:615-27. doi: 10.1016/j.ejmech.2014.09.050. Epub 2014 Sep 16.

Authors

Tsung-Chih Chen¹, Chia-Lun Wu², Chia-Chung Lee¹, Chun-Liang Chen¹, Dah-Shyong Yu³, Hsu-Shan Huang⁴

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.
³ Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan; Uro-Oncology Laboratory, Division of Urology, Department of Surgery, Tri-Service General Hospital, Taipei 114, Taiwan. Electronic address: yuds@ms21.hinet.net.
⁴ 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; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan. Electronic address: huanghs99@gmail.com.

PMID: 25799376
DOI: 10.1016/j.ejmech.2014.09.050

Abstract

A series of tetracyclic heterocyclic azathioxanthones were synthesized and evaluated for cell proliferations, topoisomerase inhibitions, and NCI-60 cell panel assay, respectively. Compounds 5, 7, 8, 16, and 19 were selected for topoisomerase assay after MTT assay. 7 not only showed cytotoxic effect (IC50 = 2.84 ± 0.64 μM) in PC-3 cells but also revealed topoisomerases inhibition with IC50 (10-25 μM) and increased apoptotic cleavage of PARP and caspase 3 activity. The overall of novel azathioxanthones with different cytostatic and cytotoxic activities should be further developed as new potential candidates for anticancer drugs.

Keywords: Azathioxanthones; Cytostatic and cytotoxic activities; MTT assay; NCI-60 human tumor cell lines; Topoisomerase assays.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
DNA Topoisomerases, Type I / metabolism
DNA Topoisomerases, Type II / metabolism
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology*
Humans
Molecular Structure
Quinolines / chemistry*
Quinolines / pharmacology*
Structure-Activity Relationship
Thioxanthenes / chemistry*
Thioxanthenes / pharmacology*
Topoisomerase I Inhibitors / chemical synthesis
Topoisomerase I Inhibitors / chemistry
Topoisomerase I Inhibitors / pharmacology
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / chemistry
Topoisomerase II Inhibitors / pharmacology

Substances

10-chloro-6-(piperazin-1-yl)-12H-thiochromeno(2,3-c)quinolin-12-one
Antineoplastic Agents
Heterocyclic Compounds
Quinolines
Thioxanthenes
Topoisomerase I Inhibitors
Topoisomerase II Inhibitors
DNA Topoisomerases, Type I
DNA Topoisomerases, Type II