Design, synthesis and evaluation of 4-substituted anthra[2,1-c][1,2,5]thiadiazole-6,11-dione derivatives as novel non-camptothecin topoisomerase I inhibitors

Guoqiang Dong; Yuxin Fang; Yang Liu; Na Liu; Shanchao Wu; Wannian Zhang; Chunquan Sheng

doi:10.1016/j.bmcl.2017.03.039

Design, synthesis and evaluation of 4-substituted anthra[2,1-c][1,2,5]thiadiazole-6,11-dione derivatives as novel non-camptothecin topoisomerase I inhibitors

Bioorg Med Chem Lett. 2017 May 1;27(9):1929-1933. doi: 10.1016/j.bmcl.2017.03.039. Epub 2017 Mar 18.

Authors

Guoqiang Dong¹, Yuxin Fang¹, Yang Liu², Na Liu¹, Shanchao Wu¹, Wannian Zhang¹, Chunquan Sheng³

Affiliations

¹ School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
² Department of Pharmacy, No. 401 Hospital of Chinese People's Liberation Army, Qingdao 266071, People's Republic of China.
³ School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China. Electronic address: [email protected].

PMID: 28351590
DOI: 10.1016/j.bmcl.2017.03.039

Abstract

Previously, 4-tosylanthra[1,2-c][1,2,5]thiadiazole-6,11-dione (1) was identified as a novel non-camptothecin topoisomerase I (Top1) inhibitor by structure-based virtual screening. Herein, a series of 4-substituted derivatives were designed and synthesized. Most of them showed potent Top1 inhibitory activity. Their in vitro antiproliferative activity was also evaluated in A549, HCT-116 and ZR-75-30 human cancer cell lines. Compound 8s showed good antiproliferative activity with IC₅₀ of 0.52μM and 0.42μM against HCT-116 and ZR-75-30 cell line, respectively. Top1 unwinding assay and molecular modeling studies rationalized the mode of action of this new class of inhibitors.

Keywords: Anthrathiadiazole; Antiproliferative activity; Structure-activity relationship; Topoisomerase I inhibitors.

Publication types

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

MeSH terms

Anthraquinones / chemical synthesis
Anthraquinones / chemistry*
Anthraquinones / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
DNA Topoisomerases, Type I / metabolism
Drug Design
Humans
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / enzymology
Thiadiazoles / chemical synthesis
Thiadiazoles / chemistry*
Thiadiazoles / pharmacology*
Topoisomerase I Inhibitors / chemical synthesis
Topoisomerase I Inhibitors / chemistry*
Topoisomerase I Inhibitors / pharmacology*

Substances

Anthraquinones
Antineoplastic Agents
Thiadiazoles
Topoisomerase I Inhibitors
anthra(2,1-c)(1,2,5)thiadiazole-6,11-dione
DNA Topoisomerases, Type I
TOP1 protein, human