Discovery and optimization of 2-thio-5-amino substituted benzoquinones as potent anticancer agents

Yuqiong Zhao; Yihuan Lu; Ridong Li; Jianan He; Han Zhang; Xin Wang; Zemei Ge; Runtao Li

doi:10.1016/j.ejmech.2018.02.059

Discovery and optimization of 2-thio-5-amino substituted benzoquinones as potent anticancer agents

Eur J Med Chem. 2018 Apr 10:149:1-9. doi: 10.1016/j.ejmech.2018.02.059. Epub 2018 Feb 21.

Authors

Yuqiong Zhao¹, Yihuan Lu¹, Ridong Li², Jianan He¹, Han Zhang¹, Xin Wang¹, Zemei Ge³, Runtao Li⁴

Affiliations

¹ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
² State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China; Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University, Beijing 100191, PR China.
³ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: zmge@bjmu.edu.cn.
⁴ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: lirt@bjmu.edu.cn.

PMID: 29486369
DOI: 10.1016/j.ejmech.2018.02.059

Abstract

Based on our discovered novel lead compound 1 through phenotypic drug discovery (PDD) approaches, systematic structural optimization was performed. A series of 2-allylthio-5-amino substituted benzoquinones were synthesized and evaluated for their in-vitro anticancer activities against human prostate cancer cell line PC3. The compound 7a was found inhibit the growth of PC3 with an IC₅₀ of 0.22 μM, which is over 20-fold improvement compared to lead compound 1. It is noteworthy that compound 7a also showed potent anti-proliferation activity toward a panel of cancer cells with relatively less cytotoxicity to nonmalignant cell, as well as good water solubility.

Keywords: 2-Thio-5-amino substituted benzoquinones; Anti-tumor activity; Structure-activity relationship; Synthesis.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzoquinones / pharmacology*
Benzoquinones / therapeutic use
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design*
Drug Discovery
Drug Screening Assays, Antitumor
Humans
Inhibitory Concentration 50
Solubility
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzoquinones