2-Substituted 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-diones as specific L-shaped NQO1-mediated redox modulators for the treatment of non-small cell lung cancer

Xiaojin Zhang; Jinlei Bian; Xiang Li; Xingsen Wu; Yanan Dong; Qidong You

doi:10.1016/j.ejmech.2017.06.028

2-Substituted 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-diones as specific L-shaped NQO1-mediated redox modulators for the treatment of non-small cell lung cancer

Eur J Med Chem. 2017 Sep 29:138:616-629. doi: 10.1016/j.ejmech.2017.06.028. Epub 2017 Jun 15.

Authors

Xiaojin Zhang¹, Jinlei Bian², Xiang Li³, Xingsen Wu¹, Yanan Dong³, Qidong You⁴

Affiliations

¹ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 211198, China.
² State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
³ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
⁴ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqd@163.com.

PMID: 28710963
DOI: 10.1016/j.ejmech.2017.06.028

Abstract

Based on the scaffold of 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione, a series of L-shaped derivatives with substituted side chains at the position of C2 were designed by analyzing the binding mode with NQO1. The drug-like compound 6q (named as DDO-7178) emerged as the most specific substrate of the two-electron oxidoreductase NQO1 and could hardly be reduced by one-electron oxidoreductases CPR (NQO1/CPR = 20.8). In addition, compound 6q showed much improved physicochemical properties such as water solubility than the control β-lap. The follow-up studies indicated that 6q showed a NQO1-expressing cancer-cell-selective killing property. Preliminary mechanism studies on the anticancer effect indicated that 6q induced ROS production in an NQO1 dependent manner and activated Akt/MAPK pathways in a ROS-dependent fashion, thereby inducing apoptosis. In addition, emphasized compound 6q showed more significant antitumor efficacy than β-lap without producing obvious toxic effects in vivo, which gave us a new tool for further investigation of NQO1-mediated redox modulators as anticancer drugs for the treatment of NQO1-overexpressed NSCLC.

Keywords: Anticancer; NQO1; NSCLC; ROS; β-lap.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / pathology
Cell Death / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Furans / chemical synthesis
Furans / chemistry
Furans / pharmacology*
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / pathology
Models, Molecular
Molecular Structure
NAD(P)H Dehydrogenase (Quinone) / metabolism*
Naphthalenes / chemical synthesis
Naphthalenes / chemistry
Naphthalenes / pharmacology*
Oxidation-Reduction
Reactive Oxygen Species / metabolism
Structure-Activity Relationship

Substances

3,7,8-trimethylnaphtho(1,2-b)furan-4,5-dione
Antineoplastic Agents
Furans
Naphthalenes
Reactive Oxygen Species
NAD(P)H Dehydrogenase (Quinone)
NQO1 protein, human