2-Substituted 3-methylnaphtho[1,2-b]furan-4,5-diones as novel L-shaped ortho-quinone substrates for NAD(P)H:quinone oxidoreductase (NQO1)

Jinlei Bian; Bang Deng; Lili Xu; Xiaoli Xu; Nan Wang; Tianhan Hu; Zeyu Yao; Jianyao Du; Li Yang; Yonghua Lei; Xiang Li; Haopeng Sun; Xiaojin Zhang; Qidong You

doi:10.1016/j.ejmech.2014.05.041

2-Substituted 3-methylnaphtho[1,2-b]furan-4,5-diones as novel L-shaped ortho-quinone substrates for NAD(P)H:quinone oxidoreductase (NQO1)

Eur J Med Chem. 2014 Jul 23:82:56-67. doi: 10.1016/j.ejmech.2014.05.041. Epub 2014 May 14.

Authors

Jinlei Bian¹, Bang Deng¹, Lili Xu¹, Xiaoli Xu¹, Nan Wang¹, Tianhan Hu², Zeyu Yao², Jianyao Du², Li Yang¹, Yonghua Lei¹, Xiang Li³, Haopeng Sun¹, Xiaojin Zhang⁴, Qidong You⁵

Affiliations

¹ 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.
² Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
³ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
⁴ 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 210009, China. Electronic address: zhangxiaojin@outlook.com.
⁵ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqidong@gmail.com.

PMID: 24874653
DOI: 10.1016/j.ejmech.2014.05.041

Abstract

A series of L-shaped ortho-quinone analogs were designed by analyzing the binding mode with NQO1. Metabolic studies demonstrated that compounds 2m, 2n and 2q exhibited higher metabolic rates than β-lapachone. The docking studies, which supported the rationalization of the metabolic studies, constituted a prospective rational basis for the development of optimized ortho-quinone analogs. Besides, good substrates (2m, 2n and 2r) for NQO1 showed higher selective toxicity than β-lapachone toward A549 (NQO1-rich) cancer cells versus H596 (NQO1-deficient) cells. Determination of superoxide (O2(•-)) production and in vitro cytotoxicity evaluation in the presence of the NQO1 inhibitor dicoumarol confirmed that the ortho-quinones exerted their antitumor activity through NQO1-mediated ROS production by redox cycling. It was suggested that the L-shaped quinone substrates for NQO1 possessed better specificity and safety than β-lapachone.

Keywords: Antitumor; NQO1 substrates; Ortho-quinones; Tanshione IIA; β-Lapachone.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Furans / chemical synthesis
Furans / chemistry
Furans / pharmacology*
Humans
Models, Molecular
Molecular Structure
NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors*
NAD(P)H Dehydrogenase (Quinone) / metabolism
Naphthalenes / chemical synthesis
Naphthalenes / chemistry
Naphthalenes / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Enzyme Inhibitors
Furans
Naphthalenes
NAD(P)H Dehydrogenase (Quinone)
NQO1 protein, human