Discovery of New Monocarbonyl Ligustrazine-Curcumin Hybrids for Intervention of Drug-Sensitive and Drug-Resistant Lung Cancer

Yong Ai; Bin Zhu; Caiping Ren; Fenghua Kang; Jinlong Li; Zhangjian Huang; Yisheng Lai; Sixun Peng; Ke Ding; Jide Tian; Yihua Zhang

doi:10.1021/acs.jmedchem.5b01203

Discovery of New Monocarbonyl Ligustrazine-Curcumin Hybrids for Intervention of Drug-Sensitive and Drug-Resistant Lung Cancer

J Med Chem. 2016 Mar 10;59(5):1747-60. doi: 10.1021/acs.jmedchem.5b01203. Epub 2016 Feb 26.

Authors

Yong Ai^{1

2}, Bin Zhu³, Caiping Ren³, Fenghua Kang^{1

2}, Jinlong Li³, Zhangjian Huang^{1

2}, Yisheng Lai^{1

2}, Sixun Peng^{1

2}, Ke Ding⁴, Jide Tian⁵, Yihua Zhang^{1

2}

Affiliations

¹ State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.
² Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
³ Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Sciences, Central South University , Changsha 410078, China.
⁴ Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, China.
⁵ Department of Molecular and Medical Pharmacology, University of California , Los Angeles, California 90095, United States.

PMID: 26891099
DOI: 10.1021/acs.jmedchem.5b01203

Abstract

The elevation of oxidative stress preferentially in cancer cells by inhibiting thioredoxin reductase (TrxR) and/or enhancing reactive oxygen species (ROS) production has emerged as an effective strategy for selectively targeting cancer cells. In this study, we designed and synthesized 21 ligustrazine-curcumin hybrids (10a-u). Biological evaluation indicated that the most active compound 10d significantly inhibited the proliferation of drug-sensitive (A549, SPC-A-1, LTEP-G-2) and drug-resistant (A549/DDP) lung cancer cells but had little effect on nontumor lung epithelial-like cells (HBE). Furthermore, 10d suppressed the TrxR/Trx system and promoted intracellular ROS accumulation and cancer cell apoptosis. Additionally, 10d inhibited the NF-κB, AKT, and ERK signaling, P-gp-mediated efflux of rhodamine 123, P-gp ATPase activity, and P-gp expression in A549/DDP cells. Finally, 10d repressed the growth of implanted human drug-resistant lung cancer in mice. Together, 10d acts a novel TrxR inhibitor and may be a promising candidate for intervention of lung cancer.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Curcumin / chemistry
Curcumin / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Mice
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Pyrazines / chemistry
Pyrazines / pharmacology*
Reactive Oxygen Species / metabolism
Structure-Activity Relationship
Thioredoxin-Disulfide Reductase / antagonists & inhibitors
Thioredoxin-Disulfide Reductase / metabolism

Substances

Antineoplastic Agents
Enzyme Inhibitors
Pyrazines
Reactive Oxygen Species
Thioredoxin-Disulfide Reductase
Curcumin
tetramethylpyrazine