2. Academic Validation
  3. Discovery of New Monocarbonyl Ligustrazine-Curcumin Hybrids for Intervention of Drug-Sensitive and Drug-Resistant Lung Cancer

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.
Yong Ai 1 2,  Bin Zhu 3,  Caiping Ren 3,  Fenghua Kang 1 2,  Jinlong Li 3,  Zhangjian Huang 1 2,  Yisheng Lai 1 2,  Sixun Peng 1 2,  Ke Ding 4,  Jide Tian 5,  Yihua Zhang 1 2
Affiliations

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.

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