Insights into the importance for designing curcumin-inspired anticancer agents by a prooxidant strategy: The case of diarylpentanoids.
Developing anticancer agents by a prooxidant strategy has attracted increasing attention in recent years, although it is not conventional in medicinal chemistry and is completely opposite to antioxidant therapy. In this work, a panel of diarylpentanoids as the curcumin mono-carbonyl analogs were designed and synthesized, and their cytotoxic and proapoptotic mechanisms against human lung cancer A549 cells were investigated at the frontiers of chemistry and biology. It was found that compared with curcumin, the compounds (A1, B1, and C1) bearing two ortho substituents on the aromatic rings, especially A1, exhibit significantly increased cytotoxic and proapoptotic activities through a Michael acceptor unit-dependent prooxidant-mediated mechanism. The prooxidative ability is governed not only by their electrophilicity but also by their geometry, cellular uptake and metabolic stability, and TrxR-inhibitory activity. Mechanistic investigation reveals that the compound A1 could effectively and irreversibly modify the TrxR by virtue of the above optimal biochemical parameters, and convert this antioxidant enzyme into a reactive oxygen species (ROS) promoter, resulting in a burst of the intracellular ROS including H2O2 and O2(-)•. The ROS generation is associated with falling apart in the redox buffering system, and subsequently induces increases in Ca(2+) influx and oxidative stress, collapse of mitochondrial membrane potential, and activation of caspase-9 and caspase-3, ultimately leading to cell apoptosis. This work highlights the feasibility in designing curcumin-inspired anticancer agents by a prooxidant strategy, and gives us useful information on how to design them.
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
Fang
F
Dai
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
Guo-Yun
GY
Liu
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
Yan
Y
Li
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
Wen-Jing
WJ
Yan
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
Qi
Q
Wang
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
Jie
J
Yang
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
Dong-Liang
DL
Lu
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
De-Jun
DJ
Ding
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
Dong
D
Lin
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China. Electronic address: bozhou@lzu.edu.cn.
Bo
B
Zhou
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003474:Curcumin / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010421:Pentanoic Acids / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D010421:Pentanoic Acids; D017382:Reactive Oxygen Species; D003474:Curcumin
Apoptosis; Curcumin; Electrophilicity; Prooxidant; Thioredoxin reductase