Tetrodotoxin, one of the most powerful naturally occurring neurotoxins, has fascinated researchers for decades due to its potential applications in pain management and medical treatments. A team of scientists, led by Dr. Xiangbing Qi from the National Institute of Biological Sciences, Beijing, has now successfully developed a scalable and asymmetric total synthesis of tetrodotoxin and its congener, a closely related compound of tetrodotoxin. Their significant findings have been published in the peer-reviewed journal Nature Communications.
Tetrodotoxin is well known for its ability to block sodium channels that control nerve signals, making it an effective and powerful pain blocker and numbing agent. However, its complex structure has made laboratory production a formidable challenge. The researchers overcame these difficulties by designing a practical step-by-step method to create it starting from a common and easy-to-obtain starting material. “Our strategy streamlined the incorporation of dense heteroatom-substituted architecture, a molecular structure containing different types of atoms such as oxygen and nitrogen that affect its properties, enabling a practical route to synthesize tetrodotoxin at an unprecedented scale,” explained Dr. Qi.
Their method employs a stereoselective Diels-Alder reactionthat helps build the molecule’s core cyclohexane framework, a six-carbon ring structure that forms the backbone of many organic molecules, followed by carefully orchestrated functional group interconversions, controlled decarboxylative hydroxylation of the highly oxygenated cyclohexane frameworks to adjust its structural diversity. Notably, a carefully controlled oxo-bridge ring opening and reduction that breaks and rearranges the key parts of the molecule, and an innovative technique using a metal catalyst to refine the molecule’s structure played crucial roles in assembling the final structure. These precise synthetic steps enabled the researchers to produce tetrodotoxin and its 9-epi isomer in quantities exceeding a substantial amount, marking a significant scale-up compared to previous efforts.
The ability to synthesize tetrodotoxin efficiently opens new doors for medical research and drug development. The neurotoxin has already shown promise in treating severe pain, particularly in cancer patients who do not respond well to opioid-based medications, strong painkillers that work by blocking pain signals in the nervous system but can be addictive. “Establishing a reliable synthetic source of tetrodotoxin is critical for further studies to explore its effects on the body and potential therapeutic applications,” said Qi. Moreover, the study’s approach demonstrates the feasibility of assembling other complex, naturally occurring compounds rich in oxygen that have medical benefits, which could lead to advances in medicinal chemistry, the study of designing and developing compounds for use in medicine.
Beyond its medical implications, this research represents an important step in the science of creating complex molecules in a lab, refining strategies for tackling intricate densely functionalized, stereochemically complex architecturesespecially highly oxygenated polycyclic natural products. The findings not only highlight an innovative synthetic approach but also pave the way for further explorations into tetrodotoxin derivatives and their pharmacological potential. With an efficient synthetic route now established, researchers are poised to explore novel applications of this potent neurotoxin in medicine and beyond.
Journal Reference
Peihao Chen, Jing Wang, Shuangfeng Zhang, Yan Wang, Yuze Sun, Songlin Bai, Qingcui Wu, Xinyu Cheng, Peng Cao, Xiangbing Qi. “Total syntheses of Tetrodotoxin and 9-epiTetrodotoxin.” Nature Communications, 2024. DOI: https://doi.org/10.1038/s41467-024-45037-0
About the Author
Dr. Qi obtained his PhD in Chemistry and Biochemistry from University of Texas Southwestern Medical Center, Dallas in 2009. After postdoctoral training at the University of Illinois Urbana-Champaign and medicinal chemistry research at UT Southwestern Medical Center, Dr. Qi joined the National Institute of Biological Science (NIBS), Beijing in 2013 and currently is the associate PI and the Director of Chemistry Center at NIBS and Tsinghua University.
His research program primarily focuses on the interface of synthetic chemistry, chemical biology, and medicinal chemistry. His group has developed a novel cross-coupling reaction utilizing alkyl zirconium reagents for the activation, functionalization, and formation of sp³C–sp³C and sp³C–heteroatom single bonds. He has successfully achieved the total synthesis of several highly biologically active and structurally complex natural products, including tetrodotoxin and strychnine. His group has made groundbreaking contributions to drug discovery, including the development of bile acid derivatives that inhibit hepatitis B virus infection, the first drug candidate capable of regulating the circadian clock for 12 hours, and two novel molecular glues for targeted protein degradation and precision cancer therapy.
Email: qixiangbing@nibs.ac.cn Phone: (086)13011059717; Homepage: http://qigroup.nibs.ac.cn/
