Recently, Zhibo Liu group from the College of Chemistry and Molecular Engineering, Peking University published an article entitled “Radiotherapy Reduces N-Oxides for Prodrug Activation in Tumors” in the Journal of the American Chemical Society. This study reported that clinical doses of nuclear radiation can efficiently reduce N-oxide to corresponding tertiary aromatic amines or aromatic heterocyclic compounds in test tubes, living cells, and tumors. Using this reaction, the authors successfully achieved radiotherapy-induced tumor selective N-oxide prodrug activation.
Fig. 1 Radiotherapy reduces N-oxides for prodrug activation in tumors.
In clinical practice, combined chemoradiotherapy is the first-line treatment for more than 50% of cancer patients. However, due to the toxic and side effects of traditional chemotherapy drugs, the therapeutic effect needs to be improved. Developing tumor selective prodrug activation strategies is the key to solving these problems, which is also a long-standing challenge in drug discovery. Compared with other prodrug activation methods, nuclear radiation (e.g., X-rays, gamma rays, etc.) can accurately penetrate deep tissue and has the advantage of high temporal and spatial resolution. Moreover, it is clinically relevant. Radiolysis of water produces a variety of active species, among which hydroxyl radicals and hydrated electrons are of the highest yield. In 2020, Zhibo Liu group first reported radiation-induced in vivo cleavage chemistry (Angew Chem Int Ed, 2020, 59, 21546), which was based on in situ oxidation of hydroxyl radicals. Subsequently, Bradley group from the University of Edinburgh reported cleavage chemistry based on hydrogen radicals (Nat Chem, 2021, 13, 805). However, the yield of hydrated electrons increased in hypoxic and reductive environments of tumors. Therefore developing in vivo chemistry mediated by hydrated electrons is beneficial for improving the efficiency of prodrug activation.
The authors first found that hydrated electrons generated by radiation can reduce N-oxides to their corresponding tertiary amines in test tubes and living cells. Subsequently, the authors designed and synthesized different N-oxides including aromatic tertiary amines, aromatic heterocyclic, and alkyl types, and found that the reaction was suitable for aromatic amines and aromatic heterocyclic N-oxides with larger conjugated structures. The reaction mechanism was also reasonably predicted based on theoretical calculation. Considering that aromatic nitrogen heterocyclic is the active center of many drugs, the authors designed and synthesized a series of N-oxides drugs, which are highly atom economic and can be reduced to the parent drugs by radiotherapy. Among them, N-oxides of the anti-tumor drug camptothecin (CPT) was selected as the model prodrug, which proved that radiotherapy could accurately activate the prodrug and effectively inhibit tumor growth. In conclusion, this work reported the development of novel in vivo chemical tools and precise chemotherapeutic drug release strategies. It is expected to lead to a key breakthrough in combined tumor chemoradiotherapy.
Dr. Zexuan Ding is the first author of this paper. Prof. Zhibo Liu is the corresponding author. This research was funded by the National Natural Science Foundation of China, the Ministry of Science and Technology of the People's Republic of China, the Beijing Municipal Natural Science Foundation, the Special Foundation of Beijing Municipal Education Commission, Peking University Ge Li and Ning Zhao Life Science Research Fund for Young Scientists, the Peking-Tsinghua Center for Life Sciences and the Beijing National Laboratory for Molecular Sciences.
Original link for the paper: https://pubs.acs.org/doi/10.1021/jacs.2c02521.
