Recently, high impact journal Angewandte Chemie International Edition (IF:16.823) publishes online the latest research article by the research team of Professor Xiaojin Zhang from CPU School of Science “A Carbon-Carbon Bond Cleavage–Based Prodrug Activation Strategy Applied to β-Lapachone for Cancer-Specific Targeting.” The first author is Doctoral candidate Qijie Gon. Professor Xiaojin Zhang is the only corresponding author. China Pharmaceutical University is the only corresponding unit of this article.
Prodrugs are an important strategy for drug molecular design. Existing prodrug strategies often shield active groups such as hydroxyl, carboxyl, and amino groups in the original drug structure through chemical modification of carbon-hetero bonds (such as C-O, C-N bonds). The carbon-hetero bond is broken to release the original drug and exert its efficacy. The o-quinone structure of ortho-quinone antitumor drugs is not only a pharmacophore, but also a toxic group that mediates side effects. Due to the lack of the above-mentioned modifiable groups in the o-quinone structure, it is difficult to design chemically stable prodrug molecules by conventional means.
In this study, a prodrug design strategy based on C-C bond cleavage was developed: by chemical modification of C-C bond to stably shield the o-quinone active group, a prodrug molecule with α-hydroxyketone structure was designed and synthesized. The prodrug molecule also contains a ROS-responsive group of phenylboronic acid structure, which can release o-quinone antitumor drugs by selectively react in tumor tissue through 1,6-elimination-based C-C bond cleavage and rapid oxidation cascade triggered by high levels of ROS in tumor tissue. Density functional theory (DFT) calculations showed that the activation energy of the key C-C bond cleavage release step was only 8.3 kcal/mol, which could enable rapid drug release under physiological conditions, and the driving force might be derived from the aromatization effect of the product. The authors applied this prodrug strategy to several o-quinone antitumor natural products. The representative β-lap prodrug molecule has good anti-pancreatic cancer efficacy in vivo, and has no obvious toxicity or side effects to normal tissues at a dose of 810 mg/kg, the safety is significantly better than the original drug (LD50 = 115.8 mg/kg). The prodrug strategy based on C-C bond cleavage developed in this study provides new methods and ideas for prodrug design and safety improvement of orthoquinone drugs.
The research work was supported by the Jiangsu Provincial Fund for Distinguished Young Scholars, the General Program of the National Natural Science Foundation of China, the Pharmaceutical Development Scholars Program of China Pharmaceutical University, and the Jiangsu Key Laboratory of Drug Molecular Design and Druggability Optimization.
Link: https://onlinelibrary.wiley.com/doi/10.1002/anie.202210001
