Scripps Research chemists have developed a new set of copper-catalyzed organic synthesis reactions inspired by the efficiency of human liver enzymes, aiming to improve drug discovery and optimization processes. Their study, published in Nature, demonstrated that their new methods could perform dehydrogenations and lactonizations on a variety of starting compounds using a simple copper-based catalyst. This approach is expected to be particularly useful for late-stage modifications of natural products and drug molecules.
The research initially focused on finding a better method for carbon-hydrogen (CH) activation, a crucial step in drug synthesis, especially in replacing hydrogen with oxygen atoms. This transformation is commonly used in constructing or modifying biologically active molecules, but laboratory methods for it have been complex and limited. By taking inspiration from cytochrome P450 enzymes found in human livers, the chemists aimed to develop a general organic synthesis method that could efficiently perform oxygenation or dehydrogenation reactions, similar to the enzymes’ bimodal capabilities.
Through experimentation, the team successfully developed a new dehydrogenation method that could efficiently produce unsaturated primary amides, a class of compounds that includes many drug molecules, from methoxyamides using inexpensive copper fluoride as a catalyst. They also discovered a lactonization reaction, indicating oxygenation had occurred. By controlling the reaction conditions, they could influence whether dehydrogenation or lactonization took place. This versatility allowed them to modify various compounds, including drugs like valproic acid and gemfibrozil, showcasing the potential impact of their new approach in drug discovery and optimization.
The chemists are now working on a similar approach for lactone- and amide-related compounds known as lactams, some of which are antibiotics. The interest in this new method from pharmaceutical industry chemists is high, indicating potential applications beyond drug discovery. The study, co-authored by researcher Shupeng Zhou, Zi-Jun Zhang, and Jin-Quan Yu, was supported by the National Institutes of Health (NIH), highlighting the importance of this research in advancing organic synthesis and pharmaceutical development.
Overall, the development of copper-catalyzed organic synthesis reactions based on the efficiency of human liver enzymes represents a significant advancement in the field of drug discovery and optimization. By simplifying complex reactions like dehydrogenation and lactonization, the new methods offer a more efficient and cost-effective approach to modifying pharmaceuticals and other molecules. The ability to control the direction of the reaction, inspired by bimodal enzymes, highlights the versatility of this approach and its potential to revolutionize drug synthesis and chemical industries.