Cyclopentadiene Derivatives for Bioorthogonal Cycloadditions

Bioorthogonal ligations are chemical reactions that can be used to join two molecules together while being performed in a living system without interfering with it. One might even say that these reactions are orthogonal to biology or life. This opens up a plethora of interesting applications, especially in the fields of medicinal chemistry, biological chemistry and biochemistry. For example, one can target tumor tissue selectively with compounds bearing one bioorthogonal reagent and then use the complementary reagent to selectively bind reporter molecules for detection (imaging) of the tumor or even use this bioorthogonal ligation to deliver therapeutics directly into the target tissue, thus reducing side effects and improving therapeutic outcome and quality of life for the patient. However, while these bioorthogonal ligations have become important tools in many fields of research, ranging from material science to chemical biology, the most prominent reactions still have several drawbacks. The aim of this project is to eliminate some of these problems and provide an additional bioorthogonal tool by the development and optimization of a new type of bioorthogonal ligation, based on recently reported and very promising compounds. Within this project computational chemistry will be used for investigations and optimizations of these ligations. This means we are using quantum mechanics to understand the reactions on a fundamental level and predict experimental results. In addition to providing in-depth understanding of the underlying processes, this computational approach saves money and reduces waste and the risk associated with laboratory work. Most promising compounds of this theoretical examination will be chosen and investigated experimentally. Thus, this project will further deepen our understanding on bioorthogonal reactions and provide new tools for bioorthogonal chemistry.

When thinking about chemical reactions the picture of glass flasks with bubbling, colored liquids come first to mind. While classical organic chemistry this representation is not that far from the truth, there are interesting developments in modern chemistry that differ strongly from this picture. Of big interest to the chemical community are biocompatible chemical reactions. Those are reactions between reactions partners that are so selective and fast that they can be performed in living organisms. This means one can connect or release chemicals selectively. A plethora of interesting applications, mainly in the field of medicine, are enabled by these biocompatible reactions, for example in diagnostics they can find applications in PET scan methods. The targeted release of a compound in a living organism can be used to selectively release a drug in the target tissue. This leads to a better therapeutic result and fewer side-effects. However, the application of such reactions in living organisms is not trivial and produces a lot of challenges. The reaction partners must have certain properties, e.g., show high stability, and not interfere with the biological system in any negative way. In the last decade several such biocompatible reactions have been developed, each with their own strengths and weaknesses. In this project a class of such biocompatible reactions were investigated in more detail. A detailed study of this reaction led to a better understanding and allowed us to optimize it further, allowing for the application in broader fields of chemistry. The reactions were primarily investigated using computational methods. Computational chemistry is a field of chemistry that uses computer simulations of molecules and reactions to gain insight and predict the behavior and properties of such species. This allows for insights that are not possible with experimental methods. These findings were then used to design better reactions. The resulting reactions were investigated experimentally afterwards. This project was conducted at UCLA in the group of Professor Kendall Houk. Prof. Houk is one of the leading computational chemists and known for a theoretical method that allows us to investigate interactions between reactions partners in detail. In this project a software package was developed that allows for such an analysis to be performed fully automatic. Using this analysis method, we investigated several biocompatible reactions. Important insights could be gain on the interaction between the reaction partners. The influence of different structural elements was investigated as well. Besides several important findings one of the most important results is the identification of a new kind of interaction between reaction partners. This interaction was found in one of the biocompatible reactions and was published in the prestigious journal "Journal of the American Chemical Society" (J. Am. Chem. Soc. 2019, 141, 6, 2224-2227).