How did you get interested in Medicinal Chemistry?
When I was an undergraduate student at Tübingen University, Prof. Hermann J. Roth presented an excellent lecture on Pharmaceutical Chemistry. Later, I chose him as my PhD supervisor and mentor. During that time I spent much time in the library of our institute, and there my favourite journal was the Journal of Medicinal Chemistry, which I loved to read. And I dreamed of publishing myself in that journal.
Where and when did you obtain your PhD diploma?
I completed my PhD in 1988 at the University of Tübingen, a small town in the State of Baden-Württemberg, in the South of Germany, about 60 km north of the city where I was born (Rottweil).
What was the topic of your PhD project?
Synthesis and properties of chiral amphiphiles and liposomal prodrugs with unsymmetrically substituted disulfide bridge. The compounds that I synthesized had terrible physicochemical properties. But I learned a lot about stereochemistry, prodrugs, lipids, amphiphilic compounds, liposomes and cancer therapy.
Where did you have your postdoc position?
At the National Institutes of Health in the Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, in Bethesda, Maryland, USA with Dr. John W. Daly. That was a whole new world for me which I had the privilege to discover. I would recommend everybody to work for some time in a top laboratory abroad, preferably on a different continent. You will have a new view on your previous work and life from a distance.
Where do you work at the moment and what is your current position?
I have been a Full Professor of Pharmaceutical Chemistry at Bonn University since 1998 – for exactly 20 years. And I still enjoy the possibilities as a University Professor at one of the top German universities.
What are your current research interests?
My scientific interests are focused on the medicinal chemistry and molecular pharmacology of purine-binding membrane proteins (purine receptors, ectonucleotidases) and orphan G protein-coupled receptors. Disease indications include neurodegenerative and inflammatory diseases, cancer, and rare diseases. My activities are ranging from basic research to collaborative drug development projects with pharma industry partners. Recently I have become interested in new modalities in drug development.
What do you like most in your job?
Working with young, talented people and sharing my insights with them; contemplating about tricky scientific question and difficult issues - and finding solutions; contributing to the development of drugs that are beneficial for patients; collaborating with experts from different areas and from all over the world; reading scientific literature and learning something new every day.
What kind of tasks your job includes?
Teaching, research and administration
What kind of skills your job requires?
You have to be an allrounder and a hard worker; it requires creativity, organisational skills, problem-solving and leadership ability, team-working and collaboration competencies, teaching qualities, high motivation, patience, persistence, resilience - and you have to deeply enjoy what you are doing.
What do you consider your biggest achievement in your scientific career?
Actually, I have always been broadly interested and contributed to different areas related to medicinal chemistry.
• Together with my coworkers and collaborators, I have developed many tool compounds for a variety of receptors and enzymes, that are nowadays widely used in many labs all over the world. Since I have been working at Bonn University, we name them PSB (Pharmaceutical Sciences Bonn) compounds (e.g. PSB-603, a potent and selective adenosine A2B receptor antagonist).
• I created a proprietary compound collection at Bonn University – the PharmaCenter Bonn compound library - which even contains the compounds that I had synthesized for my PhD. We do not only collect compounds prepared in Bonn, but also those from other groups. If we identify a screening hit for a target of interest, we collaborate with the colleagues that provided the hit compound.
• Recently, we developed the first potent and selective antagonists for the orphan G protein-coupled receptor GPR17, which bear great promise for the disease-modifying treatment of demyelinating diseases such as multiple sclerosis (MS). Patents have been filed and the compounds are being developed in collaboration with a pharmaceutical company. If clinical trials are successful, this could change MS patients‘ lives.
• Early in my carreer I have developed synthetic methods, which are useful and are nowadays applied in a number of labs, e.g. the synthesis of 3-substituted 6 aminouracils, which are important precursors for xanthine derivatives (Müller, C.E., Tetrahedron Lett. 1991, 32, 6539).
• My group has developed a number of new assays for various targets.
How many PhD and postdoc students do you have at the moment?
Are you currently looking for a new PhD and postdoc students?
My group is quite big, but this is necessary for our approach which combines chemistry and biology. The techniques established in my lab range from synthetic chemistry, (bio)analytical studies, and molecular modeling to in vitro pharmacology, and molecular and structural biology.
I have 20 PhD students, currently more than usually, but several students are about to complete their thesis, and it is always good to have some overlap on a topic in order not to lose the knowledge regarding certain lab techniques.
If excellent students and postdocs apply to my lab, I always try to find a way to finance them.
What are the features of a successful PhD student or postdoc?
High motivation is most important, in addition to creativity and talent, and persistence.
Regarding a young scientist‘s CV it is always good to have publications (quality is more important than quantity), to have shown mobility, and to be supported by previous supervisors.
How would you describe yourself as a supervisor?
Since I have a big group, I am not closely controlling each student. The students and postdocs will get some freedom to develop themselves as scientists, e.g. to realize some of their own ideas. In the inital phase, they will be co-supervised by a postdoc in the lab. I am always approachable to discuss results or problems and to suggest solutions, and I am carefully watching the progress of each project, and interfere if necessary to push it into the right direction and to make it successful. I do care for my students and coworkers.
What is the most embarrassing thing you did in the lab while doing experiments, e.g. explosions?
I had (small) explosions and fires. Once, I upscaled a reaction from a 10 g to a 30 g scale, it was the regioselective alkylation of silylated uracil with propargyl bromide in the presence of iodide, the procedure that I had invented. After the reaction was completed, and the excess of the silylation reagent had been removed by evaporation, the silylated product was carefully hydrolyzed by the addition of ice-water. This is an exothermic reaction, and it became too hot, resulting in violent reaction involving the triple bond. Fortunately, the fire was under the hood and could quickly be controlled, with the help of my labmate.
Which scientist do you admire the most and why?
Marie Curie. She was the first woman to get a Noble Prize in science, and later on, she even got a second one. She achieved this as a Polish immigrant in Paris, at a time when women hardly had a chance to study.
Did you experience any unfair situations during your scientific career?
Yes, but I was also lucky. In fact, I was the first woman who got a full professorship in Pharmaceutical Chemistry in Germany, and I got this chance only because at that time, in the late 1980s, it was more attractive to take a job in industry than to stay in academia.
Luckily, the University of Bonn had had good experiences with female science professors, and they offered me a chair without hesitation.
My perception is that not always the best scientists are successful, but the ones who are well connected within networks. The way you are treated is not always fair. On the other hand, data bases creating (more or less) objective assessments, nowadays can help in supporting fair decisions.
Another problem I have observed and encountered is envy, which can be very destructive. There seems to be increasing egoism and ruthlessness in parts of the younger generation.
Which paper of yours you are the proudest of and why?
Difficult to select because I have published around 400 papers so far, and there are a number of papers which I am proud of, including three publications which I co-authored and which were published in Nature.
Since I am supposed to select only a single paper, I would select this one:
Thomas Borrmann, Sonja Hinz, Daniela C. G. Bertarelli, Wenjin Li, Nicole C. Florin, Anja B. Scheiff, Christa E. Müller; 1-Alkyl-8-(piperazine-1-sulfonyl)phenylxanthines: development and characterization of adenosine A2B receptor antagonists and a new radioligand with subnanomolar affinity and subtype specifity. J. Med. Chem. 2009, 52, 3994-4006.
This manuscript describes adenosine receptor antagonists with low nanomolar affinity including the preparation of an A2B-specific radioligand. It contains a lot of information (which easily could have been divided into two or three papers, but I prefer papers with broad content). The described antagonists, e.g. PSB-603 and [3H]PSB-603, are currently among the most frequently used A2B antagonists due to their high potency, selectivity and metabolic stability. A long time after we had developed the first A2B-selective antagonists, such compounds have recently become of great interest for the (immuno)therapy of cancer.
Which field of medicinal chemistry do you consider the most promising in the future?
• Immunotherapy of cancer using small molecules, in combination with targeted cancer therapies.
• Personalized drug therapy and diagnostics.
• Artificial intelligence and computational approaches
• Structural biology – insights into drug-target interactions
What would you like to ask from other medicinal chemists?
• Which fields of medicinal chemistry would you consider the most promising in the future?
• How do you select the right targets?
• How did you manage to found a company (this is something I have not achieved yet) - and what are your recommendations?
What would you guess to be the next major breakthrough in medicinal chemistry?
Small molecules are clinically successful and will be approved for the immunotherapy of cancer - further revolutionizing cancer therapy.