Medicinal Chemistry

Heterocyclic Chemistry

The chemistry of heterocycles is one of the most important fields of chemistry since heterocycles are found in such diverse compounds as pharmaceuticals, agrochemicals, natural compounds, organic materials, and many more. Therefore, this subject is tackled in the Mihovilovic research group from a number of sides and treated in many projects. Our activities include the development of efficient methods for the decoration and synthesis of heterocyclic compounds as well as the exploration of the properties, especially the biological activity of heterocyclic compounds.

Small molecules induced regenerative medicine

This project aims at the development of synthetic small molecules (SSMs) which have the ability to convert an easily accessible cell type, e.g. a muscle cell, into other tissues such as heart muscle cells (cardiomyocytes) or neurons. The therapeutic potential of such compounds is immense. Compared to other organs and tissues, the ability to regenerate itself is in the heart and neuronal tissue very limited.
Taking into account that heart attacks and follow up problems are one of the most frequent causes of death in the developed world, methods to regenerate the heart function (even if only partially) after such an heart attack can significantly improve the quality of life of a patient and also decrease the financial burden of the health care system.
Regarding neurogenesis, the treatment of neurodegenerative diseases (such as Alzheimer, Parkinson etc.) or the treatment of paralyzed people could be achieved using tissues from the patient himself and therefore, repulsion of implanted tissue is not an issue. Secondly, the state of the art method for obtaining specific cell lines takes advantage of embryonic stem cells (ESCs). ESC research is always accompanied by ethical discussions due to the problematic source of such cells. This could again be circumvented by an SSM approach. Additionally, SSM are for a long time in use as drugs and the procedures to bring such a compound to the market are well established.

Structural modification of natural compound GABA_A receptor modulators

Natural products have been historically an important source for drugs and up to now provide structurally unique leads and inspiration for medicinal chemistry. Piperine has recently been identified as a GABA_A receptor modulator in addition to the known interaction with TRPV1 receptors (Zaugg et al. 2010). Piperine will serve as model case study to elucidate the target (GABAA vs. TRPV1) specific properties of the molecule. Consequently, a focus of this project involves the structural modification of piperine and generation of an appropriate library of derivatives. Such analogs to piperine will be assessed for potency and efficiency on GABA_A and TRPV1 receptors in close cooperation with the group of S. Hering. In addition, sub-type specitivity of novel ligands on various GABA_A receptors will be studied in collaboration with the group of M. Ernst.

Scaffold optimization of GABA_A receptor ligands

Recently, valerenic acid - a chiral bicyclic terpenoidal natural compound - was identified as a subtype specific GABA_A receptor ligand (Khom et al. 2010). We aim to start from this principal scaffold and identify the critical structural motifs associated to biological activity. Based on this concept, a first generation of simplified structures will be outlined and synthesized, followed by biological assessment (in cooperation with S. Hering). Based on the results of ligand-receptor binding studies and biological efficacy in cell culture (determined primarily via electrophysiological changes), a computer model will be generated and subsequent generations of synthetic targets will be developed. This part of the project will take advantage of the high degree of instrumentation of the synthetic group, allowing for rapid generation of focused compound libraries.

Drugs from Nature targeting inflammation - Lead-Modification of Medicinal Plant Constituents and Synthetic Lead Up-scaling

One part of the project focuses on moderate structural modifications of established bioactive compounds as proposed by the consortium partners. Implementation of concepts from green chemistry especially focusing on streamlining synthetic routes by single-operations multiple-step transformations and continuous processes will be an integral part of this project part. Another aspect will be the synthesis and up-scaling of promising bioactive compounds. Access to plant-derived bioactive compounds is usually of limited efficiency based on extraction; in particular after structural modification (as outlined above) synthetic efforts have to be invested in order to provide access to sufficient quantities for in-depth biological studies.