The Design and Synthesis of Versatile Molecular Building Blocks: Working Towards the Controlled Self-Assembly of Novel Functional Materials

Our research goals are focused on the preparation of novel molecule-based materials that possess specifically designed properties in solution or in the solid state e.g. self-assembly, magnetism, conductivity and spin crossover phenomena. Most of our systems incorporate paramagnetic transition metal ions and the search for new molecule-based magnetic materials is a prominent theme. Specific areas of research include the preparation and study of oxalate based 2D and 3D magnets, probing the versatility of octacyanometalate building blocks as precursors for new molecular magnets, and the preparation of new tetrathiafulvalene (TIF) derivatives for applications in molecular and supramolecular chemistry.

Molecular-Based Magnetism in High-Spin Molecular Clusters and Three-Dimensional Networks Based on Cyanometalate Building Blocks

The field of molecule-based magnets is a relatively new branch of chemistry, which involves the design and study of molecular compounds that exhibit a spontaneous magnetic ordering below a critical temperature, Tc. One major goal involves the design of materials with tuneable Tc's for specific applications in memory storage devices. Molecule-based magnets with high magnetic ordering temperatures have recently been obtained from bimetallic and mixed-valence transition metal μ-cyanide complexes of the Prussian blue family. Since the μ-cyanide linkages permit an interaction between paramagnetic metal ions, cyanometalate building blocks have found useful applications in the field of molecule-based magnets. Our work involves the use of octacyanometalate building blocks for the self-assembly of two new classes of magnetic materials namely, high-spin molecular clusters which exhibit both ferromagnetic intra- and intercluster coupling, and specific extended network topologies which show long-range ferromagnetic ordering.

An Intergenic Regulatory Region Mediates Drosophila Myc -Induced Apoptosis and Blocks Tissue Hyperplasia

Induction of cell-autonomous apoptosis following oncogene-induced overproliferation is a major tumor-suppressive mechanism in vertebrates. However, the detailed mechanism mediating this process remains enigmatic. In this study, we demonstrate that dMyc-induced cell-autonomous apoptosis in the fruit fly Drosophila melanogaster relies on an intergenic sequence termed the IRER (irradiation-responsive enhancer region). The IRER mediates the expression of surrounding proapoptotic genes, and we use an in vivo reporter of the IRER chromatin state to gather evidence that epigenetic control of DNA accessibility within the IRER is an important determinant of the strength of this response to excess dMyc. In a previous work, we showed that the IRER also mediates P53-dependent induction of proapoptotic genes following DNA damage, and the chromatin conformation within IRER is regulated by polycomb group-mediated histone modifications. dMyc-induced apoptosis and the P53-mediated DNA damage response thus overlap in a requirement for the IRER. The epigenetic mechanisms controlling IRER accessibility appear to set thresholds for the P53- and dMyc-induced expression of apoptotic genes in vivo and may have a profound impact on cellular sensitivity to oncogene-induced stress.

The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites.

Protein degradation is regulated during the cell cycle of all eukaryotic cells and is mediated by the ubiquitin-proteasome pathway. Potent and specific peptide-derived inhibitors of the 20S proteasome have been developed recently as anti-cancer agents, based on their ability to induce apoptosis in rapidly dividing cells. Here, we tested a novel small molecule dipeptidyl boronic acid proteasome inhibitor, named MLN-273 on blood and liver stages of Plasmodium species, both of which undergo active replication, probably requiring extensive proteasome activity. The inhibitor blocked Plasmodium falciparum erythrocytic development at an early ring stage as well as P. berghei exoerythrocytic progression to schizonts. Importantly, neither uninfected erythrocytes nor hepatocytes were affected by the drug. MLN-273 caused an overall reduction in protein degradation in P. falciparum, as demonstrated by immunoblots using anti-ubiquitin antibodies to label ubiquitin-tagged protein conjugates. This led us to conclude that the target of the drug was the parasite proteasome. The fact that proteasome inhibitors are presently used as anti-cancer drugs in humans forms a solid basis for further development and makes them potentially attractive drugs also for malaria chemotherapy.