CAGEDRUGS · Design and elaboration of novel topological drugs based on cage compounds

Design and elaboration of novel topological drugs based on cage compounds

CAGEDRUGS Project (2011-2015), supported by the Marie Curie IRSES Scheme of the 7th EU Framework Program (FP7-PEOPLE-2011-IRSES, grant 295160), brought together five research centres (Faculty of Chemistry University of Wroclaw, UWR, Department of Chemistry Friedrich-Alexander-Universität ErlangenNürnberg, FAU, Department of Chemistry National Taras Shevchenko University, TSNUK, Nesmeyanov Institute of Organoelement Compounds Russian Academy of Sciences,INEOS RAS, and Vernadskii Institute of General and Inorganic Chemistry NAS of Ukraine, IGIC NASU) devoted to the development of new nanomaterials for biomedical use based on macrobicyclic cage metal complexes (clathrochelates) [1, 2]. This joint exchange programme promoted and strengthened the complementarity of the participants and stimulated cross-fertilization, thus forming an excellent centre of synergy in research, innovation and technology in the area of functional nanomaterials. This network offered a complete training in the synthesis and characterization of new cage metal-containing materials for biomedical applications. During the course of the project a series of new cltrhochelate compounds based on tris-dioximate (a) and tris-oxalodihydrazide (b) structures (Scheme 1) has been obtained. Their design, synthesis and physicochemical characteristics, as well as biological activities were performed in five work packages (WP1: Design and template synthesis, WP2: Identification and structure studies, WP3: Spectral and physico-chemical characterisation, WP4: Reactivity and functionalisation, WP5: Biomedical applications of cage compounds). The following main types of interactions between the macrobicyclic iron(II) complexes (clathrochelates) and biological systems were studied during this project: (1) their binding with globular proteins with formation of stable supramolecular assembles in which bulky three-dimensional clathrochelate molecules occupy hydrophobic cavity in the protein structures and additionally bind with them through multicentered interactions with polar functional groups. Binding to such transport proteins (albumins) plays an important role in the transport and detoxification of clathrochelates (their bioavailability); (2) inhibition of fibrillization by these three-dimentional macrobicyclic molecules; (3) "topological inhibition" of RNA and DNA transcriptions (Scheme 1c) by functionalized clathrochelates with suitable apical and ribbed substituents due to the formation of supramolecular assemblies of these clathrochelate inhibitors with macromolecular complexes “protein – matrix DNA – resulted RNA (DNA); (4) paramagnetic probes with record magnetic anisotropy. So, these cage complexes are promising for the search of potential antiviral and antitumor prodrugs, antifibrillogenic agents and paramagnetic probes for structural biology as well. Thus, macropolycyclic clathrochelate frameworks provide unique opportunities for the design of biologically active compounds, which are able to the transport in the living body due to specific protein-binding ability as well as to the formation of supramolecular assemblies with macromolecules and their complexes and to inhibition of various biological processes.

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