Transition Metal-Analogues of Natural Cobalt-Corrins

The B12-cofactors are metabolic players essential in all three kingdoms of life, including humans and animals, giving them the role of the most broadly relevant organometallic biocatalysts. Exciting recent advances were made in this field on the topics B12-biosynthesis, B12-uptake and metabolism in humans, animals and bacteria, and the biological uses of B12-cofactors in enzymes and in metabolic regulation. Vitamin B12 is a micronutrient indispensable for humans and the only complex natural product dependent upon cobalt. We are intrigued by the specific role and interaction of this transition metal with the complex corrin macrocycle, a unique chemical structure only found in the B12- cofactors and so relevant for Life. The present project is founded on our recently gained access to metal-free B12-derivatives for the rational syntheses of analogues of the B12-cofactors with transition metals other than cobalt, a holy grail in the B12-field. Such B12-analogues may represent metabolically inert structural B12-mimics, among them some exceptional antivitamins B12. These latter are expected to effectively cause B12-deficiency in B12-dependent organisms, generating crucial insights into the metabolic activity of the B12-cofactors. In this contribution to the B12-field the synthesis of novel transition metal analogues of the B12- cofactors are proposed, selected on the basis of their hypothetical structural properties and chemical reactivity. We develop here a rational and direct, chemical biological synthesis approach to such transition metal analogues of the natural cobalt-corrins, applying preparative methods used in related fields, but hardly explored in the B12-area. We will study the chemistry of non-cobalt transition metal-ions, when bound to the unique natural corrin ligand. This work will provide first insights into the coordination chemistry of such metal-ions bound by natural corrins, and open up new means for studying the molecular basis of the biological roles of B12- cofactors. Modern spectroscopic, crystallographic and electro-chemical methods will be used for the characterization of the new B12-analogues and of their biomimetic molecular features. New insights into the bio-macromolecular interactions of B12-cofactors, into hypothetical modes of action of B12-dependent enzymatic transformations and into the molecular mechanisms of B12-dependent gene regulation are expected from the further planned collaborative biochemical, biological and bio-structural studies, using our metal analogues. By opening up a new horizon for the B12-field the proposed studies will provide the researchers involved with experimental expertise and training at the state-of-the-art level in an exciting exploration of a hardly touched area in chemistry and chemical biology, embedded in a collaborative, interdisciplinary research environment.

Transition Metal-Analogues of Natural Cobalt-Corrins - Chemistry of Metal-Corrins, Antivitamins B12 and other B12-Mimics (P-33059) B12-cofactors perhaps represent the most broadly relevant organometallic biocatalysts and are essential for life in every one of its three kingdoms. This project is a contribution to the particular field of vitamin B12, an indispensable micronutrient for humans and animals. In this wider research context, we have begun to realize an 'old dream' in the B12-field, the study of metal-free and transition metal analogues of the B12-cofactors, by finding an unprecedented, rational and widely applicable synthetic access to some of them. Well-designed transition metal analogues of B12 may primarily behave as antivitamins B12, metabolically inert structural B12-cofactor mimics that induce B12-deficiency in humans, animals and other B12-dependent organisms. The use of such antivitamins B12 in studies of B12-biosynthesis pathways, of mechanisms of B12-uptake and metabolism, of the function of B12-cofactors in enzymes and in gene regulation promises to become an area for exciting discoveries. Insights gained with antivitamins B12 may also help to learn about the chemical foundation of the cobalt-coordinated corrinoid B12-cofactors. The availability of specific metal free ligands of the B12-cofactors from biological and newly explored chemical synthesis has provided rational synthetic routes to transition metal analogues of cobalt-containing natural corrinoids and B12-biosynthesis intermediates. As further contributions to the chemistry of non-cobalt transition metal-ions bound to natural corrin ligands, selected rhodium- and copper-corrins were prepared, and their structures and chemical reactivity studied with modern spectroscopic, mass spectrometric and X-ray crystallographic methods, broadened by complementary ESR-spectroscopic studies. In collaborative biochemical, biological and bio-structural studies transition-metal analogues of vitamin B12-cofactors were tested in cellular transport, enzyme catalysis and gene regulation, revealing essential and basic features of the inhibitory activity of such antivitamins B12. This work has opened preparative paths to novel antivitamins B12, compounds of wide biological and biomedical interest. Our studies have given access not only to promising candidates as novel potential antibiotics or as anti-cancerous agents, but, furthermore, have also allowed for a specific new branch of chemical-biological and structural-biological investigations into the unique molecular basis of the biological roles of the cobalt-based (natural) B12-cofactors.