Transition Metal Analogues of B12-Cofactors

Vitamin B12 and related cobalamins (Cbls) are indispensable micro-nutrients, important for humans, animals and a broad range of other living organisms. Natural B12-derivatives are an exclusive domain of cobalt-complexes of the characteristic and unique corrin-ligand. The question why cobalt is so specifically essential for the biological roles of B12-derivatives? has frequently been asked. Surprisingly, this fundamental question cannot be answered nowadays, since corrin-complexes with metals other than cobalt have hardly become accessible. Comparison of their properties with those of vitamin B12 and other Cbls would help clarify the specific role of cobalt in Cbls. This project will open the hardly explored territory of metal analogues of Cbls (metbalamins). To reach this goal, a metal-free analogue of vitamin B12 will be first prepared, making use of recent biotechnological developments. Subsequent incorporation of (transition) metals will require purely chemical methods and will furnish a range of corresponding metbalamins. We will, thus, explore a strategy of combining the current means of chemistry and of synthetic biology to generate a selection of metbalamins. A focus of the project will be on investigations with rhodium and iridium. Metbalamins of these group-IX homologues of cobalt, i.e. rhodibalamins (Rhbls) and iridibalamins (Irbls), are presumed to feature chemistry related to that of the Cbls: Rhbls and Irbls are expected to show structures rather similar to those of the biologically important Cbls, but not to mimic closely their reactivity. This hypothesis will be tested thoroughly, in this project. Structure and reactivity of Rhbls and Irbls will be investigated in detail, with a focus on derivatives related to the biologically relevant organometallic B12-cofactors. In representative bio-chemical studies with Rhbls and Irbls basic consequences of the replacement of cobalt (in Cbls) will be tested. Rhbls and Irbls may be effective inhibitors of B12- dependent metabolic processes, thus representing potent B12-antimetabolites or antivitamins B12. Selected, other metbalamins will be prepared, and will likewise be studied extensively. They are presumed to display a range of structures and reactivity, less related, typically, to those of known B12- derivatives. The insights gained with transition-metal corrinoids will, first of all, help to answer the old cobalt-question. These studies will, thus, expand the specific horizon of basic research on vitamin B12. It will also contribute to modern bio-inorganic and organometallic chemistry, as well as to current B12-related topics of interests. Indeed, the eventual availability of potent antivitamins B12 on the basis of suitable metbalamins is expected to provide opportunities to learn more about the still puzzling biological roles of B12-derivatives in humans and elsewhere in the living Nature, and giving the scientific basis for the development of novel biological and bio-medicinal tools.

Project P-28892 Abstract The complex and highly structured B12-vitamins represent a specific combination of the unique natural corrin ligand and the transition metal cobalt. The basis of the exceptional reactivity of cobalt in the B12-cofactors is an old key question in a field that concerns all kingdoms of life, including us humans. This project was to contribute to this intriguing question indirectly, by extending research in the B12-field to metal analogues of vitamin B12. Interestingly, to date, the topic of the transition-metal analogues of the natural cobalt-corrins, collectively named metbalamins, has suffered from a lack of an efficient access to such fully characterized B12-metal analogues. Unfortunately, an apparently obvious path to metbalamins has had no success that relies on the removal of the cobalt centre from vitamin B12 and its replacement by incorporation of other metal ions in the so generated metal-free corrin ligand. However, sparked by a combined chemical-biological total synthesis of adenosylrhodibalamin, the Rh(III)-homologue of the Co(III)-corrin coenzyme B12, this project has led to two practical and presumably general methodologies for the synthesis of metbalamins, both starting with the biosynthetic B12-ligand hydrogenobyric acid. The structural analysis of this unique metal-free corrin has provided profound insights into the 'molecular logic' of the B12-deriatives. The incorporation of the transition metals rhodium, nickel and zinc allowed the detailed chemical characterization of the corresponding metbalamins that represent structural mimics of biocatalytically relevant vitamin B12-derivatives carrying either hexa-coordinate, penta-coordinate or tetra-coordinate cobalt centres. Thus, these B12-metal analogues represent a full set of structural B12-mimics, considered perfect B12-dummies or potential antivitamins B12. The metbalamins promise to be useful in biochemical, biological, bio-structural and biomedical investigations related to the still puzzling biological roles of vitamin B12, as well as exploring the physiological roles of vitamin B12 and the pathological effects of B12-deficiency in humans. Studies with antivitamins B12 relating to age- and nutrition-related neuropathological effects of B12-deficiency may be particularly helpful and important in this growing area of topical biomedical research. The specific metal based potential antivitamins B12, generated here, also promise to find broader application as inhibitors of cell growth and proliferation, an essential role of anti-cancerous agents. In addition, some transition metal based B12-mimics may qualify as B12-antimetabolites that pave an alternative route to drugs useful in the fight against hospital resistant bacteria. Hence, further research with metbalamins may lead to a novel class of antibiotics. Our engagement in basic chemical and chemical-biological research may thus eventually provide metal complexes that could enlarge today's molecular toolbox in the medicinal and pharmaceutical sciences.