Antivitamins B₁₂—Some Inaugural Milestones

Abstract

The recently delineated structure‐ and reactivity‐based concept of antivitamins B12 has begun to bear fruit by the generation, and study, of a range of such B12‐dummies, either vitamin B12‐derived, or transition metal analogues that also represent potential antivitamins B12 or specific B12‐antimetabolites. As reviewed here, this has opened up new research avenues in organometallic B12‐chemistry and bioinorganic coordination chemistry. Exploratory studies with antivitamins B12 have, furthermore, revealed some of their potential, as pharmacologically interesting compounds, for inducing B12‐deficiency in a range of organisms, from hospital resistant bacteria to laboratory mice. The derived capacity of antivitamins B12 to induce functional B12‐deficiency in mammalian cells and organs also suggest their valuable potential as growth inhibitors of cancerous human and animal cells.

Solution, Crystal and in Silico Structures of the Organometallic Vitamin B12‐Derivative Acetylcobalamin and of its Novel Rhodium‐Analogue Acetylrhodibalamin

“…Rhodibalamins (Rbls) hold significant potential as antivitamins B 12 , [13,14,51] or as specific B 12antimetabolites, [26,52,53] and, in this regard, the function of AcRhbl requires further investigation within a biological context. In this respect, the biological activity of AcRhbl underwent exploratory tests using a Salmonella enterica B 12 auxotroph that relies on a B 12dependent methionine synthase for growth on minimal media.…”

“…[2,8] In line with studies on metal-analogues of the cobalamins (Cbls) [9 -12] we have become particularly interested in gaining access to well characterized rhodium analogues of the natural B 12 -derivatives, in order to study the effect of the replacement of the natural cobalt-centers by the homologous transition metal rhodium. [13,14] As discovered in the course of the comparison of the structures of coenzyme B 12 (5'-deoxy-5'-adenosylcobalamin, AdoCbl) and of 5'-deoxy-5'-adenosylrhodibalamin (AdoRhbl), the structural features of the latter suggested the corrin ligand to provide a slightly better fit for the Rh(III)-center, rather than for the natural Co(III)-ion. [9] A similar conclusion resulted from a comparison of the crystal structures of chlorocobalamin (ClCbl) and chlororhodibalamin (ClRhbl).…”

Cobalamin Riboswitches Are Broadly Sensitive to Corrinoid Cofactors to Enable an Efficient Gene Regulatory Strategy

“…Broader consideration of the conformational dynamics of larger types of effector molecules, including organic cofactors, antibiotics, and their analogs could aid efforts to engineer synthetic RNA-based regulatory platforms that function robustly in vivo . This could also inform future efforts to develop synthetic antimetabolites that, for example, elicit gene mis-regulation, instead of a more common strategy of creating inhibitors for enzymes ( 108 , 109 ).…”

Cobalamin riboswitches are broadly sensitive to corrinoid cofactors to enable an efficient gene regulatory strategy

“…Broader consideration of the conformational dynamics of larger types of effector molecules including organic cofactors, antibiotics, and their analogs could aid efforts to engineer synthetic RNA-based regulatory platforms that function robustly in vivo . This could also inform future efforts to develop synthetic antimetabolites that, for example, elicit gene mis-regulation, instead of a more common strategy of creating inhibitors for enzymes (Kräutler, 2020; Zelder et al, 2015).…”