Antivitamins B-12: Synthesis and application as inhibitory ligand of the B-12-tailoring enzyme CblC

Antivitamins B-12 are non-natural corrinoids that have been designed to counteract the metabolic effects of vitamin B-12 and related cobalamins (Cbls) in humans and other mammals. A basic structure- and reactivity-based concept typifies antivitamins B-12 as close structural mimics of vitamin B-12 that are not transformed by the cellular metabolism into organometallic B-12-cofactors. Antivitamins B-12 have the correct structure for efficient take-up and transport via the natural mammalian pathway for cobalamin assimilation. Thus they can be delivered to every cell in the body, where they are proposed to target and inhibit the Cbl tailoring enzyme CblC. Antivitamins B-12 may be specifically inert Cbls or isostructural Cbl-analogues that carry a metal centre other than a cobalt-ion. The syntheses of two antivitamins B-12 are detailed here, as are biochemical and crystallographic studies that provide insights into the crucial binding interactions of Cbl-based antivitamins B-12 with the human B-12-tailoring enzyme CblC. This key enzyme binds genuine antivitamins B-12 as inert substrate mimics and enzyme inhibitors, effectively repressing the metabolic generation of the B-12-cofactors. Hence, antivitamins B-12 induce the diagnostic symptoms of (functional) B-12-deficiency, as observed in healthy laboratory mice.