Antivitamins B₁₂: Synthesis and application as inhibitory ligand of the B₁₂-tailoring enzyme CblC

Antivitamins B₁₂ are non-natural corrinoids that have been designed to counteract the metabolic effects of vitamin B₁₂ and related cobalamins (Cbls) in humans and other mammals. A basic structure- and reactivity-based concept typifies antivitamins B₁₂ as close structural mimics of vitamin B₁₂ that are not transformed by the cellular metabolism into organometallic B₁₂-cofactors. Antivitamins B₁₂ 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 B₁₂ may be specifically inert Cbls or isostructural Cbl-analogues that carry a metal centre other than a cobalt-ion. The syntheses of two antivitamins B₁₂ are detailed here, as are biochemical and crystallographic studies that provide insights into the crucial binding interactions of Cbl-based antivitamins B₁₂ with the human B₁₂-tailoring enzyme CblC. This key enzyme binds genuine antivitamins B₁₂ as inert substrate mimics and enzyme inhibitors, effectively repressing the metabolic generation of the B₁₂-cofactors. Hence, antivitamins B₁₂ induce the diagnostic symptoms of (functional) B₁₂-deficiency, as observed in healthy laboratory mice.