Functionalisation of vitamin B12 derivatives with a cobalt β-phenyl ligand boosters antimetabolite activity in bacteria

Abstract

This study describes the syntheses of four singly- and two doubly-modified vitamin B₁₂ derivatives for generating antimetabolites of Lactobacillus delbrueckii (L. delbrueckii). The two most potent antagonists, a Co_β-phenyl-cobalamin-c,8-lactam and a 10-bromo-Co_β-phenylcobalamin combine a c-lactam or 10-bromo modification at the “eastern” site of the corrin ring with an artificial organometallic phenyl group instead of a cyano ligand at the β-site of the cobalt center. These two doubly-modified B₁₂ antagonists (10 nM) inhibit fully B₁₂-dependent (0.1 nM) growth of L. delbrueckii. In contrast to potent 10-bromo-Co_β-phenylcobalamin, single modified 10-bromo-Co_β-cyanocobalamin lacking the artificial organometallic phenyl ligand does not show any inhibitory effect. These results suggest, that the organometallic β-phenyl ligand at the Co center ultimately steers the metabolic effect of the 10-bromo-analogue.