Functionalisation of vitamin B(12) derivatives with a cobalt β-phenyl ligand boosters antimetabolite activity in bacteria

This study describes the syntheses of four singly- and two doubly-modified vitamin B(12) 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 B(12) antagonists (10 nM) inhibit fully B(12)-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.