Dendritic cobalamin ligands: The first dendritic ligands for vitamin B12 were identified from a combinatorial library of peptide dendrimers that feature metal‐coordinating residues at the core. Molecular recognition and discrimination among different amino acid sequences revealed dendrimers with a polyanionic shell of glutamates and a coordinating cysteine or histidine at the core that displays favorable binding towards aquocobalamin.

The third-generation peptide-dendrimer B1 (AcES)8(BEA)4(K-Amb-Y)2BCD-NH2 (B=branching (S)-2,3-diaminopropanoic acid, K=branching lysine, Amb=4-aminomethyl-benzoic acid) is the first synthetic model for cobalamin-binding proteins and binds cobalamin strongly (K(a)=5.0 x 10(6) M(-1)) and rapidly (k(2)=346 M(-1) s(-1)) by coordination of cobalt to the cysteine residue at the dendrimer core. A structure-activity relationship study is reported concerning the role of negative charges in binding. Substituting glutamates (E) for glutamines (Q) in the outer branches of B1 to form N3 (AcQS)8(BQA)4(B-Amb-Y)(2)BCD-NH2 leads to stronger (K(a)=12.0 x 10(6) M(-1)) but slower (k(2)=67 M(-1) s(-1)) cobalamin binding. CD and FTIR spectra show that the dendrimers and their cobalamin complexes exist as random-coil structures without aggregation in solution. The hydrodynamic radii of the dendrimers determined by diffusion NMR either remains constant or slightly decreases upon binding to cobalamin; this indicates the formation of compact, presumably hydrophobically collapsed complexes.

Peptide dendrimers with multiple histidines or N-terminal prolines efficiently catalyze ester hydrolysis or aldol reactions in aqueous medium. Part of the catalytic proficiency of these dendritic enzyme models stems from multivalency effects observed in G2, G3 and G4 dendrimers displaying multiple catalytic groups in their branches. To study multivalency in higher generation systems, G4, G5 and G6 peptide dendrimers were prepared by a convergent assembly. Thus, peptide dendrimers bearing four or eight chloroacetyl groups at their N-termini underwent multiple thioether ligation with G2 and G3 peptide dendrimers with a cysteine residue at their focal point, to give G4, G5 and G6 dendrimers containing up to 341 amino acids, including multiple histidines or N-terminal prolines. While the efficiency of the esterase catalysts was comparable to that of their lower generation analogs, a remarkable reactivity increase was observed in G5 and G6 aldolase dendrimers.

The metal coordinating ability of a bipyridine ligand at the core of a peptide dendrimer was found to be controlled by the nature of amino acids placed at the dendrimer periphery, with coordination being promoted by anionic residues and inhibited by cationic residues; heterotrimers with mixed charges were preferentially formed.

Libraries of cyclic decapeptides were screened with vitamin B(12) derivatives to give cyclic peptide ligands incorporating histidine and cysteine as coordinating residues and negatively charged amino acids. Two hits, cyclo-(HisAspGluProGlyIleAlaThrProdGln) and cyclo-(ValAspGluProGlyGluAspCysProdGln) were resynthesized in good yields for solution experiments. The peptides bind aquocobalamin with coordination of His or Cys to the cobalt with high affinities (K(a) approximately 10(5) M(-1)). Additional interactions between the peptide side chains and the vitamin B(12) corrin moiety were determined by studying the (1)H NMR solution structure. The cyclopeptide-cobalamin complex with the histidine residue showed enhanced stability towards cyanide exchange, demonstrating the shielding effect of the ligand on the metal center.