Synthesis and structural characterization of the heavy tricysteinylpnictines, models of protein-bound As(III), Sb(III), and Bi(III)

Abstract

The heavier group 15 elements As, Sb, and Bi are more restricted in their biochemistry than the nearly ubiquitous lighter congeners N and P, but organisms do encounter compounds of these elements as environmental toxins, starting materials for secondary metabolite biosynthesis, substrates for primary metabolism, or exogenously applied medicines. Under many physiological conditions, these compounds are transformed into pnictogen(III) species, the soft Lewis acidic character of which leads them to interact strongly with biologically relevant soft Lewis bases such as small-molecule thiols or cysteine residues of proteins and peptides. The archetypal complexes As(Cys)₃, Sb(Cys)₃, and Bi(Cys)₃ have been studied in the past but a lack of detailed information about their molecular structures has hampered the analysis of protein structures featuring As(III), Sb(III), and Bi(III) bound to cysteine thiolate residues. In many cases, the formation of such protein adducts is proposed to play a key role in the mechanism of action of inorganic drugs that feature these elements. Here, we refine synthetic strategies to access As(Cys)₃, Sb(Cys)₃, and Bi(Cys)₃, describe their crystal structures, analyze structural trends across the series and across Pn(SR)₃ compounds deposited in the Cambridge Structural Database, and compare their features to the structures of proteins with these centers bound to Cys₃ motifs. Significant differences were noted for many of the protein structures.