d-Penicillamine Tripodal Derivatives as Efficient Copper(I) Chelators

Abstract

New tripodal metal-chelating agents derived from nitrilotriacetic acid (NTA) and extended by three unnatural amino acids D-penicillamine (D-Pen) are presented. D-Pen is actually the drug most extensively used to treat copper (Cu) overload in Wilson's disease and as such is a very attractive building block for the design of chelating agents. D-Pen is also a bulkier analogue of cysteine, with the β-methylene hydrogen atoms replaced by larger methyl groups. The hindrance of the gem-dimethyl group close to the thiol functions is demonstrated to influence the speciation and stability of the metal complexes. The ligands L(4) (ester) and L(5) (amide) were obtained from NTA and commercial D-Pen synthons in four and five steps with overall yields of 14 and 24%, respectively. Their ability to bind Cu(I), thanks to their three thiolate functions, has been investigated using both spectroscopic and analytical methods. UV, CD, and NMR spectroscopy and mass spectrometry evidence the formation of two Cu(I) complexes with L(5): the mononuclear complex CuL(5) and one cluster (Cu2L(5))2. In contrast, the bulkier ethyl ester derivative L(4) cannot accommodate the mononuclear complex in solution and thus forms exclusively the cluster (Cu2L(4))2. Cu K-edge X-ray absorption spectroscopy (XAS and EXAFS) confirms that Cu(I) is bound in trigonal-planar sulfur-only environments in all of these complexes with Cu- - -S distances ranging from 2.22 to 2.23 Å. Such C3-symmetric CuS3 cores are coordination modes frequently adopted in Cu(I) proteins such as metallothioneins. These two ligands bind Cu(I) tightly and selectively, which makes them promising chelators for intracellular copper detoxification in vivo.

Mercury Complexes with Tripodal Pseudopeptides Derived from D‐Penicillamine Favour a HgS3 Coordination

“…[31] The characterization of their mercury(II) complexes with a variety of analytical and spectroscopic techniques is presented in the following.…”

“…[22][23][24][25][26] These scaffolds were functionalized with d-Pen, which is a bulkier analogue of cysteine with the β-methylene hydrogen atoms replaced by larger methyl groups. [31] d-Pen is an interesting unnatural amino acid that provides more steric bulk in peptide sequences and has been demonstrated to favour a MS 3 coordination of Cd II [28] or Co II . [29] The two pseudopeptides derived from d-Pen, L 4 and L 5 , coordinate Hg II in a mononuclear complex at physiological pH with a HgS 3 coordination mode.…”

“…[31] Since both chelators L 4 and L 5 are susceptible to air oxidation, the samples for physicochemical studies were all prepared in the glove box under an argon atmosphere and sealed if used outside the glove box. All solutions were deoxygenated and stored in the glove box.…”

“…[30] The two d-Pen tripodal derivatives L 4 and L 5 ( Figure 1) have been previously reported to efficiently bind Cu I in mononuclear and cluster-type complexes with a unique trigonal planar sulfur-only coordination (Figure 1). [31] In this paper, we focus on the chelation properties of the two d-Pen tripodal derivatives L 4 and L 5 towards the toxic Hg II ion. In particular, their ability to foster the uncommon HgS 3 coordination mode is demonstrated in solution at physiological pH.…”

Update on the clinical management of Wilson's disease

“…This strategy for chelating intracellular copper is expected to avoid systemic toxicity caused by excessive release of copper from the liver and thus, maintaining free copper plasma in the safe range. One example of this concept is a novel chelator that is a tripodal cysteine-based ligand inspired by metallothioneins 85,86. Its high affinity to the liver has been achieved with specific recognition elements of the asialoglycoprotein receptor that is specific for targeting hepatocytes.…”