## 2 Zinc Binding Groups in Chelation Therapy
### Inhibition of Matrix Metalloproteinases  
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases. They are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan [41]. Their overexpression is associated with many diseases, such as cancer and chronic inflammation. MMP inhibitors (MMPIs) usually contain a zinc binding group (ZBG) linked to a backbone that interacts with the specificity pocket S1' [42]. For this reason, the essential requirement for a MMPI is the presence of a group that may be able to  
Figure 6: Structures of PP-BIM (**6a**); PZ-BIM (**6b**); and TAC-BIM (**6c**); and their supposed chelation mechanism (**6d**) [25]. Figure 7: Bifunctional molecules for the treatment of Alzheimer’s disease (AD) and their supposed chelation mechanism (**7d**) [40]. bind or better chelate Zn\({}^{2+}\) in the active site of the enzyme [43]. The majority of MMPIs belong to the classes of carboxylic acids, hydroxamic acids, thiols, phosphorus-based ligands or sulfodilines, and others [42; 44]. Among MMPs, the gelatinase subfamily, consisting of gelatinase A (MMP-2) and gelatinase B (MMP-9), is involved in pathological events leading to cancer, inflammatory diseases, cardiovascular diseases, and neurological disorders [45]. Recently \(\alpha\)-sulfonamide-based hydroxamates proved to be interesting MMP inhibitors, due to the hydroxamate moiety's activity as a ZBG, while the sulfonyl group forms an important hydrogen bond with the enzyme's peptidic backbone. In this regard, a new series of compounds (Figure 8) endowed with good potency and selectivity for MMP-2 and MMP-9, without inhibition of MMP-1 was recently described: the sulfonyl group was moved from \(\alpha\)- to \(\beta\)-position, while in \(\alpha\)-position a linker consisting of a heteroatom such as O or N replaced the sulfonamide, with the possibility to chelate zinc with an improved MMP-9 inhibition at the nanomolar range, although the authors report the classical bidentate mechanism of hydroxamic acids as being the most likely [45]. A subsequent work of the same group studied the introduction and the optimization of an \(\alpha\)-amino substituent in a series of congeners. This modification leads to new MMP-2/MMP-9 inhibitors characterized by improved inhibitory activities and ADME properties. In particular, compounds containing the \(\alpha\)-cyclic amino group showed low protein binding, good water solubility, and enhanced pharmacokinetic properties [46]. [PERSON] et al. reported the synthesis and in vitro evaluation of a new series of selective MMP-13 inhibitors. MMP-13 catalyzes the hydrolysis of type II collagen (the main structural component of the cartilage matrix) and high levels of MMP-13 are associated with diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) and is an important therapeutic target [47]. The reported compounds are N-isopropyloxy-arylsulfonamides in which different aryl substituents on the sulfonamide portion are introduced. Among these inhibitors, the compound shown in Figure 9 exhibited a nanomolar inhibiting activity for MMP-13 (IC\({}_{50}\) = 3.0 \(\pm\) 0.2 nM) and was highly selective for this enzyme compared to other MMPs. They tried to explain this selectivity through the investigation of binding between the compound and MMP-13 in a docking study, but they concluded that X-ray crystallography is necessary to elucidate the mechanism of coordination and inhibition [48]. Figure 8: General structure of zinc chelators [44]. Figure 9: MMP-13 inhibitor synthesized by [PERSON] et al. [48]. Unfortunately, hydroxamic acids are frequently affected by rapid excretion, low oral bioavailability, and in vivo hydrolysis since their discovery in 90 s [49], which encouraged the development of alternative ZBGs.