Developments in Carbohydrate-Based Metzincin Inhibitors

Abstract

Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. Upregulation of metzincin activity is a major feature in many serious pathologies such as cancer, inflammations, and infections. In the last decades, many classes of small molecules have been developed directed to inhibit these enzymes. The principal shortcomings that have hindered clinical development of metzincin inhibitors are low selectivity for the target enzyme, poor water solubility, and long-term toxicity. Over the last 15 years, a novel approach to improve solubility and bioavailability of metzincin inhibitors has been the synthesis of carbohydrate-based compounds. This strategy consists of linking a hydrophilic sugar moiety to an aromatic lipophilic scaffold. This review aims to describe the development of sugar-based and azasugar-based derivatives as metzincin inhibitors and their activity in several pathological models.

Bacterial Zinc Metalloenzyme Inhibitors: Recent Advances and Future Perspectives

“…Moreover, in the binding pocket the MMPs present the same subsites of the M4 enzymes [37]. However, the particular depth of the S1 subsite might represent a selectivity factor between the M4 and M10 enzymes [38].…”

“…However, all new derivatives displayed a loss of LpxC inhibitory and antibacterial activity [80]. The discovery of inhibitors without a hydroxamate group as ZBG represents an interesting approach in order to avoid side effects due to the lack of specificity previously seen in many matrix metalloproteinase (MMP) inhibitors [38]. Moreover, the hydroxamate group is typical of HDAC inhibitors [81] but also represents the main cause of their mutagenicity [82].…”

Discovery of novel benzimidazole acyclic C‐nucleoside DNA intercalators halting breast cancer growth

“…Along these lines, the “sugar approach” design of various anticancer agents [ 12–16 ] sparked our interest, where carbohydrate appendages were tethered to pharmacophoric motifs as exemplified by the widespread active carbohydrate‐based scaffolds acting as potent carbonic anhydrases inhibitors [ 13 ] as well as carbohydrate‐based matrix as metalloproteinases inhibitors. [ 14 ] Nevertheless, many carbohydrate‐containing compounds showing broad‐spectrum anticancer activities have been reported. [ 17–19 ] Notably, C ‐nucleosides attracted considerable interest despite the difficulty of their chemical modification.…”

“…[7] Continuous progress has resulted in a variety of small compounds targeting DNA, [8][9][10][11] mirrored by molecular investigations explaining the cellular response to induced DNA damage. Along these lines, the "sugar approach" design of various anticancer agents [12][13][14][15][16] sparked our interest, where carbohydrate appendages were tethered to pharmacophoric motifs as exemplified by the widespread active carbohydrate-based scaffolds acting as potent carbonic anhydrases inhibitors [13] as well as carbohydrate-based matrix as metalloproteinases inhibitors. [14] Nevertheless, many carbohydrate-containing compounds showing broad-spectrum anticancer activities have been reported.…”