Targeting Metalloenzymes by Boron-Containing Metal-Binding Pharmacophores

Abstract

Metalloenzymes have critical roles in a wide range of biological processes and are directly involved in many human diseases; hence, they are considered as important targets for therapeutic intervention. The specific characteristics of metal ion(s)-containing active sites make exploitation of metal-binding pharmacophores (MBPs) critical to inhibitor development targeting metalloenzymes. This Perspective focuses on boron-containing MBPs, which display unique binding modes with metalloenzyme active sites, particularly via mimicking native substrates or tetrahedral transition states. The design concepts regarding boron-containing MBPs are highlighted through the case analyses on five distinct classes of clinically relevant nucleophilic metalloenzymes from medicinal chemistry perspectives. The challenges (e.g., selectivity) faced by some boron-containing MBPs and possible strategies (e.g., bioisosteres) for metalloenzyme inhibitor transformation are also discussed.

Exploiting Enantiopure β‐Amino Boronic Acids in Isocyanide‐Based Multicomponent Reactions

“…With the optimal conditions in hand (entry 8), the generality of this transformation was evaluated with respect to all components, as reported in Scheme 1. (S)-β-phenyl β-amino boronate 1 a reacted smoothly with various acids components (R 3 are deposited in the Supporting Information). [27] Also acetone proved to be suitable for this multicomponent transformation, affording compound 2 d in a yield only slightly lower than that of the corresponding, formaldehyde-derived compound 2 c. Finally, the scope of the reaction was evaluated with respect to the (S)-β-substituted β-amino boronate 1.…”

“…Boron has been referred to as the “fifth element” of drug design (in addition to the “big four” – H, C, N, and O) some years ago [1] and as a ‘magic element’ in biomedical science quite recently [2] . Effectively, over the last two decades, the approval of five boronic acid‐containing drugs by the FDA has vastly impacted the use of boron in medicinal chemistry, [3] chemical biology, [4] drug delivery and biomaterial exploration, [5] firmly establishing boronic acids and derivatives as one of the most important emerging classes of building blocks in organic and medicinal chemistry [6]…”

“…Boron has been referred to as the "fifth element" of drug design (in addition to the "big four" -H, C, N, and O) some years ago [1] and as a 'magic element' in biomedical science quite recently. [2] Effectively, over the last two decades, the approval of five boronic acid-containing drugs by the FDA has vastly impacted the use of boron in medicinal chemistry, [3] chemical biology, [4] drug delivery and biomaterial exploration, [5] firmly establishing boronic acids and derivatives as one of the most important emerging classes of building blocks in organic and medicinal chemistry. [6] Among all boron-based chemotypes, amino boronic acids derivatives are currently predominant in drug discovery, due to their ability to act as amino acid bioisosteres and reversible covalent inhibitors addressing hydroxyl groups in biomolecules (mostly serine/threonine side chain residues).…”

Boronic Acid: A Novel Pharmacophore Targeting Src Homology 2 (SH2) Domain of STAT3

“…25,26 Furthermore, additional clinical trials involving compounds containing boronic acid are also undergoing. 27,28 However, to the best of our knowledge, boronic acid has never been explored as an efficient pharmacophore to target the SH2 domain. In view of its favorable druglike properties and covalent functionality, we are interested in exploring the feasibility of targeting the SH2 domain with a boronic acid group.…”

“…Therefore, boronic acid-derived drug discovery attracted increasing attention over the past decade, and a number of boronic acid-containing drugs have been approved for diverse therapeutic applications, such as bortezomib and ixazomib as anticancer agents, tavaborole and crisaborole as antifungal agents, and vaborbactam as antibiotics (Figure ). , Furthermore, additional clinical trials involving compounds containing boronic acid are also undergoing. , However, to the best of our knowledge, boronic acid has never been explored as an efficient pharmacophore to target the SH2 domain. In view of its favorable druglike properties and covalent functionality, we are interested in exploring the feasibility of targeting the SH2 domain with a boronic acid group.…”