Synthesis and Application of Constrained Amidoboronic Acids Using Amphoteric Boron-Containing Building Blocks.

Amidoboronic acid-containing peptidomimetics are an important class of scaffolds in chemistry and drug discovery. Despite increasing interest in boron-based enzyme inhibitors, constrained amidoboronic acids have received little attention due to the limited options available for their synthesis. We describe a new methodology to prepare both α- and ß-amidoboronic acids that impose restrictions on backbone angles. Lewis acid-promoted Boyer-Schmidt-Aube lactam ring expansions using an azidoalkylboronate enabled generation of constrained α-amidoboronic acid derivatives, whereas assembly of the homologous ß-amidoboronic acids was achieved through a novel boronic acid-mediated lactamization process stemming from an α-boryl aldehyde. The results of quantum chemical calculations suggest carboxylate-boron coordination to be rate-limiting for small ring sizes, whereas the tetrahedral intermediate formation is rate limiting in the case of larger rings. As part of this study, an application of ß-amidoboronic acid derivatives as novel VIM-2 metallo-ß-lactamase inhibitors has been demonstrated.

α-Aminoboronates: recent advances in their preparation and synthetic applications.

α-Aminoboronic acids and their derivatives are useful as bioactive agents. Thus far, three compounds containing an α-aminoboronate motif have been approved by the Food and Drug Administration (FDA) as protease inhibitors, and more are currently undergoing clinical trials. In addition, α-aminoboronic acids and their derivatives have found applications in organic synthesis, e.g. as α-aminomethylation reagents for the synthesis of chiral nitrogen-containing molecules, as nucleophiles for preparing valuable vicinal amino alcohols, and as bis-nucleophiles in the construction of valuable small molecule scaffolds. This review summarizes new methodology for the preparation of α-aminoboronates, including highlights of asymmetric synthetic methods and mechanistic explanations of reactivity. Applications of α-aminoboronates as versatile synthetic building blocks are also discussed.

Synthesis of Fluorinated Aminoalkylboronic Acids from Amphoteric α-Boryl Aldehydes.

Our ongoing search for underdeveloped functional group combinations has brought to light α-fluorinated aminoalkylboronic acids, a new class of molecules featuring the B-CF linkage. These compounds can now be generated from secondary amines and α-boryl aldehydes through electrophilic fluorination of boryl enamines or enamides. Fluorinated ß-aminoalkylboronic acids show no signs of degradation under ambient conditions. We present evidence for the involvement of chair-like motifs, favored over the acyclic forms by up to 1.7±0.1 kcal mol-1 in water and held together by an amine-boronate hydrogen bond. Fluorinated ß-aminoalkylboronic acids are stable over a wide pH range and are characterized by a pKa of 3.4, which is the lowest of any alkylboronic acid.

Heterocycles: Versatile control elements in bioactive macrocycles.

The potential of macrocyclic peptides as therapeutics has garnered much attention over the last several years. Unlike their linear counterparts, macrocycles have higher resistance to enzymatic degradation and often display improved bioavailability. However, macrocycles are typically not lipophilic enough for cellular membrane penetration, which prevents them from interacting with intracellular targets. Methods to increase cellular permeability have involved the incorporation of bicyclic scaffolds, d-amino acids and N-methylation of amides. These modifications exert their effect through conformational control of macrocycles and have been well studied in the literature. In contrast, the structural consequences of heterocycle incorporation into macrocyclic rings has not been as exhaustively investigated. In this mini-review we discuss key examples in which heterocycles influence the conformational stability and other properties of macrocycles.

An excimer-based, turn-on fluorescent sensor for the selective detection of diphosphorylated proteins in aqueous solution and polyacrylamide gels.

Protein phosphorylation is a ubiquitous post-translational modification, which often acts as a switch to proteins' activation and is frequently perturbed in diseases. Although many general phospho-protein detection tools are available, none of them offers information about the relative spatial arrangement of phosphorylated residues. Specifically, proximally phosphorylated residues are hallmarks of certain activated disease-relevant proteins. We herein report the first turn-on fluorescent sensor for the selective detection of proximally phosphorylated protein sites, suitable for application in both aqueous solutions and polyacrylamide gels.