Recent Advances in the Medicinal Chemistry of α-Aminoboronic Acids, Amine-Carboxyboranes and Their Derivatives

Abstract

This article describes recent developments in the synthesis and biological activity of alpha-aminoboronic acids, amine-carboxyboranes and their derivatives as potential therapeutic agents. alpha-Amino acid analogues are of considerable interest as inhibitors of enzymes involved in amino acid and peptide metabolism. In particular, alpha-amino alkylphosphonic acids and alpha-amino alkylboronic acids, in which the carboxyl group of amino acids is replaced by a phosphonic acid or boronic acid function, respectively, constitute a unique class of amino acid mimics from which a number of potent enzyme inhibitors have been synthesized. The inhibitory activity mainly stems from the fact that the tetrahedral phosphonic moiety or the tetrahedral adduct of electrophilic boronic acid is a good mimic of the putative tetrahedral transition state or intermediate encountered in the enzymatic hydrolysis or formation of peptides. Since the peptide hydrolysis and formation invariably involves the tetrahedral high energy species in the course of the reaction, these amino acid mimics serve as a general key element for inhibitors of a broad spectrum of proteases and peptide ligases. Serine protease inhibitors provide promising compounds having a P site binding moiety and a boronic acid chelating moiety. The compounds have been shown to have high inhibitory activity.

Selective Inhibition of Fibroblast Activation Protein Protease Based on Dipeptide Substrate Specificity

“…For this, we coupled the Ac-Gly-Pro specificity motif to an electrophilic boronic acid moiety capable of reacting with the active site serine of the protease (42). The resulting peptide boronic acid, Ac-Gly-BoroPro, was then tested for FAP and DPP-4 inhibition.…”

Chemistry of α‐Aminoboronic Acids and their Derivatives

“…This resemblance has inspired extensive biological screening of these molecules, and the promising early results led to the syntheses of a large number of ester [96][97][98][99], amide [100,101], peptide [102,103], hydroxamic acid [104], and transition metal [105][106][107] derivatives of amine-carboxyboranes (A-BH 2 COX, X ¼ OR, NR 1 R 2 , or NHOH) containing a broad range substitutes, among other amine-boranes, which have been reviewed recently [2,108,109].…”

“…In recent years there has been increasing interest in new practical methods to prepare novel non-natural (R) amino acid derivatives to serve as building blocks in combinatorial chemistry and drug discovery [1][2][3][4][5]. Although many routes to amino acids have been developed, there is still a need for concise and convergent approaches that allow structure variability and facile incorporation of functional groups and ring systems [6][7][8][9][10].…”

“…Boronic acids [RB(OH) 2 ] and boronate esters [RB(OR 1 ) 2 ] have been found to facilitate the transport of various ribonucleosides in and out of liposomes -an important attribute in the area of drug design [18][19][20]. Simple aminoboron compounds have also found some utility in boron neutron capture therapy [21,22] and other forms of cancer therapy [1][2][3]. As a result, much effort has been focused on the synthesis of boron-containing amino acid and peptide derivatives [23,24].…”

“…Treatment of (11) with AcOH/Ac 2 O yielded the acetoamidoboronic ester (12), which was cleaved with BCl 3 to yield (S)-N-acetylboraphenylalanine (13) (Scheme 4.2). Compound (13) was a potent inhibitor of certain enzymes [2]. Some other routes for the synthesis of (13) have been described [8,40].…”