Target Recognition by Boron-Containing Pharmacophores: Tetrahedral-State Mimicry, cis-Diol Trapping, and Bimetal-Center Coordination
Target Recognition by Boron-Containing Pharmacophores: Tetrahedral-State Mimicry, cis-Diol Trapping, and Bimetal-Center Coordination
Introduction
Pharmacophores such as boronic acids, cyclic boronic acids, and benzoxaboroles share a common coordination-chemical feature: the boron center can interconvert between a three-coordinate, approximately trigonal-planar state and a four-coordinate, approximately tetrahedral state. Three-coordinate boron is electron-deficient and Lewis acidic and can accept an electron pair from an oxygen-containing nucleophile. Formation of a boron–oxygen bond changes both the coordination number and the local spatial geometry of boron.[1,2]
Biological active sites can use different oxygen-containing groups to stabilize four-coordinate boron. Bortezomib and vaborbactam form reversible covalent adducts with catalytic threonine and serine, respectively, converting boron into a nearly tetrahedral coordination state and exploiting binding environments originally used by hydrolases to stabilize tetrahedral reaction states. Tavaborole forms a cyclic boronate ester-type adduct with the 2′,3′-diol of the ribose in the terminal adenosine of transfer RNA, trapping the transfer RNA in the editing site of leucyl-tRNA synthetase. The phenoxybenzoxaborole phosphodiesterase 4 inhibitor AN2898 instead forms a tetrahedral boron structure through coordination of boron by a water molecule organized by the zinc/magnesium bimetallic catalytic center.[3–11]
These modes of action share a common basis of selectivity: the electronic properties and coordination equilibrium of the boron center determine the binding states it can form; the active site spatially preorganizes the oxygen-containing group and the boron center; and the surrounding molecular scaffold governs entry into a specific binding pocket and defines the position and orientation of boron. The reactivity of the boron center, four-coordinate geometry, target microenvironment, and recognition of the molecular scaffold therefore collectively establish the pharmacological selectivity of boron-containing pharmacophores.
1. Three-Coordinate–Four-Coordinate Interconversion Is the Chemical Basis of Boron-Containing Pharmacophores
1.1 Electronic Structure of Three-Coordinate Boron
A typical organoboronic acid can be represented as R–B(OH)₂. In its neutral state, boron is generally three-coordinate and approximately trigonal planar, with a vacant orbital capable of accepting an electron pair, and is therefore Lewis acidic. Hydroxyl groups, hydroxide ions, and other suitable oxygen- or nitrogen-containing nucleophiles can coordinate or add to boron, converting it into a four-coordinate state.[2]
In aqueous solution, the acid–base equilibrium of an organoboronic acid can be represented by the following overall reaction:
R–B(OH)₂ + H₂O ⇌ [R–B(OH)₃]⁻ + H⁺
The pKₐ of a boronic acid is therefore associated with the coordination of water to the boron center and the formation of four-coordinate hydroxyboronate species. pH, substituent electronic effects, and ring structure all alter the relative stability of three-coordinate and four-coordinate boron species.[2]
1.2 Reversible B–O Adducts and Local Reaction Selectivity
Boronic acids can form reversible B–O adducts with alcohols, vicinal diols, and oxygen-containing nucleophiles in enzyme active sites. The surrounding drug scaffold first undergoes noncovalent recognition by the binding pocket, positioning the boron center at an appropriate distance and orientation relative to the target oxygen-containing group. A four-coordinate boron structure then forms, further stabilizing the complex.
This process can be summarized as follows:
Molecular-scaffold recognition → Active-site preorganization → Boron-center coordination or nucleophilic addition → Stabilization of the four-coordinate adduct
The reactivity of the boron center therefore determines the types of adducts that can form, whereas target selectivity depends on whether the entire binding site can effectively position and stabilize the corresponding reaction state.
2. How Tetrahedral Boron Mimics Hydrolytic Reaction States
2.1 From a Planar Carbonyl to a Tetrahedral Intermediate
Ser/Thr hydrolases commonly use an activated Ser–OH or Thr–OH group to attack a substrate carbonyl nucleophilically. The initially approximately planar carbonyl carbon is thereby converted into a tetrahedral structure, generating an oxyanion-like intermediate. The oxyanion hole and hydrogen-bonding network in the enzyme active site stabilize this reaction state.
The basic process can be represented as follows:
Planar carbonyl substrate → Ser/Thr nucleophilic attack → Tetrahedral intermediate → Subsequent acyl transfer or bond cleavage
When a boronic acid enters a similar catalytic environment, a nucleophilic oxygen in the active site can attack the electron-deficient boron, converting three-coordinate boron into a four-coordinate structure. The spatial arrangement of the resulting tetrahedral boron and its surrounding oxygen atoms can match that of the tetrahedral reaction state formed during normal enzyme catalysis.
Four-coordinate boron adducts resemble the tetrahedral high-energy states of catalytic processes in their geometry and charge distribution and can therefore serve as stable mimics of the corresponding reaction states. Crystal structures capture these stable inhibitor complexes rather than the transient transition states themselves.[1–3]
In crystal structures of subtilisin BPN′ complexed with boronic acid inhibitors, Matthews et al. observed direct bonding between the Oγ atom of catalytic Ser221 and boron, with one boronic acid oxygen positioned in the oxyanion hole. These findings provided early structural evidence that boronic acid adducts can mimic the tetrahedral state of a hydrolytic reaction.[3]
2.2 Mimicry of the Tetrahedral State in β-Lactam Hydrolysis by Cyclic Boronic Acids
β-Lactamases provide a further illustration of this geometric matching. Serine β-lactamases (SBLs) use a catalytic Ser residue for nucleophilic attack, whereas metallo-β-lactamases (MBLs) primarily use water or hydroxide activated by Zn²⁺ to attack the substrate. Although the two enzyme families use different catalytic machinery, hydrolysis of the β-lactam ring in both cases proceeds through a first tetrahedral intermediate with similar small-molecule geometric features.
Cahill et al. found that cyclic boronic acids inhibit different classes of β-lactamases and proposed that their activity is based on mimicry of the first tetrahedral intermediate shared by SBL- and MBL-catalyzed reactions.[5] Panels A and B of Figure 1 in the original article show the hydrolytic pathways of the two β-lactamase families, while panel C compares cyclic boronic acids with the tetrahedral intermediate formed during cephalexin hydrolysis.
Figure 1. Mimicry of the tetrahedral intermediate in β-lactamase catalysis by cyclic boronic acids.
(A) Basic process of cephalosporin hydrolysis catalyzed by a serine β-lactamase; (B) basic process of cephalosporin hydrolysis catalyzed by a metallo-β-lactamase. Although the two enzyme families use different catalytic mechanisms, both form a first tetrahedral intermediate, EI₁, with shared small-molecule structural features. (C) The two cyclic boronic acids investigated in the study and the common first tetrahedral intermediate represented using cephalexin as an example. The cyclic boronic acids mimic this reaction state through a four-coordinate boron structure.[5]
Source: Cahill, S. T.; Cain, R.; Wang, D. Y.; et al. Cyclic Boronates Inhibit All Classes of β-Lactamases. Antimicrobial Agents and Chemotherapy 2017, 61, e02260-16, Figure 1; the original article is published under the Creative Commons Attribution 4.0 International License.
Figure 1 shows that the active site does not recognize an isolated boron atom, but rather the three-dimensional state collectively formed by tetrahedral boron, oxygen-containing coordinating groups, and the surrounding scaffold. The same principle applies to cyclic boronic acid β-lactamase inhibitors developed subsequently.
3. Bortezomib and Vaborbactam: Recognition of Four-Coordinate Boron by Different Hydrolases
3.1 Bortezomib and Proteasomal Threonine 1
The catalytic β subunits of the 20S proteasome belong to the N-terminal threonine hydrolase family. In the mature subunits, the side-chain hydroxyl group of N-terminal threonine 1 (Thr1) serves as the catalytic nucleophile. The yeast 20S proteasome–bortezomib complex solved by Groll et al.〔Protein Data Bank (PDB) entry 2F16〕shows that the boronic acid group of bortezomib enters the catalytic center and that the side-chain Oγ atom of Thr1 forms a reversible covalent B–O linkage with boron, producing a four-coordinate adduct.[4]
Within this adduct, the oxygen-containing groups of the boronic acid moiety form additional hydrogen bonds with the catalytic center. One oxygen interacts with the backbone amide nitrogen of Gly47, which contributes to the oxyanion-stabilizing environment, while the other oxygen interacts with the N-terminal amino group of Thr1. The peptide-like portion of bortezomib occupies the substrate-recognition region of the proteasome and stabilizes the bound conformation through hydrogen bonds and hydrophobic interactions.[4]
Binding of bortezomib to the proteasome therefore depends on both the four-coordinate reversible covalent adduct formed between Thr1 and boron and the spatial and noncovalent complementarity between the peptide-like scaffold and the substrate-binding subsites. The former stabilizes the bound state in the catalytic center, while the latter determines whether the boronic acid group can approach the catalytic threonine in an appropriate position and orientation.
3.2 Vaborbactam and β-Lactamase Serine 70
Vaborbactam is a cyclic boronic acid β-lactamase inhibitor that inhibits class A serine β-lactamases, including Klebsiella pneumoniae carbapenemase (KPC).[6,7] The crystal structure of vaborbactam bound to KPC-2 was determined at a resolution of 1.25 Å〔PDB 6V7I〕and provides structural evidence for its binding mode.[7]
In this complex, the side-chain Oγ atom of catalytic serine 70 (Ser70) forms a reversible covalent bond with boron, producing a four-coordinate boron configuration. The exocyclic hydroxyl oxygen of vaborbactam enters the oxyanion hole formed by the backbone amide NH groups of Ser70 and threonine 237 (Thr237) and forms hydrogen bonds with both. The endocyclic oxygen forms an additional hydrogen bond with the backbone amide NH of Thr237. Peripheral groups, including the carboxyl and amide groups, form further polar interactions with active-site residues.[7]
Structural comparisons show that the overall spatial positions of the exocyclic hydroxyl oxygen and endocyclic oxygen in vaborbactam more closely resemble the tetrahedral transition-state model for the acylation step of class A β-lactamases than the corresponding state in the deacylation step. The reversible Ser70–O–B covalent linkage, the geometry of four-coordinate boron, and stabilization of the oxygen-containing groups by the oxyanion hole therefore collectively form the basis of binding.[7]
Kinetic studies further show that peripheral active-site residues affect vaborbactam inhibition. Substitution of tryptophan 105 (W105) in KPC-2 can significantly alter the efficiency of covalent-adduct formation (k₂/K), while having a comparatively small effect on the dissociation rate. This indicates that the residue primarily affects initial binding and/or covalent-adduct formation, with relatively little effect on dissociation of the adduct once formed. Differences in dissociation rates among class A β-lactamases may be associated with the Ser70–O–B linkage and the local stabilization of the adduct by hydrogen bonds in the oxyanion hole.[7]
Bortezomib and vaborbactam both use a catalytic hydroxyl group to form a four-coordinate reversible covalent adduct with boron. However, the proteasome and β-lactamases have different requirements for the surrounding molecular scaffold, substrate-recognition region, and local hydrogen-bonding network. Similar boron-coordination chemistry can therefore be used against different enzyme targets, while specific target recognition continues to depend on structural complementarity between the entire molecule and its binding pocket.
4. Tavaborole: Trapping Transfer RNA through the A76 Ribose 2′,3′-Diol
4.1 A Covalent Adduct Forms Between Tavaborole and Transfer RNA
Tavaborole, originally designated AN2690, is a benzoxaborole antifungal agent that targets the editing site of leucyl-tRNA synthetase.
Leucyl-tRNA synthetase attaches leucine to its cognate transfer RNA and uses its editing domain to remove incorrectly aminoacylated products. After tavaborole enters the editing site, its boron center forms a cyclic boronate ester-type adduct with the 2′-O and 3′-O atoms of the ribose in adenosine A76 at the 3′ terminus of the transfer RNA. This traps the transfer RNA in the editing conformation and thereby blocks normal catalytic turnover.[8]
The basic process can be represented as follows:
Transfer RNA enters the editing site
→ Tavaborole approaches the A76 ribose
→ The 2′-O and 3′-O atoms of the A76 ribose form a cyclic adduct with boron
→ The transfer RNA is stabilized in the editing conformation
In a subsequent structural study, Liu et al. represented this process using a reaction scheme. Figure 6A of the original article illustrates adduct formation between tavaborole and transfer RNA A76〔or 5′-adenosine monophosphate as a model〕in the editing site. The article also states that covalent attachment of tavaborole to A76 prevents the transfer RNA from leaving the editing conformation.
Figure 2. Reaction mode for adduct formation between tavaborole and the ribose of terminal A76 in transfer RNA.
The boron center of tavaborole forms a cyclic boronate ester-type adduct with the 2′-O and 3′-O atoms of the A76 ribose, trapping the transfer RNA in the editing site of leucyl-tRNA synthetase. This reaction provides the chemical basis for the oxaborole-mediated transfer-RNA trapping mechanism.[8,9]
Source: Liu, R.-J.; Long, T.; Li, H.; et al. Nucleic Acids Research 2020, 48, 4946–4959, Figure 6A; CC BY 4.0.
Tavaborole binding is also influenced by the spatial environment of the editing site. The relative positioning of the drug and A76 within the binding site favors formation and stabilization of the cyclic adduct between boron and the ribose. Unlike bortezomib and vaborbactam, in this system it is the enzyme-bound transfer-RNA substrate, rather than a catalytic amino acid residue of the enzyme itself, that forms the reversible covalent adduct directly with boron.
4.2 Ring Structure and Aromatic Substitution Modulate the pKₐ and Diol-Binding Properties of Benzoxaboroles
Tomsho et al. measured an aqueous pKₐ of 7.34 ± 0.02 for the parent benzoxaborole; for comparison, phenylboronic acid has a pKₐ of approximately 8.8. Expanding the five-membered ring to a six-membered-ring analogue increased the pKₐ to 8.40 ± 0.03, while introducing gem-dimethyl substitution at C3 of the five-membered ring produced a pKₐ of 8.32 ± 0.03.[10]
The original study attributed the lower pKₐ of the parent benzoxaborole to the geometric constraint imposed by the five-membered ring on the neutral trigonal-planar boron configuration. This ring strain is relieved when the boron center ionizes and adopts a tetrahedral configuration. The six-membered ring causes less geometric distortion around the boron center, while the gem-dimethyl effect at C3 may increase the bond angle around boron and reduce angular distortion, making ionization less favorable. Both structural changes therefore increase the pKₐ.[10]
Aromatic substituents can also modulate the pKₐ of benzoxaboroles through electronic effects. Tomsho et al. further used 5′-adenosine monophosphate (5′-AMP) as a simplified model of the terminal adenosine of transfer RNA and measured the binding constants of the parent benzoxaborole and two representative aromatic-ring-substituted derivatives with its ribose diol. The results showed that, in phosphate buffer at pH 7.4, stronger electron-withdrawing effects of the aromatic substituent were associated with a lower benzoxaborole pKₐ and stronger binding to 5′-AMP. The authors attributed both changes to the increased stability of anionic tetrahedral products following a reduction in electron density around boron.[10]
These structure–property relationships can be divided into two interconnected pathways:
Ring size or 3,3-dimethyl substitution
→ Modifies the geometric constraints around the boron center
→ Modifies the pKₐ
Electronic effects of aromatic substituents
→ Simultaneously modulate the pKₐ and binding to the ribose diol of 5′-AMP
In the actual leucyl-tRNA synthetase system, these acid–base and diol-binding properties measured in solution must act together with the spatial preorganization of tavaborole and A76 in the editing site to enable efficient formation and stabilization of the cyclic A76 adduct and contribute to the corresponding target recognition.
5. Bimetal-Center Recognition: Phosphodiesterase 4 Uses Activated Water to Form Four-Coordinate Boron
Phosphodiesterase 4 hydrolyzes adenosine 3′,5′-cyclic monophosphate. Its catalytic center contains Zn²⁺ and Mg²⁺, which jointly organize and activate the water molecule involved in catalysis.
Crisaborole (AN2728) is a phenoxybenzoxaborole phosphodiesterase 4 inhibitor. Freund et al. investigated AN2728 and the related compound AN2898 and found that both are competitive, reversible phosphodiesterase 4 inhibitors. The AN2898–phosphodiesterase 4B co-crystal structure〔Protein Data Bank entry 3O0J, resolution 1.95 Å〕directly reveals how the boron center of this class of compounds binds.[11]
In this structure, a water molecule jointly organized and activated by Zn²⁺ and Mg²⁺ coordinates to the boron atom of AN2898, producing a four-coordinate, approximately tetrahedral configuration. The fused benzene ring and dicyanophenoxy portion of AN2898 simultaneously interact with hydrophobic regions of the catalytic pocket.[11]
Superposition of this structure with that of 5′-adenosine monophosphate in the phosphodiesterase 4 active site shows that the tetrahedral boron group of AN2898 occupies a position that approximately overlaps the phosphate group of 5′-adenosine monophosphate and has a similar spatial relationship with the bimetallic center.[11]
The principal connectivity can be represented as follows:
Zn²⁺/Mg²⁺ bimetallic center → Activated water → Coordination to the boron center → Formation of four-coordinate boron
This system does not depend on formation of a direct covalent bond between boron and a protein amino acid side chain. Instead, it uses water activated by the bimetallic center to position boron within the catalytic region, while the surrounding aromatic structure further stabilizes the inhibitor conformation in the binding pocket.
Coordination to the bimetallic center alone is insufficient to explain the selectivity of this series for PDE4 over other phosphodiesterases. Interactions between the surrounding molecular scaffold and other regions of the active site also contribute to this selectivity.[11]
6. Common Basis of the Pharmacological Selectivity of Boron Centers
Although the four systems described above use different oxygen-containing components to form four-coordinate boron, their selectivity is collectively determined by the properties of the boron center, the spatial environment of the target, and the surrounding molecular scaffold.
Representative System | Oxygen-Containing Component Interacting Directly with Boron | Key State Formed | Recognition Environment Provided by the Target |
Bortezomib–20S proteasome | Thr1 side-chain oxygen | Thr–O–B four-coordinate reversible covalent adduct | N-terminal threonine catalytic center, oxyanion-stabilizing environment, and substrate-binding subsites |
Vaborbactam–KPC-2 | Ser70 side-chain oxygen | Ser–O–B four-coordinate reversible covalent adduct | β-Lactamase catalytic center, oxyanion hole, and peripheral binding residues |
Tavaborole–leucyl-tRNA synthetase–transfer RNA | 2′-O and 3′-O atoms of the A76 ribose | Cyclic boronate ester-type adduct | Co-positioning of the drug and A76 by the editing site |
AN2898–phosphodiesterase 4B | Water activated by the bimetallic center | Four-coordinate boron involving coordination by activated water | Zn²⁺/Mg²⁺ bimetallic center and the surrounding hydrophobic binding region |
6.1 Boron-Center Reactivity Must Match the Target Environment
The Lewis acidity, pKₐ, ring structure, and substituent electronic effects of the boron center all influence the tendency to form four-coordinate species.[10] These physicochemical parameters determine the coordination processes in which the boron center can participate, but changing any one parameter alone does not directly predict pharmacological activity. Actual binding also depends on the local environment provided by the target.
6.2 Spatial Preorganization by the Active Site Favors Formation of the Target Adduct
Formation of a stable adduct between the boron center and an oxygen-containing group requires an appropriate distance and orientation between them within the binding site. Protein or nucleic acid binding sites restrict ligand conformation and organize oxygen-containing components, increasing the probability that the target four-coordinate state will form and remain stable.
This spatial preorganization allows a boron center with a general capacity to bind oxygen-containing ligands to display selectivity within a specific target environment.
6.3 The Surrounding Molecular Scaffold Controls Target Positioning of the Boron Center
A boron-containing pharmacophore is generally only one component of the complete molecular structure. Surrounding peptide-like structures, aromatic rings, carboxyl groups, amide groups, and other substituents participate in initial noncovalent recognition and restrict the bound conformation, thereby controlling the position and orientation of the boron center in the active site.
Similar four-coordinate boron chemistry can therefore occur in different targets, whereas specific target selectivity depends on structural complementarity between the complete molecule and the binding pocket.
6.4 Binding Kinetics Influence Adduct Formation and the Duration of Target Occupancy
Reversible covalent or coordination adducts exist in a dynamic equilibrium. Their inhibitory behavior depends not only on equilibrium binding strength but also on the efficiency of adduct formation and the dissociation rate. Adduct formation affects the rate at which target occupancy is established, whereas dissociation determines how long the complex can persist after the concentration of free inhibitor decreases.
Studies of vaborbactam and KPC-2 showed that substitution of tryptophan 105 (W105) can significantly alter the formation-efficiency parameter k₂/K of the reversible covalent complex while having a comparatively small effect on the dissociation rate. This indicates that W105-associated interactions primarily affect initial noncovalent binding and/or covalent-adduct formation, with relatively little effect on dissociation of the adduct once formed.[7]
For a reversible adduct that has already formed, slower dissociation generally corresponds to a longer residence time and longer target occupancy. However, residence time reflects the kinetic stability of the drug–target complex and cannot by itself be equated with the duration of pharmacological activity in vivo, which is also influenced by drug exposure, target turnover, and other factors.
Evaluation of reversible boron-containing inhibitors can therefore combine measurements of adduct-formation efficiency, dissociation rate, residence time, and recovery of enzyme activity after rapid dilution, rather than relying exclusively on an IC₅₀ measured at a single incubation time.
7. Experimental Validation of the Involvement of Boron Centers in Binding Mechanisms
7.1 Complex Structures Reveal the Binding Sites and Coordination Configurations of Boron Centers
Co-crystal or complex structures can directly reveal the atoms bonded to or coordinated with boron, the four-coordinate geometry of the boron center, and the position of the boron-containing pharmacophore in the active site.
Representative structures discussed in this article include:
① Bortezomib–20S proteasome: Protein Data Bank entry 2F16;[4]
② Vaborbactam–KPC-2: 6V7I;[7]
③ Tavaborole–leucyl-tRNA synthetase–transfer RNA complex: 2V0G;[8]
④ AN2898–phosphodiesterase 4B: 3O0J.[11]
PDB 2V0G is a Thermus thermophilus LeuRS–tRNA–AN2690 complex structure and directly shows formation of an adduct between the boron center of AN2690 and the 2′- and 3′-oxygen atoms of the terminal A76 ribose of transfer RNA. The antifungal target of tavaborole, in turn, is supported by biochemical experiments on yeast cytosolic LeuRS.[8]
7.2 Kinetic and Dilution Experiments Verify Binding Reversibility
Preincubation dependence, measurements of adduct-formation and dissociation rates, and rapid-dilution experiments can determine whether the binding states formed by boron-containing inhibitors are reversible and can distinguish different kinetic behaviors.
Following preincubation of AN2898 with phosphodiesterase 4B, approximately 86% of enzyme activity was recovered immediately after 200-fold dilution, supporting the reversibility of inhibition.[11]
Kinetic measurements therefore complement static structures by providing information about adduct formation, persistence, and dissociation that cannot be obtained from structural data alone.
7.3 Structural Controls and Solution Measurements Verify the Functional Contribution of Boron Centers
Structural analogues can be used to determine whether activity depends on the boron center and its four-coordinate geometry. In the phosphodiesterase 4 system, replacement of the oxaborole ring with a boron-free cyclic hemiacetal structure markedly reduced the enzyme-inhibitory and cytokine-inhibitory activities of AN2913, supporting the contribution of the boron center and its four-coordinate structure to the activity of this series.[11]
For benzoxaboroles, pKₐ measurements and diol-binding constants can further relate structural modifications to boron-center ionization and diol-binding capacity. The study by Tomsho et al. showed that the electronic effects of aromatic substituents influence not only the pKₐ but also binding to the ribose diol of 5′-adenosine monophosphate in a systematic manner.[10]
8. Representative Chemicals Related to the Pharmacological Selectivity of Boron Centers, Tetrahedral-State Mimicry, cis-Diol Trapping, and Bimetal-Center Recognition
Table 1. Chemicals Related to Tetrahedral-State Mimicry and Reversible Covalent Inhibition
Category | CAS No. | Aladdin Cat. No. | Name | Specification or Purity | Product Features and Applications |
Proteasomal threonine-targeted reversible covalent inhibitor | 179324-69-7 | Bortezomib (PS-341) | Moligand™, ≥98% | The boronic acid group can form a four-coordinate B–O reversible covalent adduct with catalytic Thr1 of the proteasome. Used to investigate proteasome inhibition, tetrahedral reaction-state mimicry, and the mechanisms of action of boronic acid pharmacophores. | |
Boronic acid-type proteasome inhibitor | 1072833-77-2 | Ixazomib (MLN2238) | Moligand™, ≥98% | An active boronic acid-type proteasome inhibitor used to investigate recognition of the proteasomal catalytic threonine, reversible covalent inhibition, and structure–activity relationships of boronic acid pharmacophores. | |
Proteasome inhibitor prodrug | 1239908-20-3 | Ixazomib citrate (MLN9708) | ≥97% | The prodrug form of ixazomib, used to investigate prodrug derivatization and release of active boronic acid pharmacophores and the design of proteasome inhibitors. | |
Cyclic boronic acid β-lactamase inhibitor | 1360457-46-0 | Vaborbactam (RPX7009) | Moligand™, ≥98% | The cyclic boronic acid can form a four-coordinate reversible covalent adduct with catalytic Ser70 of serine β-lactamases. Used to investigate β-lactamase inhibition, tetrahedral-state mimicry, and binding kinetics. | |
Substrate for functional evaluation of β-lactamase inhibition | 96036-03-2 | Meropenem | Moligand™, 10mM in DMSO | A carbapenem β-lactam antibacterial agent that can be used with vaborbactam to evaluate substrate protection following β-lactamase inhibition, enzymatic hydrolysis, and antibacterial function. | |
Boronic acid inhibitor model for serine proteases | 34420-17-2 | 2-Phenylethylboronic acid (contains varying amounts of anhydride) | ≥98% | A classical boronic acid inhibitor model used to investigate formation of tetrahedral adducts between catalytic serine and boron and the mimicry of hydrolase reaction states by boronic acids. |
Table 2. Chemicals Related to Benzoxaborole Coordination Equilibria and cis-Diol Trapping
Category | CAS No. | Aladdin Cat. No. | Name | Specification or Purity | Product Features and Applications |
Arylboronic acid benchmark compound for coordination | 98-80-6 | Phenylboronic acid (PBA) (contains varying amounts of anhydride) | ≥99.5% | A representative arylboronic acid model used to investigate boron-center acid–base equilibria, three-coordinate–four-coordinate interconversion, vicinal-diol binding, and comparisons with benzoxaborole properties. | |
Core benzoxaborole scaffold | 5735-41-1 | 2-(Hydroxymethyl)phenylboronic acid cyclic monoester | ≥97% | A five-membered cyclic boronic acid core used to investigate the effects of ring structure on boron-center pKₐ, coordination geometry, stability of four-coordinate species, and vicinal-diol binding. | |
Benzoxaborole ring-size control | 19206-51-0 | 3,4-Dihydro-1H-benzo[c][1,2]oxaborinin-1-ol | ≥98% | A six-membered boron-containing ring control used to compare the effects of ring-size changes on the geometric constraints around boron, pKₐ, and the three-coordinate–four-coordinate equilibrium. | |
Benzoxaborole ring-geometry control | 221352-10-9 | 3,3-Dimethylbenzo[c][1,2]oxaborol-1(3H)-ol | ≥98% | A ring-substituted structural model used to examine the effects of intraring spatial constraints on boron-center geometry, acid–base properties, and the stability of the four-coordinate state. | |
Leucyl-tRNA synthetase inhibitor | 174671-46-6 | 5-Fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole | ≥98% | This compound is tavaborole (AN2690), which can form a cyclic boronate ester-type adduct with the 2′,3′-diol of the terminal A76 ribose of tRNA. Used to investigate the editing site of leucyl-tRNA synthetase and the tRNA-trapping mechanism. | |
Model for binding to the terminal ribose of tRNA | 61-19-8 | 5′-Adenylic acid (5′-AMP) | Moligand™, ≥98% (HPLC) | Contains a ribose vicinal-diol structure and can serve as a model related to terminal A76 of tRNA. Used to investigate binding between benzoxaboroles and ribose diols, boronate ester formation, and binding constants. | |
Indicator for boronic acid–diol binding | 130-22-3 | Alizarin Red S (sodium alizarinsulfonate) | Indicator | Can be used for competitive indication and spectroscopic analysis of boronic acid–vicinal-diol binding and is suitable for studying the binding of boronic acids or benzoxaboroles to sugars and ribose structures. |
Table 3. Chemicals Related to Bimetal-Center Recognition by Phosphodiesterase 4
Category | CAS No. | Aladdin Cat. No. | Name | Specification or Purity | Product Features and Applications |
Natural substrate of phosphodiesterase 4 | 60-92-4 | Adenosine 3′,5′-cyclic monophosphate (3′,5′-cAMP) | Moligand™, ≥99% | The natural substrate of phosphodiesterase 4, used to investigate enzyme-catalyzed hydrolysis and bimetal-center recognition and to compare the binding region of its native phosphate group with that of boron-containing inhibitors. | |
Benzoxaborole phosphodiesterase 4 inhibitor | 906673-24-3 | Crisaborole (AN2728, inhibitor of PDE4 and cytokine release) | Moligand™, ≥98% | A benzoxaborole phosphodiesterase 4 inhibitor used to investigate boron-containing pharmacophores, recognition of the bimetallic catalytic center, and inhibition of inflammation-associated phosphodiesterase 4. | |
Compound for structural studies of bimetal-center binding | 906673-33-4 | AN2898 | —— | A representative benzoxaborole used in structural studies of phosphodiesterase 4. It can form a four-coordinate boron structure through water activated by the bimetallic center and is used to investigate recognition of Zn²⁺/Mg²⁺ catalytic sites and tetrahedral boron-coordination mechanisms. |
Note: The products listed above are representative Aladdin products related to scientific research. Specific applications should be determined in conjunction with the product specifications, batch certificate of analysis (COA), and the intended reaction or evaluation system. Additional product specifications, grades, and COA information can be found on the Aladdin website by searching by product name, CAS number, or catalog number.
References
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[2] António, J. P. M.; Russo, R.; Carvalho, C. P.; Cal, P. M. S. D.; Gois, P. M. P. Boronic Acids as Building Blocks for the Construction of Therapeutically Useful Bioconjugates. Chemical Society Reviews 2019, 48, 3513–3536. DOI: 10.1039/C9CS00184K.
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