Design, synthesis and structure of a frustrated benzoxaborole and its applications in the complexation of amines, amino acids, and protein modification

Bhangu, Jasmine; Whittal, Randy M.; Hall, Dennis G.

doi:10.1039/d0ob00572j

Cited by 4 publications

(10 citation statements)

References 28 publications

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“…Using suitably labeled ligands we observed (by 19 F-NMR) 'capture' by intermolecular PLABP (Fig. 3a,b) in H3-Bal10.…”

Section: Bal Allows Intramolecular Dynamic Lewis Acid-base Pairingmentioning

confidence: 95%

“…The extent is not only kinetically dependent 6 but can be externally modulated ('Wulff-type' 3 , see also ref. 19 ). Simple, unmodulated alkylboronic acids usually exhibit pK a higher than arylboronic acids (for example, pK a methylboronic acid 10.7 and pK a phenylboronic acid 8.8) rendering them typically 20 less suitable for binding applications in aqueous media 21 .…”

Section: Bal Allows Intramolecular Dynamic Lewis Acid-base Pairingmentioning

confidence: 99%

“…7a for poly-ols used and Supplementary Note 1 for their synthesis) was added from a stock solution in dimethylsulfoxide (DMSO) (typically 10 equiv. ), the mixture was transferred to an NMR tube and analyzed via 19 F-NMR on a Bruker Avance III HD 600 MHz NMR spectrometer equipped with a Prodigy N 2 broadband cryoprobe. Peaks for bound poly-ols appeared downfield of the nonbound species.…”

Section: Determination Of Poly-ol Binding To Bal Proteins By Nmrmentioning

confidence: 99%

“…The mixture was purified via dialysis into mQ H 2 O and lyophilized before being resuspended in NMR binding buffer buffer (NaPi 40 mM, pH 7.0, 5 M urea, 10% D 2 O). The protein was titrated with diol 4 (stock solution in DMSO) covering a concentration range from 100 µM to 64 mM and 19 F-NMR spectra were recorded (d 1 = 2 s, 3,072 scans) (Supplementary Fig. 24).…”

mentioning

confidence: 99%

“…and FDGal (6) (2.14 mg, 11.7 µmol, 1.00 equiv.) were dissolved in NaP i buffer (25 mM, pH 8.0, 10% D 2 O) and analyzed via 19 F-NMR spectrometry (Supplementary Fig. 25).…”

mentioning

confidence: 99%

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Post-translational insertion of boron in proteins to probe and modulate function

et al. 2021

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Boron is absent in proteins, yet is a micronutrient. It possesses unique bonding that could expand biological function including modes of Lewis acidity not available to typical elements of life. Here we show that post-translational Cβ–Bγ bond formation provides mild, direct, site-selective access to the minimally sized residue boronoalanine (Bal) in proteins. Precise anchoring of boron within complex biomolecular systems allows dative bond-mediated, site-dependent protein Lewis acid–base-pairing (LABP) by Bal. Dynamic protein-LABP creates tunable inter- and intramolecular ligand–host interactions, while reactive protein-LABP reveals reactively accessible sites through migratory boron-to-oxygen Cβ–Oγ covalent bond formation. These modes of dative bonding can also generate de novo function, such as control of thermo- and proteolytic stability in a target protein, or observation of transient structural features via chemical exchange. These results indicate that controlled insertion of boron facilitates stability modulation, structure determination, de novo binding activities and redox-responsive ‘mutation’.

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“…Using suitably labeled ligands we observed (by 19 F-NMR) 'capture' by intermolecular PLABP (Fig. 3a,b) in H3-Bal10.…”

Section: Bal Allows Intramolecular Dynamic Lewis Acid-base Pairingmentioning

confidence: 95%

Section: Bal Allows Intramolecular Dynamic Lewis Acid-base Pairingmentioning

confidence: 99%

Section: Determination Of Poly-ol Binding To Bal Proteins By Nmrmentioning

confidence: 99%

mentioning

confidence: 99%

“…and FDGal (6) (2.14 mg, 11.7 µmol, 1.00 equiv.) were dissolved in NaP i buffer (25 mM, pH 8.0, 10% D 2 O) and analyzed via 19 F-NMR spectrometry (Supplementary Fig. 25).…”

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confidence: 99%

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Post-translational insertion of boron in proteins to probe and modulate function

et al. 2021

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Lewis or Brønsted? A Rectification of the Acidic and Aromatic Nature of Boranol-Containing Naphthoid Heterocycles

et al. 2021

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Boron-containing heterocycles are important in a variety of applications from drug discovery to materials science; therefore a clear understanding of their structure and reactivity is desirable to optimize these functions. Although the boranol (B−OH) unit of boronic acids behaves as a Lewis acid to form a tetravalent trihydroxyborate conjugate base, it has been proposed that pseudoaromatic hemiboronic acids may possess sufficient aromatic character to act as Brønsted acids and form a boron oxy conjugate base, thereby avoiding the disruption of ring aromaticity that would occur with a tetravalent boronate anion. Until now no firm evidence existed to ascertain the structure of the conjugate base and the aromatic character of the boron-containing ring of hemiboronic "naphthoid" isosteres. Here, these questions are addressed with a combination of experimental, spectroscopic, X-ray crystallographic, and computational studies of a series of model benzoxazaborine and benzodiazaborine naphthoids. Although these hemiboronic heterocycles are unambiguously shown to behave as Lewis acids in aqueous solutions, boraza derivatives possess partial aromaticity provided their nitrogen lone electron pair is sufficiently available to participate in extended delocalization. As demonstrated by dynamic exchange and crossover experiments, these heterocycles are stable in neutral aqueous medium, and their measured pK a values are consistent with the ability of the endocyclic heteroatom substituent to stabilize a partial negative charge in the conjugate base. Altogether, this study corrects previous inaccuracies and provides conclusions regarding the properties of these compounds that are important toward the methodical application of hemiboronic and other boron heterocycles in catalysis, bioconjugation, and medicinal chemistry.

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Unraveling the Silent Hydrolysis of Cyclic B–X/C═C Isosteres: The Striking Impact of a Single Heteroatom on the Aromatic, Acidic, and Dynamic Properties of Hemiboronic Phenanthroids

et al. 2022

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Although heterocyclic hemiboronic acids are represented in several recently approved drugs, many questions remain unanswered regarding the physical properties and reactivity of these boranol (BOH)-containing compounds in aqueous media. Over the past 60 years, studies on the acidic and aromatic character of 10-hydroxy-10,9-boroxarophenanthrene and its boraza analog have been conflicting. In contradiction with the Lewis acidic behavior of arylboronic acids in aqueous conditions, it has been proposed that the central boroheterocyclic ring of these borophenanthroids confers sufficient aromatic character to compel the boranol unit to behave as a Brønsted acid and favor the boron oxy conjugate base, thereby avoiding the disruption of cyclic resonance that would otherwise occur with a tetravalent boronate anion. These questions are addressed with a combination of physical and spectroscopic characterizations, X-ray crystallographic analysis, and computational studies. Although both oxa and aza derivatives are conclusively shown to behave as Lewis acids in aqueous solutions, according to pK a measurements and MO and NICS calculations, only the boraza derivatives possess an appreciable aromatic character within the boroheterocyclic ring. For the first time, the possibility of dynamic chemical exchange via a reversible hydrolysis of the endocyclic B–heteroatom bond was examined using VT and EXSY NMR with suitable probe compounds. Whereas the boraza analog is static at neutral pH, its oxa analog undergoes a rapid hydrolytic ring opening–closing equilibrium with the transient boronic acid. Altogether, this study will guide the methodical application of these heterocycles as reaction catalysts, in bioconjugation, and as new-drug chemotypes and bioisosteres of pharmaceutically important classes of heterocycles.

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Design, synthesis and structure of a frustrated benzoxaborole and its applications in the complexation of amines, amino acids, and protein modification

Abstract: Design and synthesis of arylboronic acid 2, the first example of a permanently open “frustrated” benzoxaborole, is described along with an exploration of its application in the complexation of amines and amino acids, and protein modification.

Cited by 4 publications

References 28 publications

Post-translational insertion of boron in proteins to probe and modulate function

Post-translational insertion of boron in proteins to probe and modulate function

Lewis or Brønsted? A Rectification of the Acidic and Aromatic Nature of Boranol-Containing Naphthoid Heterocycles

Unraveling the Silent Hydrolysis of Cyclic B–X/C═C Isosteres: The Striking Impact of a Single Heteroatom on the Aromatic, Acidic, and Dynamic Properties of Hemiboronic Phenanthroids

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