Boronic Acid Assisted Bioorthogonal
Chemistry
M2 Siqi Xi
2019.08.22

ContentsIntroduction✓ Boronic Acid
✓ Bioorthogonal Chemistry✓ Boronic Acid & Bioorthogonal Chemistry

Boronic Ester
Iminoboronate
Summary2

Boronic Acid

Sumerlin. B. S et al. Chem. Rev. 2015, 116, 1375-1397.
Hall. D. G et al. Angew. Chem. Int. Ed. 2018, 57, 13028-13044.
Gois. P. M. P et al. Chem. Sco. Rev. 2019, 48, 3513-3536.

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Bioorthogonal Chemistry
Requirements of Bioorthogonal Chemistry✓ Selectivity✓ Biological inertness✓ Chemical inertness✓ Kinetics✓ Reaction biocompatibility✓ Accessible engineering

Usual Concerns of Current Biocompatible Chemistry:✓ Off-target labeling✓ Unintended immune✓ Slow kinetics✓ Side reactions with endogenous molecules.
Bertozzi, C. R et al. Acc. Chem. Res. 2011, 44, 666-676.
Gao, J et al. Acc. Chem. Res. 2018, 51, 2198-2206.

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Boronic Acid for Bioorthogonal Chemistry✓ High kinetics✓ Reaction biocompatibility

Hall. D. G et al. Angew. Chem. Int. Ed. 2018, 57, 13028-13044.

5

ContentsIntroduction
Boronic Ester✓ Boronic Ester with Sugars✓ Boronate-Mediated Biologic Delivery✓ Boronate Assisted DNA Transfection✓ Boronic Ester with Serine✓ Rhodamine-derived Bisboronic Acid
✓ Tyrosinase-Mediated Bioconjugation✓ Synergic “Click” Boronate/Thiosemicarbazone SystemIminoboronate
Summary
6

Boronic Ester with Sugars

Wang. B et al. Bio. Med. Chem. 2012, 2957-2961.

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Boronate-Mediated Biologic Delivery
Role of Glycoproteins✓ Cell-cell communication✓ Infection✓ Inflammation✓ Metastasis✓ Reproduction

ProteinRaines, R. T et al. J. Am. Chem. Soc. 2012, 8, 3631-3634.

Biologic drug delivery helped byrecognition parts of Glycoproteins8Boronate-Mediated Biologic Delivery✓ Benzoxaborole has a greateraffinity than phenyl boronic
acid for each saccharide.

Raines, R. T et al. J. Am. Chem. Soc. 2012, 8, 3631-3634.

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Boronate-Mediated Biologic Delivery✓ Lec-2 have lower levels ofsialic acid in their glycoprotein
than Pro-5.
✓ Fructose decreased theenhancement.
✓ Cell-surface sialic acid content
did not affect uptake
significantly.
Limitation: irreversible of protein.
Raines, R. T et al. J. Am. Chem. Soc. 2012, 8, 3631-3634.

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Boronate-Mediated Biologic Delivery

Trimethyl lock (TML)

Raines, R. T et al. ACS Chem. Biol. 2016, 11, 319-323.

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Boronate-Mediated Biologic Delivery✓ B-TML-GFP shows dramatic increase
compared with two others.
✓ Fructose decreases the cellular uptake.

Advantage: reversible biomodification.
Raines, R. T et al. Chem. Sci. 2012, 3, 2412-2420.

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Boronate Assisted DNA Transfection✓ Cations and anions interaction.
✓ Boronic ester improves gene cellular uptake (2 to 3 orders of magnitude).
Gois. P. M. P et al. Chem. Sco. Rev. 2019, 48, 3513-3536.

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Rhodamine-derived Bisboronic Acid✓ Cell-permeable✓ Turn-on fluorescent sensor✓ SSPGSS in 1 shows highaffinity.

Schepartz. A et al. J. Am. Chem. Soc. 2009, 131, 438-4339. Rhodamine-derived bisboronic acid (RhoBo)

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Rhodamine-derived Bisboronic Acid
✓ 1 and 10 show highfluorescence change.
✓ 2-9 show no detectable
fluorescence change.

✓ High fluorescent intensity inthe cytoplasmic region✓ Lower fluorescence intensity
in nucleus and outer plasma
membrane.
Schepartz. A et al. J. Am. Chem. Soc. 2009, 131, 438-4339.

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Tyrosinase-Mediated Bioconjugation✓ Applied to different proteins using the hemagglutinin-derived HA-tag that canintroduce exposed Tyr groups onto proteins.
Tirelli. N et al. Bioconjugate Chem. 2018, 29, 2550-2560.

16Synergic “Click” Boronate/Thiosemicarbazone System✓ Hindered, pre-organized vicinal diols mitigate the loss of entropy in the diol
substrate.
✓ Tight-binding.

Hall. D. G et al. Angew. Chem. Int. Ed. 2016, 55, 3909-3913.

17Synergic “Click” Boronate/Thiosemicarbazone SystemHall. D. G et al. Angew. Chem. Int. Ed. 2016, 55, 3909-3913.

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Synergic “Click” Boronate/Thiosemicarbazone System

Hall. D. G et al. Angew. Chem. Int. Ed. 2016, 55, 3909-3913.

19Synergic “Click” Boronate/Thiosemicarbazone System

Hall. D. G et al. Angew. Chem. Int. Ed. 2016, 55, 3909-3913.

20Synergic “Click” Boronate/Thiosemicarbazone System

Hall. D. G et al. Angew. Chem. Int. Ed. 2016, 55, 3909-3913.

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Synergic “Click” Boronate/Thiosemicarbazone System (Irreversible)

Undesirable cleavage!

Hall. D. G et al. J. Am. Chem. Soc. 2017, 139, 14285-14291.

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Synergic “Click” Boronate/Thiosemicarbazone System (Irreversible)✓ n=2 as ideal length.
✓ Second reaction
clearly improved theconversion.
✓ 2a side selectivity
with N-terminalcysteine.
✓ 2c exhibits lower
hydrophobicity.
Hall. D. G et al. J. Am. Chem. Soc. 2017, 139, 14285-14291.

23Synergic “Click” Boronate/Thiosemicarbazone System (Irreversible)

Hall. D. G et al. J. Am. Chem. Soc. 2017, 139, 14285-14291.

24Synergic “Click” Boronate/Thiosemicarbazone System (Irreversible)✓ Biological inertness
with biological diols.

Hall. D. G et al. J. Am. Chem. Soc. 2017, 139, 14285-14291.

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Synergic “Click” Boronate/Thiosemicarbazone System (Irreversible)✓ Inert towards biologicalelectrophiles

Hall. D. G et al. J. Am. Chem. Soc. 2017, 139, 14285-14291.

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Synergic “Click” Boronate/Thiosemicarbazone System (Irreversible)

Hall. D. G et al. J. Am. Chem. Soc. 2017, 139, 14285-14291.

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Contents
Introduction
Boronic Ester
Iminoboronate✓ Boronic Acid with ε-residue Lysine✓ Boronic Acid with N-terminal Cysteine✓ Boronic Acid with Oxyamines✓ Boronic Acid with Hydrazides

Summary28

Iminoboronate

2-formayl phenylboronic acid (2-FPBA)
2-acetyl phenylboronic acid (2-APBA)

Gao. J et al. Acc. Chem. Res. 2018, 51, 2198-2206.

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Boronic Acid with ε-residue Lysine

Gois. P. M. P et al. J. Am. Chem. Soc. 2012, 134, 10299-10305.

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Boronic Acid with N-terminal Cysteine

Gois. P. M. P et al. Chem. Sci. 2016, 7, 5052-5058.

31

Boronic Acid with N-terminal Cysteine

Gois. P. M. P et al. Chem. Sci. 2016, 7, 5052-5058.

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Boronic Acid with N-terminal Cysteine

Gao. J et al. Chem. Sci. 2016, 7, 4589-4593.

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Boronic Acid with Oxyamines

Gillingham. D et al. Chem. Sci. 2015, 6, 3329-3333.

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React with Oxyamines

Gillingham. D et al. Chem. Sci. 2015, 6, 3329-3333.

35

React with Oxyamines

Gillingham. D et al. Chem. Sci. 2015, 6, 3329-3333.

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Boronic Acid with Hydrazides✓ Stable aromatic-like structure.

Gois. P. M. P et al. Chem. Sco. Rev. 2019, 48, 3513-3536.

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Boronic Acid with Hydrazides

Gois. P. M. P et al. Chem. Sco. Rev. 2019, 48, 3513-3536.

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Short Summary

Gois. P. M. P et al. Chem. Sci. 2016, 7, 5052-5058.

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Contents
Introduction
Boronic Ester
Iminoboronate
Summary40

SummaryDiol Sources:✓ Sugars✓ Tetraserines✓ Catachol✓ Nopoldiol

Reversible order:✓ Primary amine, N-terminal
cysteine, oxyamine,
hydrazide (irreversible)
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Appendix

42

Boronic Acid

43

TCEP for Reversible Improvement

44Sugar45

Boronic Acid with N-terminal Lysine

Gois. P. M. P et al. J. Am. Chem. Soc. 2012, 134, 10299-10305.

46

Tyr-47

Boronic Acid with N-terminal Cysteine

Gao. J et al. Chem. Sci. 2016, 7, 4589-4593.

48

Boronic Acid with N-terminal Cysteine

Gao. J et al. Chem. Sci. 2016, 7, 4589-4593.

49

Boronic Acid with Hydrazides

Gao. J et al. Chem. Eur. J. 2015, 21, 14748-14752.

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Combine BE and Iminoboronate

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