N,O-Iminoboronates: Reversible Iminoboronates with Improved Stability for Cancer Cells Targeted Delivery

Article abstract of DOI:10.1002/chem.201802515

Herein a new class of iminoboronates obtained from 2-acetylbenzene boronic acids and aminophenols is presented. The N,O-ligand topology enabled the formation of an additional B?O bond that locks the boron center in a tetrahedral geometry. This molecular arrangement decisively contributes to improve the construct′s stability in biocompatible conditions and retaining the iminoboronate reversibility in more acidic environments. 2-Acetylbenzene boronic acid was reacted with a fluorescent amino-coumarin to yield a stable and non-fluorescent N,O-iminoboronate. This mechanism was further used to assemble a folate receptor targeting conjugate that selectively delivered the fluorescent amino-coumarin to MDA-MB-231 human breast cancer cells.

Full text of DOI:10.1002/chem.201802515

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Accepted Article
Title: N,O-Iminoboronates: Reversible Iminoboronates with Improved
Stability for Cancer Cells Targeted Delivery
Authors: Ricardo Lopes, Ana Ventura, Liana Silva, Hélio Faustino, and
Pedro Miguel pimenta Gois
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To be cited as: Chem. Eur. J. 10.1002/chem.201802515
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N,O-Iminoboronates: Reversible Iminoboronates with Improved
Stability for Cancer Cells Targeted Delivery
Ricardo M. R. M. Lopes,[a] Ana E. Ventura,[a,b] Liana C. Silva,[a,b] Hélio Faustino,*[a] Pedro M. P. Gois,*[a]
Abstract: Herein we present a new class of iminoboronates
obtained from 2-acetylbenzene boronic acids and aminophenols.
The N,O-ligand topology enabled the formation of an additional B-O
bond that locks the boron centre in a tetrahedral geometry. This
molecular arrangement decisively contributes to improve the
construct stability in biocompatible conditions, retaining the
iminoboronate reversibility in more acidic environments. 2-
Acetylbenzene boronic acid was reacted with a fluorescent amino-
coumarin to yield a stable and non-fluorescent N,O-iminoboronate.
This mechanism was further used to assemble a folate receptor
targeting conjugate that selectively delivered the fluorescent amino-
coumarin to MDA-MB-231 human breast cancer cells.
synthesis of responsive materials[18–20] or in the discovery of
innovative inhibitors of protein-protein interactions.[21] One of the
most important attributes of iminoboronates is their inherent
reversibility, which can be accelerated by endogenous
molecules like glutathione (GSH), fructose or dopamine.[6,8,14,22]
However, recent studies showed that iminoboronates also
hydrolyse spontaneously under physiological conditions.[23,24]
This lack of stability constitutes an important limitation, when
envisioning the use of this reversible linkage in the construction
of stimulus responsive conjugates, to deliver cargo selectively to
cancer cells.[8,25] Based on this issue, we set-out to improve the
stability of iminoboronates aiming at their use in the synthesis of
reversible linkers for targeting conjugates.
Recently we and Gao independently observed that the reaction
of 2-formylbenzene boronic acid (2FBBA) with cysteine
generates a fused tricyclic structure due to the formation of an
additional reversible bond between the boron atom and the
carboxyl group.[26,27] Density functional theory calculations
performed on this system have revealed that this B-O bond
contributes decisively to the stabilization of the product but does
not compromise the system's reversibility.[27] In this context,
Bane also described the formation of stabilized hydrazones
using α-amine carbohydrazides and 2-formylbenzene boronic
acids.[28] Based on these observations, we envisioned that a
strategy to improve these construct’s stability would be to design
a N,O-bidentate ligand that enables the formation of the
iminoboronate with an additional B-O bond Scheme 1.
Nature explores an array of ligation strategies to construct
functional molecules that support most of the biological
processes essential to life. Noncovalent interactions including
hydrogen bonding, electrostatic and hydrophobic interactions,
have been long established as the basis for the assembly of
reversible molecular complexes that are able to engage in
dynamic processes.[1] On the other side of the spectrum, the use
of covalent bonds typically generates more stable compounds
that often exert their activity based on their structure integrity.[2,3]
Merging the stability and reversibility attributes in the same
bonding motif is a rarer event. Though disulfide bonds stand as
a prominent example in Nature of a covalent bond that under
redox regulation is reversible, and because of that, controls
important processes such as protein folding.[4] Recent
appreciation for the unique properties of reversible-covalent
bonds resulted in their use to design enzyme inhibitors, dynamic
covalent libraries or stimulus responsive multivalent molecules.[5]
Iminoboronates are
a class of reversible-covalent based
compounds in which an imine is stabilized by the coordination
with an adjacent boronic acid.[6–13] In 2012 we used this strategy
to perform the reversible functionalization of the -amino group
of lysine residues exposed on the surface of proteins,[14] and
later, to generate cancer cell targeting folic-acid fluorescent
conjugates.[15] Since then, we and others have used
iminoboronates in areas as diverse as bioconjugation,[16,17]
[a]
R. Lopes, A. E. Ventura, Dr L. C. Silva, Dr. H. Faustino, Prof. P.
M. P. Gois
Research Institute for Medicines (iMed.ULisboa)
Faculty of Pharmacy, Universidade de Lisboa
Lisbon (Portugal)
E-mail: pedrogois@ff.ulisboa.pt
A. E. Ventura, Dr L. C. Silva
Centro de Química-Física Molecular and Institute of
Nanoscience and Nanotechnology,
Instituto Superior Técnico, Universidade de Lisboa,
Lisboa, Portugal.
Scheme 1. Left: Previously reported iminoboronate formation. Top:
Thiazolidine formation with additional bond between the boron and the
carboxylic acid. Right: unwanted oxazinane formation. Bottom: current
proposal for iminoboronate formation with improved stability.
[b]
To test this idea we selected as prerequisites for the ligand
design the presence of a primary aliphatic amine to form the
iminoboronate and a hydroxyl function with improved reactivity
towards the boron centre (Scheme 1). Based on these
Supporting information for this article is given via a link at the
end of the document.((Please delete this text if not
appropriate))
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requirements, we selected aminophenols 1 and 2 as prime
candidates to generate N,O-iminoboronates because they
exhibit the required nucleophiles and are able to accommodate
the N-B-O bonds in a more rigid six member ring. Therefore, the
synthesis of aminophenols 1 and 2 (figure 1) was performed
following reported methodologies.[29,30]
Gratifyingly, as shown in Scheme 3, the reaction with
aminophenol 1 afforded 8 in 42% yield under basic conditions
while the condensation with 2, proceeded smoothly in water to
afford the N,O-iminoboronate 5 in 72% yield. Suitable crystals
for X-ray analysis were obtained for N,O-iminoboronate 8. As
shown in Scheme 3, the structure of 8 confirmed the expected
fused bicyclic unit comprising the iminoboronate and the
formation of the B-O bond that locks the boron centre in a
tetrahedral geometry.
Figure 1. Selected aminophenols and 2ABBA.
Once prepared, we tested if this amine topology could render
the desired N,O-iminoboronates. To study this, a competition
experiment was performed in which equimolar amounts of
benzylamine 3 and aminophenol 2 were added to a solution of
2-acetylbenzene boronic acid (2ABBA) in D2O:DMSO-d6. The
reaction was monitored by 1H-NMR and the analysis of the
spectra depicted in Scheme 2, revealed that just after one 1 min.
the 2ABBA component was completly consumed to produce a
3.3:1 mixture of iminoboronates 4 and 5 respectivly. Gradually,
this ratio shifted towards the formation of 5, and after 12h, the
N,O-iminoboronate become the major product (ratio 1:6 of 4 to
5) in the mixture. These results clearly indicate that, although the
iminoboronate 4 is kineticaly favoured, the improved stability
promoted by the N,O-bidentate ligand shifts the equilibrium to
the formation of the more stable N,O-iminoboronate 5. Under
these conditions, the formation of oxazinane was never
observed.
Scheme 3.Reactions of 2ABBA or 2FBBA (2 equiv.) with aminophenols 1 and
2 in water (0.3 mM). ORTEP-3 diagram of 8, using 30% probability level
ellipsoids. CCDC 1823602 (8) contain the supplementary crystallographic data
for this paper. These data are provided free of charge by the Cambridge
Crystallographic Data Centre.
Once established the preparation of N,O-Iminoboronates, their
stability was evaluated in different biocompatible medias. In a
D2O:DMSO (5:1) mixture, compound 8 (20mM) proved to be
quite stable as no hydrolysis was detected over one week period
and upon a 10 fold dilution (2mM) (SI, figures S 3-7). In PBS
buffer (0.1 mM) at pH 7.4, N,O-Iminoboronate 8 presented less
then 10% hydrolysis after 48h, and simillar results were obtained
in the presence of frutose and dopamine. Importantly, in human
plasma, compound 8 hydrolized less than 20% after 48h (SI,
tables S2 - S8 and figures S20 - S26). Encouraged by these
results, we next studied if these constructs could still engage in
reversible mechanisms. Therefore, compound 8 (20mM) was
submitted to a cross reactivity experiment with aminophenol 2 (2
equiv., D2O:DMSO). Gratifyingly, despite been a slow process,
Scheme 2.Competition experiment between 2 (1.5 equiv.) and 3 (1.5 equiv.) in
the presence of 2ABBA (22 mM). The solvent residual peak of HOD was
removed for clarity; similar results were obtained in deuterated PBS pH 7.4
(see supporting information for the full 1H-NMR spectra).
Next, different N,O-iminoboronates were synthesized aiming at
the evaluation of their stability and reversibility properties. This
study was initiated with the reaction of aminophenols 1 and 2
with 2FBBA in aqueous media. Unfortunately, although it was
under these conditions
8 slowly converted into 5 (50%
conversion in days). These results indicate that the
5
1
possible to detected by H-NMR the presence of the expected
additiononal B-O bond contributed to improve the iminoboronate
stability but, very importantly, did not preclude its reversible
nature.
N,O-iminoboronates 6 and 7 in the reaction crude mixture, this
reaction generated an inseparable mixture of products.[31] Hence,
the same transformation was attempted with 2ABBA.
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in Scheme 5, the amino coumarin 10 proved to be highly
fluorescent in aqueous media (f = 0.80) while the N,O-
iminoboronate formation resulted in a remarkable decrease (f =
0.025) of the coumarin 10 fluorescence which confirmed the
proposed switch-off mechanism induced by the formation of the
B-O bond.
Next the stability and reversibility of 11 was monitored in PBS.
As in the previous cases, also the N,O-iminoboronate 11 proved
to be quite stable under these conditions with less than 12%
hydrolysis over 7 days.[34] Differently, when incubated in PBS at
lower pHs (3-6), 11 underwent hydrolysis with the concomitant
release of the coumarin 10. This process was confirmed by a
notorious enhancement of the fluorescence in the reaction
mixture as shown in Scheme 6.
Once established the stability and controlled reversibility of 11,
this bonding motif was used in the assemblage of a cancer cell
folate receptor targeting conjugate, featuring an acidic mediated
turn-on fluorescence. With this objective the 2ABBA component
was modified to include an azide group, envisioning the
construct post-functionalization via a strain promoted azide-
alkyne cycloaddition. Next the 14[16] was reacted with coumarin
10 under aqueous conditions to prepare the N,O-iminoboronate
15 in 84% yield. Finally the cyclooctyne-folate targeting unit 16
was prepared based on reported methodologies[35] and installed
on 15 to generate the conjugate 17.
Motivated by these results, we questioned if N,O-
Iminoboronates would exhibit a biocompatible mechanism of
reversibility that could be explored for targeted delivery. Cancer
cells are well known to exhibit moderately acidic subcellular
compartments (early endosomes – pH 6.3 and lysosomes – pH
4.5) and higher concentrations of cytoplasmic glutathione
(GSH).[18] These particular characteristics are often explored to
promote the intracelluar dissociation of functional conjugates.
Therefore, the stability of compound 8 was studyed in PBS
(1mM) at different pHs and in the presence of GSH. Regarding
the pH, compound 8 exhibit less than 20% hydrolysis after 1
week in PBS (1mM) at 6.3 while at lysosomal pH (PBS, pH 4.5)
the construct hydrolysed much faster (5.8h half-life), confirming
the reversibility of N,O-Iminoboronates in more acidic
environments. Regarding the stability under reducing conditions,
we have recently observed that GSH can promote the hydrolysis
of iminoboronate complexes via thiol addition to the more
electrophilic imine carbon centre.[18] Based on these results, we
anticipated that N,O-iminoboronates could undergo a similar
mechanism of hydrolysis in the presence of GSH. To explore
this mechanism, compound 8 (1 mM) was incubated with 10 and
100 equiv. of GSH in ammonium acetate solution (20 mM, pHs
7.4). The analysis of the reaction mixtures by ESI-MS revealed
the formation of an adduct of GSH with 8 (tentatively assigned
as adduct I, [M+H]+= 559; [M-OH]+=541; Scheme 4 and Figure
S9 in SI). Interestingly, despite the formation of adduct I, the
presence of GSH had no impact on the construct 8 stability in
PBS (pH 7.4) probably due to the reversible nature of I.
Therefore, it is not possible to ascertain the impact of
intracellular GSH on the construct hydrolysis.
4000
10 (34 M)
11 (34 M)
2000
0
400
500
600
Wavelength (nm)
Scheme 4. Conjugate 8 (0.1 mM) in the presence of GSH (1.0 mM).
All together, these results suggest that the intramolecular
formation of a B-O bond stabilizes the iminoboronate under
aqueous conditions, but it does not preclude the reversible
nature of these constructs. Therefore, N,O-iminoboronates were
next applied in the synthesis of a reversible conjugate to engage
in targeted deliver to cancer cells. For the construction of this
conjugate, folic acid was selected as the targeting unit because
many cancer cells over-express internalizing surface receptors
for this small vitamin.[32,33] Regarding the conjugate’s cargo, a
fluorescent phenolic dye was selected, because we anticipated
that the formation of the B-O bond would lead to the probe
switch-off, while the construct hydrolysis would restore the probe
fluorescence. If successful, this fluorescence off-on mechanism
would be instrumental to signal the N,O-iminoboronate
intracellular reversibility. Hence, to test this concept, the amino
coumarin 10 was synthesised from 8-acetyl-7-hydroxy-coumarin
9 and then reacted with 2ABBA to yield the expected N,O-
iminoboronate 11 in 61%. Monitoring the process by UV-Vis
spectroscopy under pseudo first order conditions, reveal that this
reaction proceeds with a k2 = 32 ± 4 M-1h-1. Then, the
photophysical properties of 10 and 11 were evaluated. As shown
Scheme 5. Top: Synthesis of 11 and fluorescence of 10 (1 mM in water) and
11 (1 mM in water) when irradiated by a 365 nm lamp. Bottom: Fluorescence
spectra (ex = 323 nm) of 10 (34M) and 11 (34M) in PBS pH 7.4.
Finally, the selective delivery of the fluorescent probe to cancer
cells was studied using MDA-MB-231 human breast cancer cells
that are well known to overexpress folate receptors. Hence, this
cell line was treated with conjugate 17 and the internalization
progress was monitored by confocal microscopy. Images
obtained at 10 and 30 minutes (see SI for details) clearly
showed the fluorescent coumarin probe dispersed throughout
the cell cytoplasm, confirming the successful iminoboronate
entry into the cells and the construct hydrolysis. Differently, the
iminoboronate 15 in the same conditions, failed to deliver the
fluorescent coumarin. This observation is a good indication of
the vectorization induced by the folic acid unit used in conjugate
17.
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Acknowledgements
in PBS (pH 7.4) over 1 week
2ABBA (34 M)
10 (34 M)
11 (34 M)
150000
100000
50000
0
0.4

ex = 323 nm
0.3
pH 3
pH 4
We acknowledge the financial support of Fundação para a
Ciência Tecnologia (FCT) Portugal (grants:
e
a
0.2
0.1
0.0
pH 5
pH 6
SFRH/BD/121664/2016,
SFRH/BD/104205/2014
PTDC/BBB-BQB/3719/2014;
SAICTPAC/0019/2015,
SFRH/BPD/102296/2014,
PTDC/QEQ-QOR/1434/2014,
FEDER-029967;
pH 7
250
300
350
400
450
400
500
Wavelength (nm)
600
Wavelength (nm)
iMed.ULisboa
grant
UID/DTP/04138/2013. L.C. Silva is a FCT Investigator 2014
(IF/00437/2014).
Scheme 6.Top: UV − Vis spectra of 2ABBA, 10 and 11 in PBS pH 7.4.
Stability of 11 (34 M) in PBS (pH 7.4) over 1 week. Bottom: Fluorescence
spectra (λex = 323 nm) of 11 (34 µM) after 1h incubation in PBS at 37 ºC at pH
values between 3 and 7.
Keywords: boronic acids · drug delivery · small-molecule–drug
conjugates · iminoboronate · reversibility
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Chemistry - A European Journal
COMMUNICATION
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Ricardo Lopes, Ana E. Ventura, Liana C.
Silva, Hélio Faustino,* Pedro M. P.
Gois,*
Page No. – Page No.
N,O-Iminoboronates: Reversible
Iminoboronates with Improved
Stability for Cancer Cells Targeted
Delivery
Text for Table of Contents
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