2-Benzoylpyridine Ligand Complexation with Gold Critical for Propargyl Ester-Based Protein Labeling

Article abstract of DOI:10.1002/chem.201802058

In previously reported work, Au^III complexes coordinated with 2-benzoylpyridine ligand, BPy-Au, were prebound to a protein and used to discover a novel protein-directed labeling approach with propargyl ester functional groups. In this work, further examination discovered that gold catalysts devoid of the 2-benzoylpyridine ligand (e.g., NaAuCl4) had significantly reduced levels of protein labeling. Mechanistic investigations then revealed that BPy-Au and propargyl esters undergo a rare example of C(sp²)?C(sp) aryl–alkynyl cross-coupling, likely through spontaneous reductive elimination. Overall, these observations appear to suggest that BPy-Au-mediated, propargyl ester-based protein labeling acts via an activated ester intermediate, which contributes to our understanding of this process and will aid the expansion/optimization of gold-catalyst usage in future bioconjugation applications, especially in vivo.

Full text of DOI:10.1002/chem.201802058

A Journal of
Accepted Article
Title: 2-Benzoylpyridine ligand complexation with gold critical for
propargyl ester-based protein labeling
Authors: Yixuan Lin, Kenward Vong, Koji Matsuoka, and Katsunori
Tanaka
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201802058
Link to VoR: http://dx.doi.org/10.1002/chem.201802058
Supported by

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2-Benzoylpyridine ligand complexation with gold critical for
propargyl ester-based protein labeling
Yixuan Lin+,[a,b] Kenward Vong+,[a] Koji Matsuoka,[b] and Katsunori Tanaka*[a,c,d]
the challenges of using metals under biological environments
(ex/ maintaining reactivity in the presence of oxygen, water, and
biological thiols). Of particular interest to this paper is protein
Abstract: Previously, Au(III) complexes coordinated with
2-benzoylpyridine ligand, BPy-Au, were prebound to a
bioconjugation based on Au(III) metal catalysts; notable
protein and used to discover a novel protein-directed
examples being cysteine conjugation via allene-based probes to
labelling approach with propargyl ester functional groups.
generate 1,2/1,3-adducts,[5] and cysteine conjugation to the
In this work, further examination discovered that gold
ligands of cyclometallated Au complexes via reductive
elimination.[6] However, these methods generally have limited
NaAuCl4) had significantly reduced levels of protein
catalysts devoid of the 2-benzoylpyridine ligand (ex/
use for proteins with low levels of surface accessible free
cysteines (ex/ albumin).
labeling. Mechanistic investigations then revealed that
BPy-Au and propargyl esters undergo a rare example of
C(sp2)-C(sp) aryl-alkynyl cross coupling, likely via
spontaneous reductive elimination. Overall, these
observations appear to suggest that BPy-Au-mediated,
propargyl ester-based protein labeling acts through an
activated ester intermediate, which contributes to our
understanding of this process and will aid the
expansion/optimization of gold-catalyst usage in future
bioconjugation applications, especially in vivo.
One intriguing example of gold catalyzed protein
bioconjugation was recently described by our group.[7] In this
study, the novel concept of organ-targeting, metal-carrier
glycoalbumins was developed (Figure 1). First, to impart organ-
targeting properties, glycoalbumins (glycan-linked albumins)
were synthesized according to previous studies that discovered
specific glycan-linkages could influence biodistribution in mice
through the multivalency effects of glycoclusters.[8] As
summarized in Figure 1A, homogenous clusters of α(2,3)-
disialo-, α(2,6)-disialo-, and galactosyl-linked glycoalbumins
showed preferential accumulation onto tumor tissues, the liver,
and intestines, respectively. Next, by using the natural ligand
binding affinities of human serum albumin, these glycoalbumins
could be further modified to become transition metal carriers.
This was done by linking desired metal complexes to a coumarin
moiety, which is known as a high affinity binder to the IB
subdomain of albumin.[9] In this manner, a 2-benzoylpyridine-
Au(III) complex (BPy-Au) was anchored to albumin, which led to
Protein bioconjugation, described as the technique of covalently
linking biological molecules of interest to proteins, has been the
focus of numerous studies in the field of bioorganic chemistry.[1]
Moving away from traditional bioconjugation approaches, such
as lysine-selective (ex/ NHS ester acylation,[2] 6π-
azaelectrocylization of imines,[3] etc) and cysteine-selective
methods,[4] there has been
a growing interest towards
the serendipitous discovery of
a protein-directed labeling
developing methods of metal-catalyzed protein bioconjugation.
Several working metal-catalyzed approaches for both natural
and unnatural amino acids have already been shown in
literature,[1h-k] where they have largely succeeded in overcoming
approach with propargyl esters via gold catalysis (Figure 1B).
Using this system, the first example of localized protein labeling
on the surface of targeted organs in vivo was successfully
shown within live mice.[7]
Herein, this paper describes our initial investigations to gain
a further understanding of the protein labeling mechanism
mediated by BPy-Au complexes. As expected, our results show
that unbound, free-in-solution BPy-Au also facilitates protein
labeling (Figure 1C). However, we were surprised to find that
with other Au(III) catalysts lacking the 2-benzoylpyridine ligand,
there was a significant decrease in protein labeling (Figure 1D).
Coupled with preliminary mechanistic investigations, this work
aims to communicate the novel and unexpected reactivity of 2-
benzoylpyridine-Au(III) complexes, and its importance to our
previously developed approach of organ-targeting, metal-carrier
glycoalbumins.[7]
[a]
Y. Lin,+ Dr. K. Vong,+ Prof. K. Tanaka
Biofunctional Synthetic Chemistry Laboratory, RIKEN Cluster for
Pioneering Research
2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan
E-mail: kotzenori@riken.jp
Y. Lin,+ Prof. K. Matsuoka
Division of Material Science, Graduate School of Science and
Engineering, Saitama University
255 Shimo-Okubo, Sakura-ku, Saitama, 338-8570, Japan
Prof. K. Tanaka
Biofunctional Chemistry Laboratory, A. Butlerov Institute of
Chemistry, Kazan Federal University
18 Kremlyovskaya Street, Kazan, 420008, Russia
Prof. K. Tanaka
[b]
[c]
[d]
[+]
JST-PRESTO
2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan
These authors contributed equally to this work
Supporting information for this article is given via a link at the end of
the document.
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Glycan Composition:
×102
6.5
α(2,3)-
A)
×108
α(2,6)-
6.0
5.5
α(2,6)-
1.4
1.2
1.0
GlcNAc
Man GlcNAc
Tumor
5.0
Neu5Ac Gal GlcNAc Man
0.8
0.6
×108
glycoalbumin
[ α(2→3)Disialo ]
Liver
glycoalbumin
[ α(2→6)Disialo ]
α(2,3)-
2.5
2.0
1.5
Man GlcNAc GlcNAc
Neu5Ac Gal GlcNAc Man
Previous Work:
Various glycan-linked albumins
found to accumulate in different
organs/tumor
1.0
0.5
glycoalbumin
[ Galactosyl ]
Intestine
Man GlcNAc GlcNAc
Gal GlcNAc Man
First example of
gold-mediated
B)
reaction in vivo
inside of live mice
“labelled
protein”
fluoro
fluoro
glycoalbumin
fluoro
“bound”
BPy-Au
membrane
protein
Previous Work:
target organ surface
C)
D)
Au
fluoro
fluoro
NaAuCl4
Organ-targeting,
metal-carrier
glycoalbumins
fluoro
“unbound”
BPy-Au
This work:
Compounds used
in this study:
Figure 1. Overview of organ-targeting, metal-carrier glycoalbumins. A) Organ-targeting properties are conferred via albumin linkage to various types of glycans.
The composition of α(2,3)-disialo-, α(2,6)-disialo-, and galactosyl-based glycans are as shown. B) Metal-carrier properties are given by anchoring a BPy-Au
complex via coumarin linkage (compound 13). Localized protein labeling on targeted mouse organs was observed. Further investigations into reactivity show
that C) unbound BPy-Au 8 also facilitates propargyl ester-based protein labeling and D) other gold catalysts devoid of 2-benzoylpyridine complexation have
significantly reduced levels of protein labeling.
To begin, various compounds were synthesized, as outlined
in the Supplementary Information. The propargyl ester-
containing fluorophore 6 was synthesized in 32% overall yield in
accordance to previous studies.[7, 10] In terms of gold catalysts,
BPy-Au 8 was synthesized according to literature.[6, 11] By further
adding a coumarin moiety to 8 via a PEG linker, the synthesis of
coumarin-BPy-Au 13 was obtained in 7% overall yield.[7] For
NaAuCl4, a commercial source was used. For the construction of
albumin complexed with coumarin-BPy-Au 13,[7] the procedure
outlined in the Supplementary Information was followed. Protein
complex formation was further confirmed via binding
fluorescence measurements, as explained in Figure S2.
depicted in Figure 2A, “unbound gold” represents a situation
where albumin labeling is facilitated by free-in-solution BPy-Au 8.
On the other hand, "bound gold" represents when the gold
catalyst is inherently anchored to albumin, which is done through
the use of coumarin-BPy-Au 13. As a negative control, metal-
free “no gold” conditions were also tested.
Upon incubation with TAMRA-linked propargyl ester 6, time-
dependent fluorescence measurements of the three reaction
conditions were taken. As shown in Figure 2B and S3,
observations indicate that protein labeling with free, unbound
gold catalyst 8 (Figure 2B, black diamond) proceeded to a
greater degree compared to protein bound gold catalyst (Figure
2B, grey squares).
In this study, the degree of labeling reactivity between
"unbound gold" and "bound gold" protein was compared. As
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Unbound Gold
Bound Gold
A)
TAMRA
TAMRA
TAMRA
No Gold
TAMRA
TAMRA
200
λex = 540 nm/λem = 565nm
B)
"Unbound Gold"
albumin + BPy-Au + propargyl
ester 6
150
100
50
8
"Bound Gold"
albumin-coumarin- + propargyl
BPy-Au 13 ester 6
"No Gold"
albumin + propargyl
ester 6
0
0
5
10
15
20
25
Time (hr)
kDa
kDa
28
C)
D)
72
coomassie
staining
55
43
17
28
72
fluorescence
imaging
albumin-linked
coumarin-BPy-Au 13
×
×
albumin
× ×
× ×
streptavidin
NaAuCl4
× × ×
×
×
BPy-Au 8
×
×
×
× ×
Propargyl ester 6
× × × ×
Figure 2. Protein labeling experiments to confirm reactivity. A) Illustrative representation of unbound, bound, and no gold protein labeling conditions. B)
Time-dependent monitoring of protein fluorescence under unbound, bound, and no gold protein labeling conditions. C) SDS-PAGE analysis to determine
propargyl ester-based labeling of albumin under various conditions. D) SDS-PAGE analysis to determine propargyl ester-based labeling of streptavidin
under various conditions.
To further confirm albumin labeling, various reaction
conditions were analyzed by SDS-PAGE (Figure 2C and S4).
Results show that albumin labeled under "unbound gold"
conditions (Figure 2C, Lane 2) was more fluorescent compared
to albumin labeled under "gold bound" conditions (Figure 2C,
Lane 3); densitometry analysis of these bands are shown in the
Supporting Information. In terms of the control conditions, none
of albumin incubated with propargyl ester 6 (Figure 2C, Lane 4),
albumin only (Figure 2C, Lane 5), albumin-linked coumarin-BPy-
Au only (Figure 2C, Lane 6), and reagents 8 and 6 only (Figure
2C, Lane 7) showed fluorescent albumin bands.
benzoylpyridine ligands (ex/ BPy-Au 8, coumarin-BPy-Au 13)
compared to others (ex/ NaAuCl4). This reactivity was confirmed
by SDS-PAGE analysis, where albumin labeled under NaAuCl4
incubation (Figure 2C, Lane 1) was shown to emit significantly
lower levels of fluorescence compared to albumin labeled under
BPy-Au containing conditions.
Another experimental condition confirmed that BPy-Au-
catalyzed, propargyl ester-based labeling could be transferred to
other proteins. With streptavidin, various conditions were tested
and analyzed by SDS-PAGE (Figure 2D). Using BPy-Au 8 as a
catalyst, labeling of streptavidin was successfully observed
(Figure 2D, Lane 10) and was more fluorescent compared to the
controls; streptavidin incubated with propargyl ester 6 (Figure 2D,
Lane 9), and streptavidin only (Figure 2D, Lane 8).
During the course of this study, an unexpected observation
noticed that propargyl ester-based protein labeling proceeded
significantly more with Au(III) catalysts coordinated to 2-
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yield. This is in contrast to the use of propargyl ester 14 under
similar conditions, which results in almost negligible yield.
Additionally, it should be noted that stable Au(III) complexes
have shown the inherent ability in several literature examples to
undergo spontaneous reductive elimination to form C(sp2)-
C(sp2),[12] C(sp2)-S,[6] C(sp2)-P,[13] and C(sp2)-CF3 bonds,[14] all
which proceed under various mild conditions (Figure 3B). To the
best of our knowledge, our example is the first to facilitate
C(sp2)-C(sp) bond formation from terminal alkynes. The only
other relevant example of C(sp2)-C(sp) bond formation requires
visible light mediation and the use of alkynyltrimethylsilanes
(transmetallation from the organosilane is said to be needed for
reactivity).[15]
fluoro
“activated ester
intermediate”
fluoro
fluoro
propargyl ester
probe
fluoro
target organ surface
Figure 4. Proposed mechanism of BPy-Au-mediated, propargyl ester-based
protein labeling, which likely acts through ester activation via initial aryl-alkynyl
cross coupling.
In conclusion, this work was able to gather sufficient
evidence to formulate two new conclusions regarding BPy-Au-
mediated, propargyl ester-based protein labeling. First, protein
labeling does not necessitate the gold catalyst to be prebound to
a protein, which was the situation mainly employed in a previous
work by our group.[7] This study shows that unbound, free-in-
solution gold catalysts also have the ability to facilitate propargyl
ester-based protein labeling, which consistently shows a higher
degree of reactivity compared to its "bound gold" equivalent. The
differences in labeling reactivities is likely explained by the fact
that "bound gold" reactivity is limited to nearby surface amine
residues, whereas "unbound gold" reactivity possibly acts on all
protein surface amines. In addition, protein labeling is not limited
to just albumin, as reactivity with streptavidin was also observed.
Second, an unexpected observation showed that if gold
catalysts are devoid of 2-benzoylpyridine ligand coordination
(ex/ NaAuCl4), protein labeling proceeded to a significantly lower
degree. This suggests that BPy-Au-mediated protein ligation
likely acts through an activated ester intermediate, which then
increases the rate of amide bond formation with protein surface
amines, as depicted in Figure 4. In addition, the observation of
the unexpected activated ester intermediate formation by aryl-
alkynyl cross coupling represents a rare synthetic example of
C(sp2)-C(sp) bond formation from the spontaneous reductive
elimination of Au(III) complexes.
Figure 3. A) Observed cross-coupling reaction between propargyl ester 14
and BPy-Au 8 to produce the active ester intermediate 15, which forms
through reductive elimination of the formed Au(III) complex to trigger C(sp2)-
C(sp) bond formation. Subsequent studies to monitor lysine amidation reveal
higher yields are obtained with activated ester 15 compared to ester 14. B)
Select literature examples of other types of bond formation via reductive
elimination of Au(III) complexes under mild conditions.
To further understand the importance and role of 2-
benzoylpyridine ligand coordination for gold-catalyzed propargyl
ester protein ligation, mechanistic investigations were conducted.
Preliminary results show that when propargyl ester compound
14 was incubated overnight in DMF under basic conditions with
only BPy-Au 8, the unexpected product 15 could be cleanly
purified in 52% yield (Figure 3A). Other constituents in the
reaction mixture were found to be unreacted starting material. In
principal, compound 15 is the cross-coupling product between
the propargyl ester and 2-benzoylpyridine. It is hypothesized that
this transformation likely creates an “activated ester intermediate”
when coordinated with remaining gold species in solution. This
could then lead to an increase in the rate of amide bond
formation with protein surface amines (ex/ lysines). As a model
study, compound 15 was incubated with AuI, which acts as a
representative gold(I) species that would be present following
reductive elimination-based cross coupling. Further reaction with
N-Ac-Lys-OMe then gave the expected amide product 16 in 40%
It should be noted that gold itself is known to be a π-philic
metal catalyst. Although the use of BPy-Au catalyst complexes
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amounts of desired product using unligated gold, such as
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direct conversion of 14 to 16 gives trace yields <1%). In this
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propargyl ester by coordinating to the alkyne moiety. One could
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glycoalbumin surfaces may in fact be facilitated by simple gold-
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This work was supported by JSPS KAKENHI Grant Numbers
JP16H03287, JP16K13104, and JP15H05843 in Middle
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from the Russian Government “Program of Competitive Growth
of Kazan Federal University among World’s Leading Academic
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using the Molecular Imager FX, Common Use Equipment, in the
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Keywords: Gold catalysis • protein conjugation • aryl-alkynyl
cross coupling
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Entry for the Table of Contents
COMMUNICATION
Yixuan Lin, Kenward Vong, Koji
Matsuoka, Katsunori Tanaka*
“activated
ester
intermediate”
fluoro
Page No. – Page No.
fluoro
fluoro
fluoro
2-Benzoylpyridine ligand
complexation with gold critical for
propargyl ester-based protein
labeling
2-Benzoylpyridine-Au(III) complexes mediate propargyl ester protein labeling
likely through an activated ester intermediate. Previous research showed gold-
catalyzed protein bioconjugation could proceed in vivo, but it’s mechanism was not
fully understood. In this work, further examination discovers that coordinated 2-
benzoylpyridine ligands are crucial for reactivity. This is hypothesized to proceed
through a rare example of C(sp2)-C(sp) aryl-alkynyl cross coupling.
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