asymmetric complexes would be useful for obtaining structural
information about protein surfaces that is necessary for
inhibitor design. Changing the central metal ion from the
ruthenium(II) to a ferric ion would lead to a fast ligand-
exchange system, which may be applicable to a dynamic
combinatorial approach. Work towards this goal is currently
in progress.
This work was supported by the Takeda Science
Foundation, the Naito Foundation, and the Suzuken Memorial
Foundation. We thank T. Enomoto for synthesizing
compound 2, and Prof. K. Yamaguchi for mass analysis of
1 and 2. J.O. sincerely thanks Profs. H. Ishida and A. D.
Hamilton for helpful discussions and suggestion for mass
analysis of 3.
Fig. 3 Inhibition activity of compounds 1–4 (75 mM) against a-ChT
(1.5 mM). Assays were carried out using the chromogenic substrate
BTNA (100 mM) in 5 mM phosphate buffer (pH 7.4, 30 1C).
The standard deviation is given for n = 3–7.
Notes and references
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not interfere with the substrate binding to the active site.
A computationally generated model suggests that a ternary
complex formation of 3a : ChT : BTNA is possible; when 3a
binds to the targeted positively charged surface of ChT, there
still seems to be enough space available for BTNA to bind to
the active site (see Fig. S3 in ESI).w Based on the model, a
plausible explanation for the inhibition mechanism is that,
while BTNA still binds to the active site, binding of 3a to the
surface of ChT may induce the conformational change of the
protein to diminish the enzyme activity. This may account for
the relatively low inhibition activity of 3a despite of its
submicromolar affinity for ChT.
In conclusion, the dendritic ruthenium tris(bipyridine)
complex 3a presented in this paper was shown to be a strong
binder to ChT with submicromolar affinity. The observation
of 1 : 2 complex formation between 3a and ChT may lead
to further applications in protein assembly engineering.5
Compound 3a also showed inhibition activity against ChT
while the activity remains moderate. This structurally tuneable
scaffold may prove useful in the investigation of structure–
activity relationships for protein surface-directed inhibitors.
Asymmetrical structural diversity may be readily introduced
to these metal complexes using methods such as stepwise
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a metal complex library including
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12 Luminescence data were analyzed using Hyperquad2006 and
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13 R. M. C. Dawson, D. C. Elliott, W. H. Elliott and K. M. Jones,
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Fig. 4 Kinetic analysis of the inhibition of ChT by 3a. ChT was
treated with varying concentrations of 3a (0 (K), 10 (J), and
30 (.) mM) with the substrate (BTNA) concentration was increased
from 12.5 to 75 mM. T = 297 K.
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6949–6951 | 6951