ACS Medicinal Chemistry Letters
Letter
NaOH, 1% v/v DMSO, and 0.1−1.0 mM compound in ddH O at
Natural Sciences and Engineering Research Council of Canada
for the E. W. R. Steacie Memorial Fellowship Supplement.
2
each pH. Ethanolic solutions for spectroscopic analysis were as above
but also included 50% v/v anhydrous ethanol. Solutions were placed
into 1 mL quartz cuvettes, and UV/visible spectral scans were taken
from 240 to 340 nm (1 nm resolution) utilizing a Cary 100 Bio UV/
vis spectrophotometer. The final solution pH was determined by
measuring the pH of mock solutions (5 mL, lacking only compounds)
on a Radiometer pH meter calibrated against aqueous buffer solutions
using a combination electrode without correction for liquid junction
potentials.
ABBREVIATIONS
■
PBA, phenyl boronic acid; AMP, adenosine monophosphate;
ARS, Alizarin Red S
REFERENCES
■
(
1) Bross, P. F.; Kane, R.; Farrell, A. T.; Abraham, S.; Benson, K.;
Data analysis included normalization of the raw scans (Abs340 nm
) followed by calculation of the spectral difference between the acid
=
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Leighton, J.; Liang, C. Y.; Lostritto, R. T.; McGuinn, W. D.; Morse, D.
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0
spectra and the spectra obtained at every other pH. The wavelengths
of maximum positive and negative deviations were determined
graphically, and the absolute values of the absorbance difference at
the chosen wavelengths were summed. The total absorbance difference
was then plotted vs pH, and the data were fit to eq 6 to obtain the pKa.
3
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(
2
(
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potential pharmaceutical agents. Med. Res. Rev. 2003, 23 (3), 346−368.
(4) Ali, H. A.; Dembitsky, V.; Srebnik, M., Contemporary Aspects of
Boron: Chemistry and Biological Applications; Elsevier: Amsterdam,
2005; Vol. 22.
where εHA and εA− are the extinction coefficients of the acid and base
forms of the compound, respectively, and [S ] is the total compound
t
concentration. When using absorbance differences, the εHA and εA−
are simply the minima and maxima of the curve.
All KAMP values were obtained by Alizarin Red S (ARS) competitive
experiments as developed by Springsteen and Wang. Prepared were
the following solutions: solution A − 0.144 mM ARS in 0.1 M
phosphate solution, pH 7.4; solution B − 15 mM 1, 4, or 9 in solution
A. Solutions A and B were mixed such that final [benzoxaborole] =
(5) Yang, W.; Gao, X.; Wang, B. Biological and medicinal
applications of boronic acids. In Boronic Acids; Hall, D. H., Ed.;
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(6) Hunter, P. Not boring at all: Boron is the new carbon in the
quest for novel drug candidates. EMBO Rep. 2009, 10 (2), 125−128.
(7) James, T. D. Boronic acid-based receptors and sensors for
saccharides. In Boronic Acids; Hall, D. G., Ed.; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, 2005; pp 441−479.
37
1
4
.2−4.0 mM. UV absorbance measurements were taken from 450 to
60 nm to obtain maximum absorbance and plotted vs [benzoxabor-
ole]. Multiple experiments were carried out to determine an average
value of KARS for each compound. To obtain the binding constant with
AMP in the three-component assay, prepared were the following
solutions: solution C − solution B with 1, 4, or 9 was diluted with
solution A such that [benzoxaborole] = 10 mM; solution D − 250 mM
AMP in each solution C. Respective solutions C and D were mixed
such that final [AMP] = 100−200 mM. UV absorbance measurements
were taken from 450 to 460 nm to obtain maximum absorbance and
(8) Yan, J.; Fang, H.; Wang, B. Boronolectins and fluorescent
boronolectins: An examination of the detailed chemistry issues
important for the design. Med. Res. Rev. 2005, 25 (5), 490−520.
(9) James, T. D. Saccharide-selective boronic acid based Photo-
induced Electron Transfer (PET) fluorescent sensors. Top. Curr.
Chem. 2007, 277, 107−152.
(10) Galbraith, E.; James, T. D. Boron based anion receptors as
sensors. Chem. Soc. Rev. 2010, 39, 3831−3842.
18
plotted as described previously.
(11) Jin, S.; Cheng, Y. F.; Reid, S.; Li, M. Y.; Wang, B. H.
Carbohydrate recognition by boronolectins, small molecules, and
ASSOCIATED CONTENT
Supporting Information
Synthetic details and characterization of 2 and 3; each
■
lectins. Med. Res. Rev. 2010, 30 (2), 171−257.
(12) Nishiyabu, R.; Kubo, Y.; James, T. D.; Fossey, J. S. Boronic acid
building blocks: Tools for sensing and separation. Chem. Commun.
*
S
2
011, 47, 1106−1123.
compound's spectra and the subsequent pK determination
a
(
13) Rock, F. L.; Mao, W. M.; Yaremchuk, A.; Tukalo, M.; Crepin,
plots; equations for the three-component, ARS method of
binding constant determination; and binding constant deter-
T.; Zhou, H. C.; Zhang, Y. K.; Hernandez, V.; Akama, T.; Baker, S. J.;
Plattner, J. J.; Shapiro, L.; Martinis, S. A.; Benkovic, S. J.; Cusack, S.;
Alley, M. R. K. An antifungal agent inhibits an aminoacyl-tRNA
synthetase by trapping tRNA in the editing site. Science 2007, 316
(5832), 1759−1761.
AUTHOR INFORMATION
(14) Torssell, K. Zur kenntnis der arylborsauren 0.3. Bromierung der
■
*
tolylborsauren nach wohl-ziegler. Arkiv Kemi 1957, 10 (6), 507−511.
Corresponding Author
(15) Snyder, H. R.; Reedy, A. J.; Lennarz, W. J. Synthesis of Aromatic
Boronic Acids - Aldehydo Boronic Acids and a Boronic Acid Analog of
Tyrosine. J. Am. Chem. Soc. 1958, 80 (4), 835−838.
Author Contributions
J.W.T. and S.J.B. designed the research, J.W.T. determined all
(
16) Adamczyk-Wozniak, A.; Cyranski, M. K.; Zubrowska, A.;
Sporzynski, A. BenzoxaborolesOld compounds with new applica-
compound pK values and prepared the manuscript, A.P.
a
tions. J. Organomet. Chem. 2009, 694 (22), 3533−3541.
determined the binding constants, J.W.T. analyzed the data,
and D.G.H. and S.J.B. provided manuscript revisions.
(17) Dowlut, M.; Hall, D. G. An improved class of sugar-binding
boronic acids, soluble and capable of complexing glycosides in neutral
water. J. Am. Chem. Soc. 2006, 128 (13), 4226−4227.
(
18) Berube, M.; Dowlut, M.; Hall, D. G. Benzoboroxoles as efficient
ACKNOWLEDGMENTS
■
glycopyranoside-binding agents in physiological conditions: Structure
and selectivity of complex formation. J. Org. Chem. 2008, 73 (17),
We thank Anacor Pharmaceuticals, Inc., of Palo Alto, CA, for
providing samples of compounds 4−9 and Scynexis, Inc., of
Research Triangle Park, NC, for providing synthetic details and
samples of compounds 2 and 3. A.P. and D.G.H. thank the
6
471−6479.
(19) Pal, A.; Berube, M.; Hall, D. H. Design, sythesis, and screening
of a library of peptidyl bis(boroxoles) as oligosaccharide receptors in
5
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dx.doi.org/10.1021/ml200215j|ACS Med. Chem. Lett. 2012, 3, 48−52