Rhodamine triazole-based fluorescent probe for the detection of Pt 2+

Article abstract of DOI:10.1021/ol102397n

A rhodamine triazole-based fluorescent chemosensor has been developed for the selective detection of platinum ions in aqueous solutions. The rhodamine 6G hydroxamate linked with a propargyl group is converted to the corresponding triazole by a click reaction. The dual binding unit composed of a hydroxamate and a triazole shows high selectivity and sensitivity toward Pt ²⁺ over a range of other metal ions in water. The fluorescent probe is applied to monitor cisplatin in aqueous solutions.

Full text of DOI:10.1021/ol102397n

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5342-5345
Rhodamine Triazole-Based Fluorescent
Probe for the Detection of Pt2+
Hyemi Kim, Sunho Lee, Jihyun Lee, and Jinsung Tae*
Department of Chemistry, Yonsei UniVersity, Seoul 120-749, Korea
jstae@yonsei.ac.kr
Received October 4, 2010
ABSTRACT
A rhodamine triazole-based fluorescent chemosensor has been developed for the selective detection of platinum ions in aqueous solutions.
The rhodamine 6G hydroxamate linked with a propargyl group is converted to the corresponding triazole by a “click” reaction. The dual
binding unit composed of a hydroxamate and a triazole shows high selectivity and sensitivity toward Pt2+ over a range of other metal ions
in water. The fluorescent probe is applied to monitor cisplatin in aqueous solutions.
Platinum has many uses such as dental crowns, catalytic
converters, fuel cells, jewelry, and anticancer drugs. Par-
ticularly, platinum complexes, such as cisplatin, carboplatin,
and oxaliplatin, are widely used as anticancer drugs.1
Although platinum-based chemotherapy is crucial for the
treatment of many types of cancer, it is considered as
potentially hazardous to human health.2 Platinum salts can
cause DNA alterations, cancers, autoimmune disorders,
respiratory and hearing problems, and damages to organs,
such as the intestine, kidney, and bone marrow.3
equipment. A fluorescent chemosensor method would be
more desirable because it is less labor-intensive and highly
sensitive. Recently, the Koide group reported fluorescent
methods for the detection of platinum species using the
Tsuji-Trost allylic oxidative insertion mechanism.5 In this
detection system, the ionic platinum species (Pt2+ and Pt4+)
are reduced by phosphine to Pt0. Herein, we report a
fluorescent detection method of Pt2+ directly from aqueous
solutions without reduction to Pt0 by using a rhodamine
hydroxamate-based probe.
Whereas the “click triazole” has been frequently utilized
as an interconnector between two functional entities in the
areas of functional materials, biology, polymer science, drug
discovery, etc.,6 its potential as a metal coordination platform
has been underexplored. Recently, 1,4-disubstituted 1,2,3-
triazoles have been employed as a binding unit for metal
ions, such as K+,7 Ca2+,8 Zn2+,9 Cu2+,10 Hg2+,11 Cd2+,12
Analytical methods,4 such as atomic absorption spectrom-
etry (AAS) and inductively coupled plasma mass spectrom-
etry (ICP-MS), are often used to detect platinum in biological
and environmental samples. However, these methods often
need serious sample-preparation steps or require expensive
(1) (a) Reedijk, J. Pure Appl. Chem. 1987, 59, 181–192. (b) Cepeda,
V.; Fuertes, M. A.; Castilla, J.; Alonso, C.; Quevedo, C.; Pe´rez, J. M.
Anticancer Agents Med. Chem. 2007, 7, 3–18.
(2) (a) Platinum; World Health Organization: Geneva, 1991. (b)
Hartmann, J. T.; Lipp, H.-P. Expert Opin. Pharmacother. 2003, 4, 889–
901.
(4) (a) Jakubowski, N.; Feldmann, I.; Stuewer, D. J. Anal. At. Spectrom.
1997, 12, 151–157. (b) Welters, M. J. P.; Fichtinger-Schepman, A. M. J.;
Baan, R. A.; Jacobs-Bergmans, A. J.; Kegel, A.; Van Der Vijgh, W. J. F.;
Braakhuis, B. J. M. Br. J. Cancer 1999, 79, 82–88. (c) Ghezzi, A. R.; Aceto,
M.; Cassino, C.; Gabano, E.; Osella, D. J. Inorg. Biochem. 2004, 98, 73–
78. (d) Klein, A. V.; Hambley, T. W. Chem. ReV. 2009, 109, 4911–4920.
(5) (a) Garner, A. L.; Koide, K. Chem. Commun. 2009, 83–85. (b)
Garner, A. L.; Koide, K. Chem. Commun. 2009, 86–88.
(3) (a) Schiller, J. H.; Bittner, G. Clin. Cancer Res. 1999, 5, 4287–
4294. (b) Rudolph, E.; Hann, S.; Stingeder, G.; Reiter, C. Anal. Bioanal.
Chem. 2005, 382, 1500–1506. (c) Danford, A. J.; Wang, D.; Wang, Q.;
Tullius, T. D.; Lippard, S. J. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 12311–
12316. (d) Ahmad, S. Chem. Biol. 2010, 7, 543–566.
10.1021/ol102397n  2010 American Chemical Society
Published on Web 10/27/2010

Pd2+,13 and Al3+,14 in the design of fluorescent chemosensors.
However, rhodamine-triazole conjugates have not been
reported as binding units to trigger the ring opening of the
rhodamine spirolactam.15,16
Thus, we envisioned that introduction of a triazole moiety
into the rhodamine hydroxamate could provide a well-
organized coordination platform for metal ions (see a
proposed complex structure A in Scheme 1). The triazole
Probe 1 shows neither color nor fluorescence in H2O
(DMSO 1% v/v) indicating that it exists in the spirocyclic
form predominantly as expected. On treatment with 5.0 equiv
of Pt2+ ions, probe 1 (5 µM) exerts strong fluorescence at
562 nm in H2O (DMSO 1% v/v). In addition, the solution
changes from colorless to pink-red color. Probe 1 could
monitor Pt2+ ions in the pH 5-9 range (see Supporting
Information).
Fluorescence titration of 1 (5 µM) with Pt2+ was conducted
by using an H2O (DMSO 1% v/v) solution at 25 °C. Upon
each addition of Pt2+, the solution is incubated for 30 min
and then fluorescence intensity is measured. About 2.0 equiv
of Pt2+ is required for the saturation of the fluorescence
intensity under the titration conditions (Figure 1a). The Job’s
plot20 shows that 1 forms a 1:1 complex with Pt2+ (see
Supporting Information). The binding constant (log K ) 5.2
( 0.7) calculated in an H2O (DMSO 1% v/v) solution from
the fluorescence titration experiments based on the 1:1
binding model shows strong binding ability of 1 with Pt2+.
Addition of ethylenediamine to the mixture of 1 and Pt2+
decreases the fluorescence intensity of the solution, which
implies the reversible binding between 1 and Pt2+ (see
Supporting Information), and the fluorescence titration of Pt2+
at 0.5 µM concentration of 1 demonstrates that the detection
of Pt2+ is possible at the 125 nM level. Under these
conditions, the fluorescence intensity of 1 is linearly pro-
portional to the amount of Pt2+ (Figure 1b).
Next, the fluorescence responses of 1 (5 µM) to other
biologically relevant metal ions in H2O (DMSO 1% v/v) were
examined. Upon additions of 5.0 equiv of metal ions (Pt2+,
Fe3+, Fe2+, Hg2+, Zn2+, Pb2+, Ca2+, Co2+, Mn2+, Mg2+, Cu2+,
Cd2+, Al3+, Cr2+, Ag+, Na+, Li+, Pd2+, Ru3+, Rh2+, Ni2+,
K+, Ba2+), only Pt2+ leads to a dramatic enhancement in
fluorescence intensity in aqueous solution. Other metal ions
develop no significant fluorescence intensity changes (Figure
2a). The competitive Pd2+ ions show very little fluorescence
intensity changes, and the fluorescent intensity changes
caused by the addition of Pt2+ are not influenced by the
Scheme 1. Synthesis of the Rhodamine-Triazole Conjugate 1
could be readily synthesized by “click reaction”17 using an
azide and a terminal alkyne-functionalized rhodamine.
Therefore, the rhodamine triazole 1 has been designed as a
new fluorescent probe as shown in Scheme 1.
Compound 1 was prepared from the known rhodamine
alkyne derivative 218 which is prepared from the known
rhodamine hydroxamic acid 319 (1, propargyl bromide, NaH,
THF; 2, benzyl azide, CuSO4, Na ascorbate, THF-H2O) as
shown in Scheme 1.
(6) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057–3064. (b) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today
2003, 8, 1128–1137. (c) Moses, J. E.; Moorhouse, A. D. Chem. Soc. ReV.
2007, 36, 1249–1262. (d) Fournier, D.; Hoogenboom, R.; Schubert, U. S.
Chem. Soc. ReV. 2007, 36, 1369–1380. (e) Angell, Y. L.; Burgess, K. Chem.
Soc. ReV. 2007, 36, 1674–1689. (f) Meldal, M.; Tornøe, C. W. Chem. ReV.
2008, 108, 2952–3015. (g) Amblard, F.; Cho, J. H.; Schinazi, R. F. Chem.
ReV. 2009, 109, 4207–4220. (h) Iha, R. K.; Wooley, K. L.; Nystro¨m, A. M.;
Burke, D. J.; Kade, M. J.; Hawker, C. J. Chem. ReV. 2009, 109, 5620–
5686. (i) Holub, J. M.; Kirshenbaum, K. Chem. Soc. ReV. 2010, 39, 1325–
(11) (a) Hung, H.-C.; Cheng, C.-W.; Wang, Y,-Y.; Chen, Y.-J.; Chung,
W.-S. Eur. J. Org. Chem. 2009, 6360–6366. (b) Kumar, A.; Pandey, P. S.
Tetrahedron Lett. 2009, 50, 5842–5845. (c) Huang, X.; Meng, J.; Dong,
Y.; Cheng, Y.; Zhu, C. Polymer 2010, 51, 3064–3067.
(12) (a) Li, H.; Yao, Y.; Han, C.; Zhan, J. Chem. Commun. 2009, 4812–
4814. (b) Zhang, Y.-M.; Chen, Y.; Li., Z.-Q.; Li, N.; Liu, Y. Bioorg. Med.
Chem. 2010, 18, 1415–1420.
(13) Zhan, J.; Tian, D.; Li, H. New J. Chem. 2009, 33, 725–728.
(14) (a) Maity, D.; Govindaraju, T. Chem. Commun. 2010, 46, 4499–
4501. (b) Kim, S. H.; Choi, H. S.; Kim, J.; Lee, S. J.; Quang, D. T.; Kim,
J. S. Org. Lett. 2010, 12, 560–563.
1337
(7) Chang, K.-C.; Su, I.-H.; Senthivelan, A.; Chung, W.-S. Org. Lett.
2007, 9, 3363–3366
(8) Chang, K.-C.; Su, I.-H.; Lee, G.-H.; Chung, W.-S. Tetrahedron Lett.
2007, 48, 7274–7278
.
.
(15) For selective examples of rhodamine amide-based fluorescent
chemosensors, see: Kim, H. N.; Lee, M. H.; Kim, H. J.; Kim, J. S.; Yoon,
J. Chem. Soc. ReV. 2008, 37, 1467–1472.
.
(9) (a) Park, S. Y.; Yoon, J. H.; Hong, C. S.; Souane, R.; Kim, J. S.;
Matthews, S. E.; Vicens, J. J. Org. Chem. 2008, 73, 8212–8218. (b) Pathak,
R. K.; Ibrahim, S. M.; Rao, C. P. Tetrahedron Lett. 2009, 50, 2730–2734.
(c) Tamanini, E.; Katewa, A.; Sedger, L. M.; Todd, M. H.; Watkinson, M.
Inorg. Chem. 2009, 48, 319–324. (d) Ballesteros-Garrido, R.; Abarca, B.;
Ballesteros, R.; Ram´ırez de Arellano, C.; Leroux, F. R.; Colobert, F.; Garc´ıa-
Espan˜a, G. New J. Chem. 2009, 33, 2102–2106. (e) Tamanini, E.; Flavin,
K.; Motevalli, M.; Piperno, S.; Gheber, L. A.; Todd, M. H.; Watkinson,
M. Inorg. Chem. 2010, 49, 3789–3800. (f) Pathak, R. K.; Dikundwar, A. G.;
(16) (a) Yang, Y.-K.; Yook, K.-J.; Tae, J. J. Am. Chem. Soc. 2005, 127,
16760–16761. (b) Ko, S.-K.; Yang, Y.-K.; Tae, J.; Shin, I. J. Am. Chem.
Soc. 2006, 128, 14150–14155. (c) Yang, Y.-K.; Ko, S.-K.; Shin, I.; Tae, J.
Nat. Protoc. 2007, 2, 1740–1745. (d) Yang, Y.-K.; Cho., H. J.; Lee, J.;
Shin, I.; Tae, J. Org. Lett. 2009, 11, 859–861.
(17) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004–2021. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–2599.
(18) Yang, Y.-K.; Lee, S.; Tae, J. Org. Lett. 2009, 11, 5610–5613.
(19) (a) Kang, S.; Kim, S.; Yang, Y.-K.; Bae, S.; Tae, J. Tetrahedron
Lett. 2009, 50, 2010–2012. (b) Moon, K.-S.; Yang, Y.-K.; Ji, S.; Tae, J.
Tetrahedron Lett. 2010, 51, 3290–3293.
Row, T. N. G.; Rao, C. P. Chem. Commun. 2010, 46, 4345–4347
.
(10) (a) Hsieh, Y.-C.; Chir., J.-L.; Wu, H.-H.; Chang, P.-S.; Wu, A.-T.
Carbohydr. Res. 2009, 344, 2236–2239. (b) Chen, Y.-B.; Wang, Y.-J.; Lin,
Y.-J.; Hu, C.-H.; Chen, S.-J.; Chir, J.-L.; Wu, A.-T. Carbohydr. Res. 2010,
345, 956–959. (c) Hsieh, Y.-C.; Chir, J.-L.; Wu, H.-H.; Guo, C.-Q.; Wu,
(20) Connors, K. A. Binding Constants-The Measurement of Molecular
Complex Stability; John Wiley & Sons: New York, 1987; Chapter 4.
A.-T. Tetrahedron Lett. 2010, 51, 109–111
.
Org. Lett., Vol. 12, No. 22, 2010
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Figure 2
. Fluorescence intensity changes of 1 (5 µM) in H2O
(DMSO 1% v/v) at 562 nm: (a) In the presence of metal ions (5.0
equiv): 1, none; 2, Pt2+; 3, Fe3+; 4, Fe2+; 5, Hg2+; 6, Zn2+; 7, Pb2+
;
8, Ca2+; 9, Co2+; 10, Mn2+; 11, Mg2+; 12, Cu2+; 13, Cd2+; 14,
Al3+; 15, Cr2+; 16, Ag+; 17, Na+; 18, Li+; 19, Pd2+; 20, Ru3+; 21,
Rh2+; 22, Ni2+; 23, K+; 24, Ba2+. (b) In the presence of Pt2+ (5.0
Figure 1. Fluorescence intensity changes of 1 upon additions of
Pt2+ in H2O (DMSO 1% v/v). Each spectrum is observed after 30
min of each Pt2+ addition at 25 °C with excitation at 500 nm. (a)
1 (5 µM). Inset: plot of fluorescence intensities at 562 nm depending
on the equivalents of Pt2+. (b) 1 (0.5 µM) upon additions of Pt2+
(by 125 nM). Inset: plot of fluorescence intensities at 553 nm
equiv) and other metal ions (5.0 equiv): 1, none; 2, Fe3+; 3, Fe2+
4, Hg2+; 5, Zn2+; 6, Pb2+; 7, Ca2+; 8, Co2+; 9, Mn2+; 10, Mg2+
;
;
11, Cu2+; 12, Cd2+; 13, Al3+; 14, Cr3+; 15, Ag+; 16, Na+; 17, Li+;
18, Pd2+; 19, Ru3+; 20, Rh2+; 21, Ni2+; 22, K+; 23, Ba2+
.
depending on the concentration of Pt2+
.
presence of other metal ions as shown in Figure 2b. The
fluorescent selectivity between Pt2+ and Pd2+ is especially
promising because it is typically difficult to discriminate these
similar metal ions.5
The fluorescence selectivity of 1 for Pt2+ is well matched
when 1 is employed as a colorimetric detector. While the
binding of 1 (5 µM) with Pt2+ results in clear colorless to
pink-red color changes in aqueous solutions, no significant
color changes are promoted by other metal ions except Pd2+
(Figure 3). Unlike the Pt2+-selective fluorescence response
of 1, both Pt2+ and Pd2+ induce color changes of 1.21 This
implies that, although both Pt2+ and Pd2+ can open the
spirocyclic form of 1 to lead to color changes, Pd2+ quenches
the expressed fluorescence efficiently.22
Figure 3. Color changes of 1 (5 µM) in the presence of metal ions
(5.0 equiv) in H2O (DMSO 1% v/v): 1, none; 2, Pt2+; 3, Fe3+; 4,
Fe2+; 5, Hg2+; 6, Zn2+; 7, Pb2+; 8, Ca2+; 9, Co2+; 10, Mn2+; 11,
Mg2+; 12, Cu2+; 13, Cd2+; 14, Al3+; 15, Cr3+; 16, Ag+; 17, Na+;
18, Li+; 19, Pd2+; 20, Ru3+; 21, Rh2+; 22, Ni2+; 23, K+; 24, Ba2+
.
in aqueous solutions. We first compared fluorescence inten-
sity changes of 1 exerted by different platinum complexes
(K2PtCl4, Pt(COD)Cl2, PtCl2, and cisplatin). The platinum
complexes were dissolved in H2O (5 mM) for 1 h at 25 °C
and then added into the solution of probe 1 (5 µM) in H2O
(DMSO 1% v/v). The resulted solutions were incubated for
24 h at 25 °C prior to the fluorescence measurement.24 Although
cisplatin shows relatively smaller fluorescence intensity changes
compared with other platinum complexes, it is possible to detect
cisplatin in aqueous solutions (Figure 4a). Fluorescence moni-
To demonstrate the potential application of this platinum
ion probe, we conducted experiments to detect cisplatin23
(21) The UV-vis absorption experiments also indicate that both Pt2+
and Pd2+ induce strong absorptions at ∼541 nm (see Supporting Informa-
tion).
(22) (a) Duan, L. P.; Xu, Y. F.; Qian, X. H. Chem. Commun. 2008,
6339–6341. (b) Li, H.; Fan, J.; Du, J.; Guo, K.; Sun, S.; Liu, X.; Peng, X.
Chem. Commun. 2010, 1079–1081.
(23) (a) For the review of the analytical detection method of cisplatin,
see ref 4d. (b) For the detection of cisplatin using a fluorescent probe, see
ref 5a.
(24) It seems that the ligand exchange reactions of the platinum
complexes take place slowly. See: Reedijk, J. Platinum Met. ReV. 2008,
52, 2–11.
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Org. Lett., Vol. 12, No. 22, 2010

of aqueous cisplatin is also possible at micromolar concentration
as shown in Figure 4c.
In conclusion, we have described a highly selective and
sensitive fluorescent chemosensor for the detection of Pt2+
in aqueous solutions. The binding platform of a triazole-
hydroxamate conjugate displays selective complexation with
Pt2+,25 and the fluorescent and colorimetirc detections of
cisplatin in aqueous solutions using probe 1 are also
demonstrated.
Acknowledgment. This research was supported by the
Midcareer Research Program (No. R01-2008-000-10245-0)
and CBMH (Yonsei University) through the National
Research Foundation of Korea (NRF) funded by the Ministry
of Education, Science and Technology.
Supporting Information Available: Experimental pro-
Figure 4. (a) Fluorescence intensities of 1 (5 µM) in the presence
1
cedures for the synthesis and copies of H NMR and 13C
of 10.0 equiv of different platinum complexes at 25 °C (at 562
nm). (b) Fluorescence intensity changes of 1 (5 µM) upon addition
of different amounts of cisplatin in H2O (DMSO 1% v/v) (at 562
nm). (c) Color change of 1 (5 µM) upon addition of different
amounts of cisplatin in H2O (DMSO 1% v/v).
NMR of 1, data for UV-vis, fluorescence of 1, and other
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL102397N
toring of cisplatin using probe 1 (5 µM) is possible at
micromolar concentration in aqueous solutions according to the
fluorescence experiment (Figure 4b), and colorimetric detection
(25) The related hydroxamate binding platforms containing a simple
binding unit, such as a pyridine and an amino group instead of a triazole,
show nonselective binding properties.
Org. Lett., Vol. 12, No. 22, 2010
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