Synthesis and binding ability of 1,2,3-triazole-based triterpenoid receptors for recognition of Hg2+ ion

Article abstract of DOI:10.1016/j.bmcl.2010.06.079

A novel type of receptors based on 1,2,3-triazole glycyrrhetinic acid derived from natural triterpenoid molecules has been synthesized via click chemistry and they showed high selectivity and affinity for Hg²⁺ ion by both the 1,2,3-triazole rin

Full text of DOI:10.1016/j.bmcl.2010.06.079

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4342–4345
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and binding ability of 1,2,3-triazole-based triterpenoid receptors
for recognition of Hg2+ ion
Jun Hu a, Meng Zhang a, Li B. Yu a, Yong Ju a,b,
*
a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084, China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel type of receptors based on 1,2,3-triazole glycyrrhetinic acid derived from natural triterpenoid
molecules has been synthesized via click chemistry and they showed high selectivity and affinity for
Hg2+ ion by both the 1,2,3-triazole rings and aldehyde groups.
Received 1 April 2010
Revised 2 June 2010
Accepted 14 June 2010
Available online 17 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Terpenoids
Mercury
Receptor
Glycyrrhetinic acid (1) is a facile pentacyclic triterpenoid pre-
senting in the form of aglycone or glycosides from medicinal
plants.1–3 It is mainly used for anti-inflammation, anti-virus and
anti-tumor.4–8 Although many reports based on steroidal units
have appeared in recognition and binding ability,9–22 there are
few reports about triterpenoid scaffolds,23 which are the biogenic
homologue with steroids and possess the similar structures, such
as chiral rigid skeleton, relative low-toxicity, biocompatibility
and so on. To design the triterpenoid scaffold as ion receptor
should open a new venue for molecular sensor development and
maybe lead to potential applications.
The mercury environmental pollution, which is caused by the
continuous release of mercury in the environment through natural
and industrial processes, has always been a matter of concern.24–26
The oxidized Hg2+ ion can be accumulated in plants, soil and water,
and mercury could also be converted into methylmercury, a highly
potent neurotoxin, by microorganisms.27,28 The exposure to mer-
cury even at low concentration leads to various health problems,
especially neurological disorders. Therefore, there are considerable
interest in the development of receptors that can show high selec-
tivity and sensitivity for Hg2+ ion.29–38
egy, has attracted much attention in the areas of polymers,
materials, organic, biological and medicinal chemistry.54–59
In this Letter, we report the synthesis of a novel type of recep-
tors based on 1,2,3-triazole glycyrrhetinic acid derived from natu-
ral triterpenoid and their binding properties toward various metal
ions for the first time.
1,2,3-Triazole-based triterpenoid receptors 11 and 12 were syn-
thesized through eight steps (Scheme 1). Glycyrrhetinic acid (1)
was first methylated to methyl ester 2 by methyl iodide, followed
by treatment with p-toluenesulfonyl chloride to give compound 3.
After refluxing in DMF with lithium carbonate and lithium bro-
mide, 2,11-diene-glycyrrhetinic acid methyl ester 4 was synthe-
sized, which subsequently reacted with m-chloroperoxybenzoic
acid at rt to give compound 5. Compound 5 was hydrolysed to af-
ford 2,3-dihydroxyl-glycyrrhetinic acid methyl ester 6. In order to
confirm the configuration of 2,3-dihydroxyl of 6, the crystal struc-
ture was determined by X-ray diffraction analysis (see Supplemen-
tary data). After reacting with bromoacetyl bromide at rt to obtain
7 and then refluxing with sodium azide in DMF, 2,3-diazido-glyc-
yrrhetinic acid methyl ester 8 was synthesized. Further treatment
with salicylaldehyde and 2-hydroxy-1-naphthaldehyde based ter-
minal alkynes 9 and 10 in the presence of CuSO4Á5H2O and ascor-
bate acid sodium salt (click reaction) gave target molecules 11 and
12, respectively.
Recently, the role of 1,2,3-triazole in the formation of stable me-
tal complexes has also been realized by providing coordination site
and accordingly some triazole-based receptors and dendrimers for
the recognition of metals have been reported.39–52 The click reac-
tion,53 which supplies a straightforward molecular linking strat-
UV–vis spectroscopy was used to investigate the affinity of
compound 11 and 12 towards Hg2+ ion by monitoring the absor-
bance changes. When Hg(ClO4)2 (0–3 equiv) was added to the solu-
tion of compound 11 (2.9 Â 10À5 M) in CH2Cl2–CH3OH (7:3, v/v),
the absorbance bands at 253 and 317 nm decreased and a new
band around 279 nm was observed with two clear isosbestic points
* Corresponding author. Fax: +86 10 62781695.
E-mail address: juyong@tsinghua.edu.cn (Y. Ju).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.079

J. Hu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4342–4345
4343
Scheme 1. Reagents and conditions: (a) CH3I, K2CO3, THF, reflux; (b) p-TsCl, pyridine, rt; (c) LiBr, Li2CO3, DMF, reflux; (d) m-CPBA, K2CO3, CH2Cl2, rt; (e) HClO4, 1,4-dioxane,
H2O, rt; (f) BrCOCH2Br, K2CO3, CH2Cl2, rt; (g) NaN3, DMF, 70 °C and (h) CuSO4Á5H2O, ascorbate acid sodium salt, t-BuOH, 50 °C.
Figure 2. Absorbance spectra of compound 12 (2.8 Â 10À5 M) in CH2Cl2–CH3OH
Figure 1. Absorbance spectra of compound 11 (2.9 Â 10À5 M) in CH2Cl2–CH3OH
(7:3, v/v) in the presence of Hg2+ (0–3equiv).
(7:3, v/v) in the presence of Hg2+ (0–3 equiv).
found to be 3.0 Â 104 and 2.7 Â 104 MÀ1 (Figs. 3 and 4) using Hilde-
brand–Benesi equation60, respectively.
at 268 and 286 nm ( Fig. 1). Compound 12 (2.8 Â 10À5 M) also
showed similar type of behavior with Hg2+ ion (Fig. 2) that the
absorbance bands at 258 and 320 nm decreased and a new band
around 282 nm appeared with two sharp isosbestic points at 272
and 295 nm. Job’s plots indicated the 1:1 complex formation in
both cases and the binding constants for receptors 11 and 12 were
The binding behavior of 11 and 12 were also examined with
other metal ions such as Cu2+, Zn2+, Cd2+ and Mg2+. In all cases,
their perchlorate salts were used for the UV–vis titration. Among
the above metal ions, only Cu2+, which is always used to dipolar
cycloaddition reaction and fluorescent chemosensor recently61–63
,

4344
J. Hu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4342–4345
Figure 3. Job’s plot showing 1:1 complex formation for (a) receptor 11 and (b) receptor 12; Hildebrand–Benesi plot based on the 1:1 for (c) receptor 11 with
Ka = 3.0 Â 104 MÀ1 and (d) receptor 12 with Ka = 2.7 Â 104 MÀ1
.
Figure 4. The 1:1 complex formation for compounds 11 and 12 with Hg2+ ion
Figure 5. Partial 1H NMR spectra of (a) compound 11 and (b) compound
11 + 3 equiv Hg(ClO4)2.
showed appreciable binding towards these receptors and the bind-
ing constants for receptor 11 (4.4 Â 10À5 M) and 12 (3.7 Â 10À5 M)
were 1.6 Â 103 MÀ1 and 5.0 Â 103 MÀ1 (absorbance spectra and
job’s plot see Supplementary data), respectively. The other metal
ions did not show any binding affinity for the receptors. These re-
sults clearly indicated that receptors 11 and 12 were selective to
bind with Hg2+ ion.
The mode of binding of Hg2+ ion with compounds 11 and 12
was ascertained by 1H NMR spectroscopy. After addition of Hg2+
ion (3 equiv) to the solution of compound 11 (5 mM) and 12
(5 mM) in CDCl3–CD3OD (7:3, v/v), respectively, the protons of
1,2,3-triazole rings were downfield shifted to
d 0.58 and
0.56 ppm, and the protons of aldehyde group attached to phenyl
rings were upfield shifted to d 0.37 and 0.25 ppm (Figs. 5 and 6).
The change of chemical shift indicated that both 1,2,3-triazole
rings and aldehyde groups of compounds 11 and 12 should bind
with Hg2+ ion.
Figure 6. Partial 1H NMR spectra of (a) compound 12 and (b) compound
12 + 3 equiv Hg(ClO4)2.

J. Hu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4342–4345
4345
22. Kumar, A.; Pandey, P. S. Tetrahedron Lett. 2009, 50, 5842.
23. Bag, B. G.; Pramanik, S. R.; Maity, G. C. Supramol. Chem. 2005, 17, 297.
In conclusion, a novel type of receptors based on 1,2,3-triazole
glycyrrhetinic acid derived from natural triterpenoid molecules
were developed and the receptors showed remarkable selectivity
and affinity for Hg2+ ion by the 1,2,3-triazole rings and aldehyde
groups simultaneously. It might lead to the potential applications
in managing environmental pollution and used as a potential anti-
dote for mercury.
24. Shotyk, W.; Weiss, D.; Appleby, P. G.; Cheburkin, A. K.; Frei, R.; Gloor, M.;
Kramers, J. D.; Reese, S.; Van Der Knaap, W. O. Science 1998, 281, 1635.
25. Benoit, J. M.; Fitzgerald, W. F.; Dammant, A. W. H. Environ. Res. 1998, 78, 118.
26. Gustin, M. S.; Coolbaugh, M. F.; Engle, M. A.; Fitzgerald, B. C.; Keislar, R. E.;
Lindberg, S. E.; Nacht, D. M.; Quashnick, J.; Rytuba, J. J.; Sladek, C.; Zhang, H.;
Zehner, R. E. Environ. Geol. 2003, 43, 339.
27. Nendza, M.; Herbst, T.; Kussatz, C.; Gies, A. Chemosphere 1997, 35, 1875.
28. Tchounwou, P. B.; Ayensu, W. K.; Ninashvili, N.; Sutton, D. Environ. Toxicol.
2003, 18, 149.
29. Nolan, E. M.; Lippard, S. J. Chem. Rev. 2008, 108, 3443.
30. Kim, H. N.; Lee, M. H.; Kim, H. J.; Kim, J. S.; Yoon, J. Chem. Soc. Rev. 2008, 37,
1465.
31. Che, Y. K.; Yang, X. M.; Zang, L. Chem. Commun. 2008, 1413.
32. Shi, W.; Ma, H. M. Chem. Commun. 2008, 1856.
Acknowledgments
The project is supported by NSFC (Nos. 20772071, 20972086)
and SRFDP (No. 20090002110060). We also thank Prof. Tong AJ
for her kind suggestion and discussion.
33. Li, D.; Wieckowska, A.; Willner, I. Angew. Chem. Int. Ed. 2008, 47, 3927.
34. Liu, C. W.; Hsieh, Y. T.; Huang, C. C.; Lin, Z. H.; Chang, H. T. Chem. Commun.
2008, 2242.
35. Zhu, M.; Yuan, M. J.; Liu, X. F.; Lv, J.; Huang, C. S.; Liu, H. B.; Li, Y. L.; Wang, S.;
Zhu, D. B. Org. Lett. 2008, 10, 1481.
Supplementary data
36. Song, F. L.; Watanabe, S.; Floreancig, P. E.; Koide, K. J. Am. Chem. Soc. 2008, 130,
16460.
37. Dhir, A.; Bhalla, V.; Kumar, M. Org. Lett. 2008, 10, 4891.
38. Shiraishi, Y.; Sumiya, S.; Kohno, Y.; Hirai, T. J. Org. Chem. 2008, 73, 8571.
39. Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2004, 6,
2853.
Synthesis and spectra data of compounds 2–12; ORTEP drawing
of compound 6; UV–vis titrations and calculation of binding con-
stants of Cu2+. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/j.bmcl.2010.
06.079.
40. Bronisz, R. Inorg. Chem. 2005, 44, 4463.
41. Mindt, T. L.; Struthers, H.; Brans, L.; Anguelov, T.; Schweinsberg, C.; Maes, V.;
Tourwe, D.; Schibli, R. J. Am. Chem. Soc. 2006, 128, 15096.
42. Meudtner, R. M.; Ostermeier, M.; Goddard, R.; Limberg, C.; Hecht, S. Chem. Eur.
J. 2007, 13, 9834.
43. Ornelas, C.; Aranzaes, J. R.; Cloutet, E.; Alves, S.; Astruc, D. Angew. Chem. Int. Ed.
2007, 46, 872.
44. Chang, K. C.; Su, I. H.; Senthilvelan, A.; Chung, W. S. Org. Lett. 2007, 9, 3363.
45. Li, Y.; Huffman, J. C.; Flood, A. H. Chem. Commun. 2007, 2692.
46. David, O.; Maisonneuve, S.; Xie, J. Tetrahedron Lett. 2007, 48, 652.
47. Colasson, B.; Save, M.; Milko, P.; Roithova, J.; Schroder, D.; Reinaud, O. Org. Lett.
2007, 9, 4987.
48. Huang, S.; Clark, R. J.; Zhu, L. Org. Lett. 2007, 9, 4999.
49. Chang, K. C.; Su, I. H.; Lee, G. H.; Chung, W. S. Tetrahedron Lett. 2007, 48, 7274.
50. 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.
References and notes
1. Morana, A.; Di Lazzaro, A.; Di Lernia, I.; Ponzone, C.; De Rosa, M. Biotechnol. Lett.
2002, 24, 1907.
2. Um, S. J.; Park, M. S.; Park, S. H.; Han, H. S.; Kwon, Y. J.; Sin, H. S. Bioorg. Med.
Chem. 2003, 11, 5345.
3. Shi, J. H.; Zhou, Y. X.; He, M. L.; Jin, J.; Xiao, Y. C.; Xiao, J. H.; Wei, D. Z. Chem. Nat.
Compd. 2006, 42, 325.
4. Su, X. D.; Lawrence, H.; Ganeshapillai, D.; Cruttenden, A.; Purohit, A.; Reed, M.
J.; Vicker, N.; Potter, B. V. L. Bioorg. Med. Chem. 2004, 12, 4439.
5. Yu, D. L.; Sakurai, Y.; Chen, C. H.; Chang, F. R.; Huang, L.; Kashiwada, Y.; Lee, K.
H. J. Med. Chem. 2006, 49, 5462.
6. Liu, D.; Song, D. D.; Guo, G.; Wang, R.; Lv, J. L.; Jing, Y. K.; Zhao, L. X. Bioorg. Med.
Chem. 2007, 15, 5432.
7. Tatsuzaki, J.; Taniguchi, M.; Bastow, K. F.; Nakagawa-Goto, K.; Morris-Natschke,
S. L.; Itokawa, H.; Baba, K.; Lee, K. H. Bioorg. Med. Chem. 2007, 15, 6193.
8. Chadalapaka, G.; Jutootu, I.; McAlees, A.; Stefanac, T.; Safe, S. Bioorg. Med. Chem.
Lett. 2008, 18, 2633.
51. Schweinfurth, D.; Hardcastle, K. I.; Bunz, U. H. F. Chem. Commun. 2008, 2203.
52. Juricek, M.; Kouwer, P. H. J.; Rehak, J.; Sly, J.; Rowan, A. E. J. Org. Chem. 2009, 74,
21.
53. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed.
2002, 41, 2596.
9. Davis, A. P.; Perry, J. J.; Williams, R. P. J. Am. Chem. Soc. 1997, 119, 1793.
10. Rai, R.; Khatri, V. K.; Pandey, P. S. Supramol. Chem. 2004, 16, 581.
11. Ghosh, S.; Choudhury, A. R.; Row, T. N. G.; Maitra, U. Org. Lett. 2005, 7, 1441.
12. Rai, R.; Pandey, P. S. Bioorg. Med. Chem. Lett. 2005, 15, 2923.
13. Khatri, V. K.; Upreti, S.; Pandey, P. S. Org. Lett. 2006, 8, 1755.
14. Chattopadhyay, P.; Pandey, P. S. Tetrahedron 2006, 62, 8620.
15. Chahar, M.; Upreti, S.; Pandey, P. S. Tetrahedron 2007, 63, 171.
16. Khatri, V. K.; Chahar, M.; Pavani, K.; Pandey, P. S. J. Org. Chem. 2007, 72, 10224.
17. Chattopadhyay, P.; Pandey, P. S. Bioorg. Med. Chem. Lett. 2007, 17, 1553.
18. Chattopadhyay, P.; Pandey, P. S. Tetrahedron Lett. 2008, 49, 4640.
19. Kumar, A.; Pandey, P. S. Org. Lett. 2008, 10, 165.
54. Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249.
55. Lutz, J. F. Angew. Chem. Int. Ed. 2007, 46, 1018.
56. Bock, V. D.; Hiemstra, H.; Van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.
57. Fournier, D.; Hoogenboom, R.; Schubert, U. S. Chem. Soc. Rev. 2007, 36, 1369.
58. Angell, Y. L.; Burgess, K. Chem. Soc. Rev. 2007, 36, 1674.
59. Meldal, M.; Tornoe, C. W. Chem. Rev. 2008, 108, 2952.
60. Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71, 2703.
61. Varazo, K.; Xie, F.; Gulledge, D.; Wang, Q. Tetrahedron Lett. 2008, 49, 5293.
62. Xie, F.; Sivakumar, K.; Zeng, Q. B.; Bruckman, M. A.; Hodges, B.; Wang, Q.
Tetrahedron 2008, 64, 2906.
63. Sivakumar, K.; Xie, F.; Cash, B. M.; Long, S.; Barnhill, H. N.; Wang, Q. Org. Lett.
2004, 6, 4603.
20. Chahar, M.; Pandey, P. S. Tetrahedron 2008, 64, 6488.
21. Chattopadhyay, P.; Nagpal, R.; Pandey, P. S. Aust. J. Chem. 2008, 61, 216.