4522
J. Am. Chem. Soc. 2000, 122, 4522-4523
Cooperative Chemical Sensing with
Bis-tritylacetylenes: Pinwheel Receptors with Metal
Ion Recognition Properties
Timothy E. Glass*
Figure 1. Newman-type representation of compound 1.
Department of Chemistry
The PennsylVania State UniVersity
UniVersity Park, PennsylVania 16802
There are several examples of homoallosteric receptors in the
literature,6 but none appeared to be sufficiently general for use
as a sensor framework. Therefore, a cooperative receptor frame-
work was designed on the basis of a novel molecular architecture
having three interacting sites (eq 1). This “pinwheel”-shaped
receptor consists of two trityl groups connected by a linear
acetylene spacer.7 Each phenyl ring of the trityl groups is
substituted at the meta position with a recognition element (R).
A pair of such recognition elements can bind an analyte across
the acetylene axis, creating a set of three identical interacting
binding pockets.
This framework is expected to exhibit cooperativity since, in
the absence of analyte, the trityl groups rotate freely about the
acetylene axis.8 Binding the first analyte forces the sensor into
an eclipsed rotamer (Figure 1). The loss of rotational freedom,
as well as the introduction of unfavorable steric interactions,
disfavors the first binding event. However, on the basis of the
symmetry of the molecule, binding the first analyte forces the
remaining recognition elements to align for binding the next two
analytes. The result is a cooperative binding event.9 For the proper
operation of this receptor, two recognition elements on the same
trityl group cannot chelate an analyte between them. Molecular
modeling of compound 1 (Macromodel 6.5) indicates that only
analytes of large dimension could interact with two recognition
elements on the same trityl group due to its propeller shape.10
ReceiVed December 16, 1999
Chemical sensors can play a critical role in the elucidation of
cellular mechanisms by giving real-time information about the
environment of a cell in a non-destructive manner.1 For example,
selective fluorescent Ca2+ sensors have provided a convenient
way to monitor changes in Ca2+ concentrations during cellular
processes.2 For these applications, sensor affinity and selectivity
are of utmost concern. A useful sensor must recognize its analyte
with high specificity and possess an affinity which is com-
mensurate with the average concentration of the analyte in
solution. The desired affinity and selectivity can be achieved, in
some cases, by using biosensors.3 Nevertheless, small molecule
chemical sensors remain an attractive approach to such problems,
given their ease of modification and cell permeability properties.
However, the highly complex and competitive nature of the
aqueous cellular environment coupled with the low concentration
at which some analytes are found presents a substantial challenge
to the design of small molecule sensors that would be effective
for biochemical applications.
The issues of affinity and selectivity could be addressed by
the use of cooperative recognition.4 The cooperative binding of
multiple analytes can, in principle, impart a higher affinity and
greater selectivity to a given sensor relative to a similar non-
cooperative system. This type of recognition is virtually unex-
plored in the field of chemical sensors5 since cooperativity is
typically associated with a sharp transition between the unbound
and bound state of the receptor. This sharp transition restricts
the range of concentrations over which the analyte can be detected.
Nevertheless, in the context of applications in which sensitivity
and selectivity are limiting factors, a smaller dynamic range should
be acceptable. Herein is described the first application of
cooperative recognition for enhancement of binding affinity to
fluorescent chemical sensing.
A simple metal binding assay was devised using compound 2
in order to evaluate the cooperative nature of the framework. A
quinoline-amine group was utilized as the recognition element
since it has appropriate metal binding and fluorescent properties.
A pair of these groups can chelate one metal ion, creating a
receptor with three tetrahedral metal binding sites (cf. eq 1).
Compound 3 was used as a functionally deficient control. Both
compounds 2 and 3 show a decrease in fluorescence upon addition
of metal ions such as Zn(II), Ag(I), Ni(II), Co(II), and Hg(II).11
(6) (a) Blanc, S.; Yakirevitch, P.; Leize, E.; Meyer, M.; Libman, J.; Van
Dorsselaer, A.; Albrecht-Gary, A. M.; Shanzer, A. J. Am. Chem. Soc. 1997,
119, 4934. (b) Kikuchi, Y.; Tanaka, Y.; Sutarto, S.; Kobayashi, K.; Toi, H.;
Aoyama, Y. J. Am. Chem. Soc. 1992, 114, 10302. (c) Petter, R. C.; Salek, J.
S.; Sikorski, C. T.; Kumaravel, G.; Line, F. T. J. Am. Chem. Soc. 1990, 112,
3860. (d) Rebek, J.; Costello, T.; Marshall, L.; Wattley, R.; Gadwood, R. C.;
Onan, K. J. Am. Chem. Soc. 1985, 107, 7481.
(7) The parent compound (1, RdH) has been prepared: Wieland, H.; Kloss,
H. Justus Liebigs Ann. Chem. 1929, 470, 202-211.
(8) Kelly, T. R.; Bowyer, M. C.; Bhaskar, K. V.; Bebbington, D.; Garcia,
A.; Lang, F.; Kim, M. H.; Jette, M. P. J. Am. Chem. Soc. 1994, 116, 3657.
(9) (a) Takeuchi, M.; Imada, T.; Shinkai, S. Angew. Chem., Int. Ed. 1998,
37, 2096. (b) Takeuchi, M.; Imada, T.; Ikeda, M.; Shinkai, S. Tetrahedron
Lett. 1998, 39, 7897.
(1) (a) Chemosensors of Ion and Molecule Recognition; Desvergne, J. P.,
Czarnik, A. W., Eds.; NATO ASI Series C: 492; Kluwer Academic Press:
Dordrecht, 1997. (b) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson T.;
Huxley, A. J. M.; McCoy, C. P.; Radermacher, J. T.; Rice, T. E. Chem. ReV.
1997, 97, 1515. (c) Czarnik, A. W. Chem. Biol. 1995, 2, 423.
(2) Tsien, R. Y. In Fluorescent Chemosensors for Ion and Molecule
Recognition; Czarnik, A. W., Ed.; ACS Symposium Series 538; American
Chemical Society: Washington, DC, 1993.
(3) (a) Hall, E. E. H. Biosensors; Prentice Hall: Englewood Cliffs, 1991.
(b) Marvin, J. S.; Hellinga, H. W. J. Am. Chem. Soc. 1998, 120, 7. (c) Tsien,
R. Y. in ref 2.
(4) (a) Nabeshima, T. Coord. Chem. ReV. 1996, 148, 151. (b) Czerlinski,
G. H. Biophys. Chem. 1989, 34, 169. (c) Rebek, J. Acc. Chem. Res. 1984, 17,
258. (d) Tabushi, I. Pure Appl. Chem. 1988, 60, 581.
(5) Marquis, K.; Desvergne, J.-P.; Bouas-Laurent, H. J. Org. Chem. 1995,
60, 7984.
(10) For an example, see: Fuji, K.; Tsubaki, K.; Tanaka, K.; Hayashi, N.;
Otsubo, T.; Kinoshita, T. J. Am. Chem. Soc. 1999, 121, 3807.
(11) Torrado, A.; Walkup, G. K.; Imperiali, B. J. Am. Chem. Soc. 1998,
120, 609.
10.1021/ja994398e CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/21/2000