pubs.acs.org/IC r XXXX American Chemical Society Inorg. Chem. XXXX, XXX, 000–000 A DOI: 10.1021/ic901939x Cyclam-Based “Clickates”: Homogeneous and Heterogeneous Fluorescent Sensors for Zn(II) Emiliano Tamanini, † Kevin Flavin, † Majid Motevalli, † Silvia Piperno, ‡ Levi A. Gheber, ‡ Matthew H. Todd,* ,§ and Michael Watkinson* ,† † The Joseph Priestly Building, School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London, E1 4NS, U.K., ‡ Department of Biotechnological Engineering, Ben Gurion University Negev, IL-84105 Beer Sheva, Israel, and § School of Chemistry, University of Sydney, NSW 2006, Australia Received October 2, 2009 In an effort to improve upon the recently reported cyclam based zinc sensor 1, the “click”-generated 1,8-disubstituted analogue 2 has been prepared. The ligand shows a 2-fold increase in its fluorescence emission compared to 1 exclusively in the presence of Zn(II) that is typical of switch-on PET fluorescent sensors. Single crystal X-ray diffraction of complexes of model ligand 10 reveals that the configuration adopted by the macrocyclic framework is extremely sensitive to the metal ion to which it coordinates. For Zn(II), Mg(II), and Li(I) the metal ions adopt an octahedral geometry with a trans III configuration of the cyclam ring. In contrast for Ni(II) the ligand adopts the rare cis V configuration, while for Cu(II) a clear preference for five-coordinate geometry is displayed with a trans I configuration of the macrocyclic ring being observed in two essentially isostructural compounds prepared via different routes. The ligand displays an increased selectivity for Zn(II) compared to 1 in the majority of cases with excellent selectivity upheld over Na(I), Mg(II), Ca(II), Mn(II), Ni(II), Co(II), and Fe(III). In contrast for Cu(II) and Hg(II) little improvement was observed for 2 compared to 1 and for Cd(II) the selectivity of the new ligand was inferior. In the light of these findings and the slower response times for ligand 2, our original “click”-generated cyclam sensor system 1 was employed in a proof of concept study to prepare a heterogeneous sol-gel based material which retains its PET response to Zn(II). The versatile nature of the sol-gel process importantly allows the simple preparation of a variety of nanostructured materials displaying high surface area-volume ratio using fabrication methods such as soft lithography, electrospin- ning, and nanopipetting. Introduction Because of the essential and varied role of metal cations in biological systems, allied to concerns over the role of certain elements as environmental pollutants, much effort has fo- cused in recent years on the development of effective sensors for a number of these ions. 1 Arguably greatest interest has focused on the development of sensors for the detection of zinc(II). 2 This reflects the fact that zinc is the second most abundant transition metal in the human body. Although over 90% of zinc is classified as “static”, playing crucial structural roles in transcription factors and related proteins, structural and catalytic roles in enzymes as well as its important role in neural signal transmission, “mobile” pools of zinc exist in certain mammalian organs such as the brain and pancreas, which are carefully regulated. Unsurprisingly it is increas- ingly recognized that the disruption of these pools of zinc is associated with a number of disease states which include type I and II diabetes, 3 neural function, 4 particularly Alzheimer’s disease 5 and certain cancers. 6 Furthermore, zinc is now recognized as an important factor in the regulation of apoptosis. 7 Consequently much effort has been directed toward the preparation of highly specific sensors for the *To whom correspondence should be addressed. E-mail: m.todd@ chem.usyd.edu.au (M.H.T.), m.watkinson@qmul.ac.uk (M.W.). (1) Domaille, D. W.; Que, E. L.; Chang, C. J. Nat. Chem. Biol. 2008, 4, 168–175. (2) (a) Gunnlaugsson, T.; Glynn, M.; Tocci, G. M.; Kruger, P. E.; Pfeffer, F. M. Coord. Chem. Rev. 2006, 250, 3094–3117. (b) Callan, J. F.; de Silva, A. P.; Magri, D. C. Tetrahedron 2005, 61, 8551–8588. (c) Carol, P.; Sreejith, S.; Ajayaghosh, A. Chem. Asian J. 2007, 2, 338–348. (d) Kikuchi, K.; Komatsu, K.; Nagano, T. Curr. Opin. Chem. Biol. 2004, 8, 182–191. (e) Lim, N. C.; Freake, H. C.; Br€ uckner, C. Chem.;Eur. J. 2005, 11, 38–49. (f) Nolan, E. M.; Lippard, S. J. Acc. Chem. Res. 2009, 42, 193–203. (3) (a) Sladek, R.; et al. Nature 2007, 445, 881–885. (b) Chimienti, F.; Devergnas, S.; Pattou, F.; Schuit, F.; Garcia-Cuenca, R.; Vandewalle, B.; Kerr- Conte, J.; Van Lommel, L.; Grunwald, D.; Favier, A.; Seve, M. J. Cell. Sci. 2006, 119, 4199–4206. (4) Que, E. L.; Domaille, D. W.; Chang, C. J. Chem. Rev. 2008, 108, 1517– 1549. (5) Frederickson, C. J.; Koh, J. Y.; Bush, A. I. Nat. Rev. Neurosci. 2005, 6, 449–462. (6) For example, see: Costello, L. C.; Franklin, R. B.; Feng, P.; Tan, M.; Bagasra, O. Cancer Cause Control 2005, 16, 901–915. (7) Zalewski, P. D.; Forbes, I. J.; Betts, W. H. Biochem. J. 1993, 296, 403–408.