10.1002/anie.202008224
Angewandte Chemie International Edition
COMMUNICATION
M. Westerhausen, A. Schiller, Chem. Commun. 2014, 50, 3644–
3660.
While CORM-2 delivers CO into the cell and produces no
changes in viscosity, hemin increases HO-1 expression,
modulating ROS inside the cell[26] and our data reveals that it
decreases viscosity. Furthermore, short-lived ROS species
may diffuse more easily through the cell due to the lower
microviscosity induced by hemin.
[2] L. Wu, R. Wang, Pharmacol. Rev. 2005, 57, 585–630.
[3] R. Motterlini, L. E. Otterbein, Nat. Rev. Drug Discov. 2010, 9, 728–
743.
[4] A. C. Kautz, P. C. Kunz, J. Janiak, Dalton Trans. 2016, 45, 18045–
18063.
[5] C. Marín-Hernández, A. Toscani, F. Sancenón, J. D. E. T. Wilton–Ely,
R. Martínez-Mañez, Chem. Commun. 2016, 52, 5902–5911.
[6] J. Wang, J. Karpus, B. S. Zhao, Z. Luo, P. R. Chen, C. A. He, Angew.
Chem. Int. Ed. 2012, 51, 9652–9656; Angew. Chem. 2012, 124,
9790–9794.
Together with the fluorescence intensity data, these results
represent the first simultaneous measurement of CO
concentration and viscosity in cells. It is also the first example
in which molecular rotor is directly linked to a metal-based
chemosensor, while preserving its sensitivity to the viscosity of
its environment, enabling dual viscosity and CO detection.
[7] B. W. Michel, A. R. Lippert, C. J. A. Chang, J. Am. Chem. Soc. 2012,
134, 15668–15671.
[8] S. Pal, M. Mukherjee, B. Sen, S. K. Mandal, S. Lohar, P.
Chattopadhyay, K. Dhara, Chem. Commun. 2015, 51, 4410–4413.
[9] a) K. Zheng, W. Lin, L. Tan, H. Chen, H. Cui, Chem. Sci. 2014, 5, 3439–
3448. b) K. Liu, X. Kong, Y. Ma, W. Lin, Angew. Chem. Int. Ed. 2017,
56, 13489-13492; Angew. Chem. 2017, 129, 13674 –13677.
[10] E. Zhou, S. Gong, G. Feng, Sens. Act. B 2019, 301, 127075.
[11] C. Zhang, H. Xie, T. Zhan, J. Zhang, B. Chen, Z. Qian, G. Zhang, W.
Zhang, J. Zhou, Chem. Commun. 2019, 55, 9444-9447
[12] K. Luby-Phelps, Int. Rev. Cytol. 2000, 192, 189–221.
[13] M. K. Kuimova, G. Yahioglu, J. A. Levitt, K. Suhling, J. Am. Chem.
Soc. 2008, 130, 6672–6673.
Many palladium-based probes have been reported with
greater sensitivity for CO than the ruthenium-based system
reported here.[8,10] However, concerns remain over the toxicity
of Pd(II) salts[11] in living systems and the slow response time
caused by the need for diffusion controlled co-location of three
reaction partners (Pd salt, fluorophore and CO) for detection to
occur. Our probe is the only competitive metal-based system
not based on palladium and successfully addresses both of
these issues. It shows no cytotoxicity even up to 200 µM and
instantaneous response to CO through its direct coordination
to the metal. Such attributes make these systems highly
effective, all-round sensors for the detection of CO in the
challenging environment of the cell. This is exemplified by the
fact that probe 4 is able to detect endogenous CO generated
through increased HO-1 expression under hypoxic conditions.
Most significantly, this design represents the first example of a
dual modality CO and viscosity probe (6), allowing
simultaneous measurement of CO through fluorescence
intensity and viscosity through fluorescence lifetime. Our
experiments show that an increase in HO-1 expression leads
to a decrease in cellular viscosity and this result may help to
elucidate how HO-1 modulates the activity of radical oxygen
species. Our proof-of-concept biological studies provide an
insight into the potential of these probes to characterise the
mechanisms of delivery and signalling ability of CO within the
body.
[14] a) M. K. Kuimova, S. W. Botchway, A. W. Parker, M. Balaz, H. A.
Collins, H. L. Anderson, K. Suhling, P. R. Ogilby, Nature Chem.
2009, 1, 69–73. b) M. Kubánková, I. López-Duarte, D. Kiryushko, M.
K. Kuimova, Soft Matter, 2018, 14, 9466-9474. c) M. Kubánková, P.
A. Summers, I. López-Duarte, D. Kiryushko, M. K. Kuimova, ACS
Appl. Mater. Interfaces 2019, 11, 36307-36315.
[15] Z. Yang, J. Cao, Y. He, J. H. Yang, T. Kim, X. Peng, J. S. Kim, Chem.
Soc. Rev. 2014, 43, 4563–4601.
[16] M. A. Haidekker, E. A. Theodorakis, Org. Biomol. Chem. 2007, 5,
1669–1678.
[17] M. K. Kuimova, Phys. Chem. Chem. Phys. 2012, 14, 12671–12686.
[18] J. E. Chambers, M. Kubánková, R. G. Huber, I. López-Duarte, E.
Avezov, P. J. Bond, S. J. Marciniak, M. K. Kuimova, ACS Nano
2018, 12, 4398-4407.
[19] a) M. E. Moragues, A. Toscani, F. Sancenón, R. Martınez-Máñez, A. J.
́
P. White, J. D. E. T. Wilton-Ely, J. Am. Chem. Soc. 2014, 136,
11930–11933. b) A. Toscani, C. Marín-Hernández, M. E. Moragues,
F. Sancenón, F. Dingwall, N. J. Brown, R. Martínez-Máñez, A. J.
White, J. D. E. T. Wilton-Ely, Chem. Eur. J. 2015, 21, 14529–14538.
c) A. Toscani, C. Marín‐Hernández, J. A. Robson, E. Chua, P.
Dingwall, A. J. P. White, F. Sancenón, C. de la Torre, R. Martínez‐
Máñez, J. D. E. T. Wilton‐Ely, Chem. Eur. J. 2019, 25, 2069–2081.
[20] C. de la Torre, A. Toscani, C. Marín‐Hernández, J. A. Robson, M. C.
Terencio, A. J. P. White, M. J. Alcaraz, J. D. E. T. Wilton-Ely, R.
Martínez‐Máñez, F. Sancenꢀn, J. Am. Chem. Soc. 2017, 139,
18484−18487.
Acknowledgements
The EPSRC is gratefully acknowledged for studentships to
J.A.R. and T.B., and to R.H. as part of the CDT in Smart
Medical Imaging (EP/L015226/1). M.K. was supported by an
EPSRC Doctoral Prize Fellowship. M.K.K. is grateful to the
EPSRC for a Career Acceleration Fellowship (EP/I003983/1).
Prof. R. Martínez-Mañez and Dr F. Sancenón are thanked for
their contributions and support.
[21] M. Klein, U. Neugebauer, A. Gheisari, A. Malassa, T. M. A. Jazzazi, F.
Froehlich, M. Westerhausen, M. Schmitt, J. Popp, J. Phys. Chem. A
2014, 118, 5381-5390.
[22] P. Podkalicka, O. Mucha, A. Józkowicz, J. Dulak, A. Łoboda, Contemp
Oncol (Pozn). 2018, 22, 23–32.
[23] T. Morita, M. A. Perrella, M. E. Lee, S. Kourembanas, PNAS 1995, 92,
1475–1479.
Keywords: Ruthenium, sensing, viscosity, carbon monoxide,
[24] C. Zhou, J. Zhou, F. Sheng, H. Zhu, X. Deng, B. Xia, J. Lin, Acta
Biochim. Biophys. Sin. 2012, 44, 815–822.
fluorescence
[25] T. Förster, G. Hoffmann, Z. Phys. Chem. 1971, 75, 63–76.
[26] J. Araujo, M. Zhang, F. Yin, Front. Pharmacol. 2012, 3, 119.
[1] a) T. Sjöstrand, Nature 1949, 164, 580–581. b) C. Szabo, Nat. Rev.
Drug Discovery 2016, 15, 185–203. c) S. H. Heinemann, T. Hoshi,
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