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ChemComm
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COMMUNICATION
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intensity experiments using cycloheximide as a positive control
indicated that 0.1 µM of 2 or 4 were effectively capable of inhibiting
up to 80% to 56% of global protein synthesis (Fig. S50-S52). As
inhibition of protein synthesis in cancer cells might activate apoptosis
induction,21 performed flow cytometry experiments revealed that 2
and 4 at 1 µM were able to induce apoptosis and deplete
mitochondrial membrane potential of cancer cells in the dark (Fig.
S53 and S54). Due to the stability of the present Ru complexes in cell
culture media upon irradiation, we hypothesized that their high
photocytotoxicity might be explained by various mode of action
simultaneously occurring, which might include PDT effects such as
ROS generation species (mainly hydrogen peroxide and superoxide
anion radicals) and proteosynthesis inhibition whenever light
irradiation is not being applied, although other cell death
mechanisms might be operating.
Angew. Chem. Int. Ed., 2020, 59, 8833–8D8O38I:.10.1039/D0CC02417A
(a) C. Imberti, P. Zhang, H. Huang and P. J. Sadler, Angew. Chem.
Int. Ed., 2020, 59, 61–73; (b) L. Zeng, P. Gupta, Y. Chen, E. Wang,
L. Ji, H. Chao and Z.-S. Chen, Chem. Soc. Rev., 2017, 46, 5771–
5804;(c) A. Zamora, G. Vigueras, V. Rodríguez, M. D. Santana and
J. Ruiz, Coord. Chem. Rev., 2018, 360, 34–76.
5
6
(a) J. Karges, F. Heinemann, M. Jakubaszek, F. Maschietto, C.
Subecz, M. Dotou, R. Vinck, O. Blacque, M. Tharaud, B. Goud, E.
Viñuelas-Zahinos, B. Spingler, I. Ciofini and G. Gasser, J. Am.
Chem. Soc., 2020, 142, 6578–6587; (b) S. A. McFarland, A.
Mandel, R. Dumoulin-White and G. Gasser, Curr. Op. Chem. Biol.,
2020, 56, 23–27; (c) A. Li, C. Turro and J. J. Kodanko, Acc. Chem.
Res., 2018, 51, 1415–1421; (d) S. Cerfontaine, S. A. M. Wehlin, B.
Elias and L. Troian-Gautier, J. Am. Chem. Soc., 2020, 142, 5549–
5555; (e) J. Li, L. Zeng, K. Xiong, T. W. Rees, C. Jin, W. Wu, Y. Chen,
L. Ji and H. Chao, Chem. Comm., 2019, 55, 10972–10975; (f) B. S.
Howerton, D. K. Heidary and E. C. Glazer, J. Am. Chem. Soc., 2012,
M. S. Meijer, M. M. Natile and S. Bonnet, Inorg. Chem., 2020,
DOI:10.1021/acs.inorgchem.0c00043.
(a) H. Huang, P. Zhang, H. Chen, L. Ji and H. Chao, Chem. Eur. J.,
2015, 21, 715–725; (b) J.-A. Cuello-Garibo, C. C. James, M. A.
Siegler, S. L. Hopkins and S. Bonnet, Chem. Eur. J., 2019, 25,
1260–1268; (c) B. Peña, A. David, C. Pavani, M. S. Baptista, J.-P.
Pellois, C. Turro and K. R. Dunbar, Organometallics, 2014, 33,
1100–1103.
In summary, we report some novel photoreactive ruthenium(II)
complexes [Ru(C^N)(N^N)2](PF6) 1-5. Importantly, the biological
study shows that the most actives complexes 2 and 4 exhibit good
phototherapeutic indexes (higher than 750 for 2) in HeLa and
A2780cis cancer cells with nanomolar IC50, under low doses of non-
harmful green light. Both complexes are active in normoxia and
hypoxia conditions, overcoming one of the Achilles heel of PDT.
Under normoxia H2O2 is the main photogenerated species by the Ru
complexes, although other ROS such as •OH or 1O2 are involved in 2
or 4-irradiated treatments, respectively; whereas under hypoxia 2
7
8
9
P. G. Bomben, T. J. Gordon, E. Schott and C. P. Berlinguette,
Angew. Chem. Int. Ed., 2011, 50, 10682–10685.
10 J. McCain, K. L. Colón, P. C. Barrett, S. M. A. Monro, T. Sainuddin,
J. Roque III, M. Pinto, H. Yin, C. G. Cameron and S. A. McFarland,
Inorg. Chem., 2019, 58, 10778–10790.
–
and 4 are able to photogenerate H2O2 and superoxide anion (•O2 )
species, but complex 3, which is a mediocre performer, only raised
11 (a) Z. Lv, H. Wei, Q. Li, X. Su, S. Liu, K. Y. Zhang, W. Lv, Q. Zhao, X.
Li and W. Huang, Chem. Sci., 2018, 9, 502–512; (b) V.
Novohradsky, A. Rovira, C. Hally, A. Galindo, G. Vigueras, A.
Gandioso, M. Svitelova, R. Bresolí-Obach, H. Kostrhunova, L.
Markova, J. Kasparkova, S. Nonell, J. Ruiz, V. Brabec and V.
Marchán, Angew. Chem. Int. Ed. Engl., 2019, 58, 6311–6315.
12 J. Pracharova, G. Vigueras, V. Novohradsky, N. Cutillas, C. Janiak,
H. Kostrhunova, J. Kasparkova, J. Ruiz and V. Brabec, Chem. Eur.
J., 2018, 24, 4607–4619.
13 V. Novohradsky, J. Yellol, O. Stuchlikova, M. D. Santana, H.
Kostrhunova, G. Yellol, J. Kasparkova, D. Bautista, J. Ruiz and V.
Brabec, Chem. Eur. J., 2017, 23, 15294–15299.
14 V. Novohradsky, A. Zamora, A. Gandioso, V. Brabec, J. Ruiz and V.
Marchán, Chem. Comm., 2017, 53, 5523–5526.
15 J. Yellol, S. A. Pérez, A. Buceta, G. Yellol, A. Donaire, P. Szumlas, P.
J. Bednarski, G. Makhloufi, C. Janiak, A. Espinosa and J. Ruiz, J.
Med. Chem., 2015, 58, 7310–7327.
16 (a) T. C. Motley, L. Troian-Gautier, M. K. Brennaman and G. J.
Meyer, Inorg. Chem., 2017, 56, 13579–13592; (b) T. Sainuddin, J.
McCain, M. Pinto, H. Yin, J. Gibson, M. Hetu and S. A. McFarland,
Inorg. Chem., 2016, 55, 83–95.
–
•O2 levels. In addition, complexes 2 and 4 acted as translation
inhibitors under dark conditions as shown by fluorescence intensity
measurements of nascent protein synthesis in cancer cells, with
much lower toxicity towards normal cells. We are planning to
investigate the in vivo efficiency of compound 2 in the future.
This work was supported by the Ministerio de Investigación, Ciencia
y Universidades, FEDER funds (Project RTI2018-096891-B-I00 and
MultiMetDrugs network RED2018-102471-T) and Séneca-CARM
Foundation (Project 20857/PI/18). F.J.B. thanks to Fundación
Séneca-CARM for Project 20277/FPI/17. E.O. thanks AECC (Project
20277/FPI/17).
Conflicts of interest
There are no conflicts to declare.
17 R. Bevernaegie, S. A. M. Wehlin, E. J. Piechota, M. Abraham, C.
Philouze, G. J. Meyer, B. Elias and L. Troian-Gautier, J. Am. Chem.
Soc., 2020, 142, 2732–2737.
18 H. Huang, S. Banerjee, K. Qiu, P. Zhang, O. Blacque, T.
Malcomson, M. J. Paterson, G. J. Clarkson, M. Staniforth, V. G.
Stavros, G. Gasser, H. Chao and P. J. Sadler, Nat. Chem., 2019, 11,
1041–1048.
19 B. A. Teicher, Cancer Metast Rev, 1994, 13, 139–168.
20 V. Novohradsky, G. Vigueras, J. Pracharova, N. Cutillas, C. Janiak,
H. Kostrhunova, V. Brabec, J. Ruiz and J. Kasparkova, Inorg. Chem.
Front., 2019, 6, 2500–2513.
21 F. J. Ballester, E. Ortega-Forte, V. Porto, H. Kostrhunova, N.
Davila-Ferreira, D. Bautista, V. Brabec, M. D. Santana, F.
Domínguez and J. Ruiz, Chem. Comm., 2019, 55, 1140-1143.
Notes and references
1
2
E. Boros, P. J. Dyson and G. Gasser, Chem, 2020, 6, 41–60.
(a) M. Jakubaszek, B. Goud, S. Ferrari and G. Gasser, Chem.
Comm., 2018, 54, 13040–13059; (b) J. Karges, T. Yempala, M.
Tharaud, D. Gibson and G. Gasser, Angew. Chem. Int. Ed., 2020,
59, 7069 – 7075; (c) J. Bai, X. Jia, W. Zhen, W. Cheng and X. Jiang,
J. Am. Chem. Soc., 2018, 140, 106–109.
3
4
S. Monro, K. L. Colón, H. Yin, J. Roque, P. Konda, S. Gujar, R. P.
Thummel, L. Lilge, C. G. Cameron and S. A. McFarland, Chem.
Rev., 2019, 119, 797–828.
(a) H. S. Jung, J. Han, H. Shi, S. Koo, H. Singh, H.-J. Kim, J. L. Sessler,
J. Y. Lee, J.-H. Kim and J. S. Kim, J. Am. Chem. Soc., 2017, 139,
7595–7602. (b) J. Zou, J. Zhu, Z. Yang, L. Li, W. Fan, L. He, W. Tang,
4 | J. Name., 2012, 00, 1-3
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