Article pubs.acs.org/Organometallics
A Phosphorescent Rhenium(I) Tricarbonyl Polypyridine Complex Appended with a Fructose Pendant That Exhibits Photocytotoxicity and Enhanced Uptake by Breast Cancer Cells Kenneth Yin Zhang, Karson Ka-Shun Tso, Man-Wai Louie, Hua-Wei Liu, and Kenneth Kam-Wing Lo* Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, People’s Republic of China S Supporting Information *
ABSTRACT: We demonstrated that the cytotoxicity of a phosphorescent rhenium(I) polypyridine complex with a fructose pendant was enhanced upon irradiation and the cellular uptake of the complex was mediated by fructose transporters and inhibited by unmodified fructose but was independent of glucose-specific transporters. This complex has been used to image breast cancer cells, where fructose transporters are overexpressed.
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INTRODUCTION Glucose transporters (GLUTs) are a group of transmembrane proteins that are involved in the cellular uptake of carbohydrates such as glucose and the maintenance of a constant supply of carbohydrates for cellular metabolism.1 They differ from each other in substrate affinities, transport kinetics, and tissue-specific expression. Since cancer cells have been found to show a high expression level of GLUTs,2 glucose conjugates with radiation,3 fluorescence,4 and phosphorescence5 properties have been designed to monitor cellular glucose uptake and image cancer cells. It is noteworthy that the substrates of GLUTs are not limited to glucose; for example, GLUT5 selectively facilitates uptake of fructose.6 This transporter is overexpressed in breast cancer tissues such as MCF-7 and MDA-MB-231 cells, but its expression in other cancer cells and normal breast tissues is very limited.7 Thus, fructose-based probes may serve as an alternative targeting strategy for diagnosis of breast cancers. Fructose conjugates 1-Cy5.5-DF and 1-NBDF functionalized with the fluorescent dyes Cy5.5 and 7-nitro-1,2,3-benzadiazole (NBD), respectively, have been used to image breast cancer cells.8 However, 1-Cy5.5-DF shows efficient uptake by both breast and liver cancer cells, implying that the internalization is not mediated by fructose transporters. Although 1-NBDF is selectively taken up by breast cancer cells, there is a lack of quantitative evidence on the inhibited uptake by unmodified fructose, and the delivery of the probe through fructose transporters remains inconclusive.8 Recently, a fluorescent 1-amino-2,5-anhydro-D -mannitol-based probe (NBDM) has been applied to investigate GLUT-mediated cellular uptake.9 The uptake efficiency of this probe by MCF-7 © XXXX American Chemical Society
cells is about double that of D-fructose and NBDF due to the preference of GLUT5 on the cyclic furanose mimic over the furano/pyrano mixture of fructose conformers.9,10 In the past several years, the cellular uptake of phosphorescent transitionmetal complexes has attracted much interest.11 Phosphorescent rhenium(I) tricarbonyl polypyridine complexes are among the most extensively studied systems; for example, Coogan and coworkers have shown that the intracellular localization of rhenium(I) complexes depends highly on their lipophilicity and formal charges.12 Also, Ford and co-workers have designed a rhenium(I) complex as carbon monoxide releasing reagent and demonstrated its interesting photoactive carbon monoxide releasing behavior in live cells.13 Since the coordination chemistry of the group VII congeners rhenium and technetium is similar, the same set of polypyridine ligands, especially tridentate ligands, can be coordinated to the [Re(CO)3]+ and [99mTc(CO)3]+ cores to yield phosphorescent probes and radiopharmaceuticals, respectively. With our interest in the development of phosphorescent rhenium(I) complexes as biological probes,14 we anticipate that modification of these complexes with a fructose moiety will generate cellular fructose uptake indicators that may be utilized as selective breast cancer imaging reagents.15
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RESULTS AND DISCUSSION Herein we report the new phosphorescent rhenium(I) polypyridine fructose complex [Re(Ph2-phen)(CO)3(pyReceived: June 26, 2013
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dx.doi.org/10.1021/om400612f | Organometallics XXXX, XXX, XXX−XXX
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Chart 1. Structures of Complexes 1 and 2
fructose)](CF3SO3) (1; Ph2-phen = 4,7-diphenyl-1,10-phenanthroline, py-fructose = 3-(N-(1-deoxy- D -fructos-1-yl)aminocarbonyl)pyridine) and its fructose-free counterpart [Re(Ph2-phen)(CO)3(py-3-Et)](CF3SO3) (2; py-3-Et = 3-(Nethylaminocarbonyl)pyridine)14a (Chart 1). The synthetic route of the py-fructose ligand is shown in Scheme S1 (Supporting Information). Complex 1 was obtained by refluxing a mixture of [Re(Ph2-phen)(CO)3(CH3CN)](CF3SO3) and py-fructose in MeOH/THF under an inert atmosphere of nitrogen (see the Supporting Information for characterization and spectroscopic data). Upon photoexcitation, the complex displayed intense and long-lived triplet metalto-ligand charge-transfer (3MLCT) emission at 505−553 nm (Table S2 and Figure S3, Supporting Information). Modification of the rhenium(I) polypyridine core with a fructose unit did not cause noticeable effects to the phosphorescence properties, as evidenced by the similar photophysical data of complexes 1 and 2 (Table S2, Supporting Information). The hydrophilic fructose pendant of complex 1 rendered it less lipophilic than complex 2 (Table 1), which subsequently led to significant differences in the cellular uptake and cytotoxicity of the complexes. ICP-MS measurements revealed that the fructose complex 1 entered MCF-7 cells 4.4-fold less efficiently than the fructose-free complex 2 (Table 1). The intracellular rhenium concentrations of both complexes were much higher than that in the medium (50 μM), suggesting that the complexes were concentrated within the cells. Treatment of the cells with complexes 1 and 2 at 4 °C resulted in reduction of uptake by 65 and 72%, respectively, indicating that the translocation of the complexes across the membrane is an energy-requiring process. Costaining experiments involving MitoTracker Deep Red FM revealed that both complexes were localized in mitochondria, with colocalization coefficients of ca. 87 and 80%, respectively (Figure 1). The mitochondrial targeting properties of both complexes have been attributed to the lipophilic nature of the rhenium(I) tricarbonyl polypyridine core and their positive formal charge. The former facilitates the access of the complexes to the mitochondrial membrane, while the latter helps their accumulation in this organelle.16 The cytotoxic activity of the complexes toward MCF-7 in the dark was determined by the MTT assay, and the IC50 values of complexes 1 and 2 were ca. 9.6 and 3.9 μM, respectively (Table 1). Under the same experimental conditions, cisplatin exhibited a much larger IC50 value (73.0 ± 9.2 μM), which is reasonable in view of the high cisplatin
Figure 1. Confocal microscopy images of MCF-7 cells costained by (left) complexes 1 (top) and 2 (bottom), (middle) MitoTracker Deep Red FM, and (right) overlaid.
resistance of MCF-7 cells.17 Upon irradiation of complexstained MCF-7 cells at λ >365 nm for 30 min, the IC50 values decreased considerably to 2.0 and 0.3 μM, respectively (Table 1). Since the photoinduced cytotoxicity of transition-metal complexes may be associated with their singlet oxygen sensitizing properties,18 we have examined the possibility of singlet oxygen generation using 1,5-dihydroxynaphthalene (DHN) as an indicator. Excitation of a mixture of each complex and DHN resulted in hypochromicity and hyperchromicity of the absorption features at ca. 301 and 427 nm, respectively (Figure S4, Supporting Information), indicative of the oxidation of DHN to Juglone by singlet oxygen. The DHN photooxidation yields were determined to be ca. 70% for both complexes (Table 1). While 1O2 appears to play a role in the photoinduced cell death, it is noteworthy that the photoinduced cytotoxicity of transition-metal complexes has been related to other causes such as DNA modification19 and NO and CO release.19,20 After the uptake and cytotoxicity of the complexes were established, we investigated the possible selectivity in the cellular uptake of complex 1. Six cell lines were used in this study, which included two human breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231), two nonbreast cancer cell lines (human lung epithelial carcinoma A549 and human hepatocarcinoma HepG2), and two nontransformed cell lines (mouse embryonic fibroblast NIH/3T3 and human embryonic kidney-293 HEK293T). These cell lines were selected because the expression levels of fructose transporters in these cells are very different.7 The MTT assay results confirmed that incubation with both complexes 1 and 2 for 1 h did not cause detectable cell death (cell viability >98%) for all of these cell lines under our experimental conditions. The intracellular amounts of rhenium taken up by the cells upon incubation with the complexes (50 μM, 37 °C, 1 h) were determined. The intracellular amounts of the fructose complex 1 in all six cell lines were lower than those of the fructose-free complex 2 (Figure 2). This is reasonable because the more lipophilic complex 2 underwent internalization through a more efficient,
Table 1. Lipophilicity, Cellular Uptake, and Cytotoxicity (Dark and Light), and Photooxidation Yields of Complexes 1 and 2 complex
log Po/w
[Re]/mMa
IC50/μM (dark)b
IC50/μM (light)b
DHN photooxidation yield/%c
1 2
2.79 3.63
0.42 ± 0.01 1.83 ± 0.08
9.6 ± 0.6 3.9 ± 0.3
2.0 ± 0.04 0.3 ± 0.01
69.7 67.1
a Concentration of rhenium associated with an average MCF-7 cell (mean volume of 3.1 pL) upon incubation with the complexes (50 μM) in a sugar-free medium at 37 °C for 1 h, as determined by ICP-MS. bMCF-7 cells, incubation in high glucose DMEM for 48 h. cIrradiation time 4 h.
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phosphorescent iridium(III) fructose complexes15 exhibit similar uptake inhibition, as revealed by confocal microscopy, this is the first report on the use of a nonradioactive phosphorescent compound to quantitatively monitor changes of uptake caused by native fructose. Importantly, we also found that this fructose-dependent cellular uptake of complex 1 was an energy-requiring process, since no significant inhibitory effect of exogenous fructose on the cellular uptake was observed at 4 °C (data not shown). Although the above experiments indicated that the uptake of complex 1 is mediated by fructose transporters, it is interesting to know whether there are any glucose-specific GLUTs that assist in the uptake. Treatment of cells with glucose (50 mM) in a sugar-free cell culture medium or the glucose-uptake inhibitors fasentin (80 μM) and cytochalasin B (10 μM)21 for 1 h had negligible effects on the uptake of both complexes 1 and 2 (uptake amounts within ± 5%). Thus, the internalization of the complexes did not occur via a glucose-specific GLUTmediated pathway. This is consistent with the results that complex 1 showed high selectivity for breast tumors over other nonbreast cancers or nontransformed cells, even if the latter overexpressed glucose-specific GLUTs. To further investigate the selectivity of complex 1 for breast cancer cells, we have designed a coculture experiment, in which cancerous MCF-7 and nontransformed HEK293T cells were grown in the same culture dish and incubated with complex 1 (50 μM, 37 °C, 1 h). The confocal microscopy image clearly showed that the emission of the MCF-7 cells due to complex 1 was much higher than that of HEK293T cells (Figure 5). This highlights the possible use of the fructose complex 1 as a biological imaging reagent for breast cancer cells and a phosphorescent fructose-uptake indicator. These results, together with the mitochondrial targeting property and photocytotoxic activity of complex 1, are anticipated to inspire the development of phototherapeutics for breast cancers.
Figure 2. Cellular uptake of rhenium by an average cell upon incubation with complexes 1 (left) and 2 (right) (50 μM, 37 °C, 1 h).
nonspecific diffusion uptake pathway. Interestingly, we found that the uptake of the fructose complex 1 by MCF-7 and MDAMB-231 was much more efficient than that by A549, HepG2, NIH/3T3, and HEK293T cells (Figure 2, left). This is in accordance with the fact that the breast cancer cells MCF-7 and MDA-MB-231 overexpress fructose transporters, while nonbreast cancer and normal cells show minimal expression.7 In sharp contrast, the uptake of complex 2 did not show any dependence on the cell lines (Figure 2, right). The cytotoxicity of complexes 1 and 2 toward the same set of cell lines has been examined (Table 2 and Figures S5 and S6, Supporting Information). Importantly, the fructose complex 1 exhibited higher cytotoxic activity toward breast adenocarcinoma among the four cancer cell lines (Table 2 and Figure S5, Supporting Information), while complex 2 did not show similar selectivity (Table 2 and Figure S6, Supporting Information). These interesting results illustrate that the fructose pendant of complex 1 enables it to be recognized and taken up more efficiently by the breast cancer cell lines, causing higher cytotoxicity. To confirm that the cellular internalization process of complex 1 was indeed mediated by fructose transporters, we performed the following uptake competition experiments. Unmodified fructose (0−50 mM) was added to the sugar-free cell culture medium. If the uptake of complex 1 involves fructose transporters such as GLUT5, there should be a competition between complex 1 and exogenous fructose for the same transporter. Confocal microscopy images showed that addition of 50 mM of exogenous fructose significantly inhibited the uptake of complex 1 by the breast cancer cells MCF-7 and MDA-MB-231 but not by the other four types of cells (Figure 3). Also, the uptake of complex 2 by all six cell lines was independent of the presence of unmodified fructose (Figure S7, Supporting Information). ICP-MS measurements quantitatively showed that the inhibition of the uptake of complex 1 by the breast cancer cells was dependent on the concentration of exogenous fructose, and about 40% of the uptake was inhibited at [fructose] = 50 mM (Figure 4). Again, for the other four cell lines, the uptake of both complexes was independent of exogenous fructose (Figure S8, Supporting Information). Although the fluorescent fructose conjugate 1-NBDF8 and
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CONCLUSION In summary, we have prepared a phosphorescent rhenium(I)based fructose-uptake indicator and breast cancer cell imaging reagent. This complex was localized in the mitochondria and exhibited photocytotoxic activity. Also, it showed selective accumulation in MCF-7 and MDA-MB-231 breast cancer cells over other cancer and noncancer cells. The inhibited uptake of the complex by native fructose clearly indicated the involvement of fructose transporters. Related studies of other phosphorescent transition-metal fructose conjugates are in progress.
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EXPERIMENTAL SECTION
All solvents were of analytical reagent grade and purified according to standard procedures.22 Chemicals for the synthesis of ligands and complexes were purchased from Acros or Aldrich. MCF-7, MDA-MB231, A549, HEK293T, HepG2, and NIH/3T3 cells were obtained from the American Type Culture Collection. High glucose Dulbecco’s modified Eagle’s medium (DMEM), phosphate-buffered saline (PBS), fetal bovine serum (FBS), trypsin-EDTA, and penicillin/streptomycin were purchased from Invitrogen.
Table 2. Cytotoxicity (IC50 values/μM, 48 h) of Complexes 1 and 2 toward Six Different Cell Lines complex
MCF-7
MDA-MB-231
A549
HepG2
NIH/3T3
HEK293T
1 2
9.6 ± 0.6 3.9 ± 0.3
4.9 ± 0.4 2.3 ± 0.2
26.8 ± 2.1 2.6 ± 0.3
33.9 ± 0.9 5.7 ± 0.4
2.1 ± 0.3 1.8 ± 0.3
6.7 ± 0.7 2.1 ± 0.2
C
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Figure 3. Laser-scanning confocal microscopy images of six different types of cells upon incubation of complex 1 (50 μM, 37 °C, 1 h) in the absence or presence of 50 mM fructose. Note that the emission intensity can only be considered qualitatively for comparison purposes, and readers are referred to the ICP-MS data (Figures 2 and 4 and Figure S8, Supporting Information) for quantitative information.
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ASSOCIATED CONTENT
S Supporting Information *
Text, a scheme, tables, and figures giving details of the synthesis, characterization, spectroscopic and photophysical properties, cellular uptake, cytotoxicity, and singlet oxygen generation of complexes 1 and 2. This material is available free of charge via the Internet at http://pubs.acs.org.
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Figure 4. Relative cellular uptake of rhenium by an average MCF-7 (left) and MDA-MB-231 (right) cell upon incubation with complexes 1 (shaded) and 2 (empty) (50 μM, 37 °C, 1 h) in a medium containing various concentrations of fructose. The uptake of the complexes was relative to their corresponding uptake at [fructose] = 0 mM.
AUTHOR INFORMATION
Corresponding Author
*K.K.-W.L.: e-mail,
[email protected]; fax, +852 3442 0522. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank The Hong Kong Research Grants Council (Project No. CityU 102212) and City University of Hong Kong (Project No. 9667081) for financial support. We thank Mr. Kenneth King-Kwan Lau, Mr. Michael Wai-Lun Chiang, and Mr. HoHang Chan for their assistance.
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Figure 5. Fluorescence (left), brightfield (middle), and overlaid (right) confocal microscopy images of a coculture of MCF-7 and HEK293T cells treated with complex 1 (50 μM, 37 °C, 1 h).
REFERENCES
(1) (a) Bell, G. I.; Burant, C. F.; Takeda, J.; Gould, G. W. J. Biol. Chem. 1993, 268, 19161. (b) Mueckler, M. Eur. J. Biochem. 1994, 219, 713. (c) Medina, R. A.; Owen, G. I. Biol. Res. 2002, 35, 9. (d) Macheda, M. L.; Rogers, S.; Best, J. D. J. Cell. Physiol. 2005, 202, 654. (2) Warburg, O. Science 1956, 123, 309. (3) Waki, A.; Kato, H.; Yano, R.; Sadato, N.; Yokoyama, A.; Ishii, Y.; Fujibayashi, Y.; Yonekura, Y. Nucl. Med. Biol. 1998, 25, 593. (4) (a) O’Neil, R. G.; Wu, L.; Mullani, N. Mol. Imaging Biol. 2005, 7, 388. (b) Park, J.; Lee, H. Y.; Cho, M.-H.; Park, S. B. Angew. Chem., Int. Ed. 2007, 46, 2018. (5) (a) Gottschaldt, M.; Schubert, U. S.; Rau, S.; Yano, S.; Vos, J. G.; Kroll, T.; Clement, J.; Hilger, I. ChemBioChem 2010, 11, 649. (b) Louie, M.-W.; Liu, H.-W.; Lam, M. H.-C.; Lam, Y.-W.; Lo, K. K.W. Chem.Eur. J. 2011, 17, 8304. (c) Law, W. H.-T.; Lee, L. C.-C.; Louie, M.-W.; Liu, H.-W.; Ang, T. W.-H.; Lo, K. K.-W. Unpublished results. (6) (a) Kayano, T.; Burant, C. F.; Fukumoto, H.; Gould, G. W.; Fan, Y. S.; Eddy, R. L.; Byers, M. G.; Shows, T. B.; Seino, S.; Bell, G. I. J. Biol. Chem. 1990, 265, 13276. (b) Burant, C. F.; Takeda, J.; BrotLaroche, E.; Bell, G. I.; Davidson, N. O. J. Biol. Chem. 1992, 267, 14523. (7) (a) Zamora-León, S. P.; Golde, D. W.; Concha, I. I.; Rivas, C. I.; Delgado-López, F.; Baselga, J.; Nualart, F.; Vera, J. C. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 1847. (b) Chan, K. K.; Chan, J. Y. W.; Chung, K.
Synthesis of [Re(Ph2-phen)(CO)3(py-fructose)](CF3SO3) (1). A mixture of [Re(Ph2-phen)(CO)3(CH3CN)](CF3SO3) (198 mg, 0.25 mmol) and py-fructose (70 mg, 0.25 mmol) was refluxed in THF/ MeOH (20 mL, 1:1, v/v) under nitrogen for 12 h. The solution was evaporated to dryness to give a yellow solid. Recrystallization of the crude product from CH2Cl2/diethyl ether afforded the complex as yellow crystals. Yield: 274 mg (66%). 1H NMR (300 MHz, CD3OD, 298 K, relative to Me4Si): δ 9.79 (d, 2H, J = 5.1 Hz, H2, H9 Ph2phen), 8.80−8.70 (m, 2H, H2, H6 pyridine), 8.32−8.13 (m, 5H, H3, H5, H6, H8 Ph2-phen, H4 of pyridine), 7.75−7.62 (m, 10H, C6H5 Ph2-phen), 7.45 (t, J = 7.0 Hz, 1H, H4 pyridine), 3.95−3.45 ppm (m, 7H, H fructose ring). 13C NMR (100 MHz, DMSO-d6, 298 K): 195.78, 192.23, 163.77, 163.69, 163.48, 155.05, 154.48, 154.38, 152.11, 151.36, 147.13, 139.29, 135.56, 135.46, 133.22, 130.54, 130.44, 130.41, 130.39, 130.34, 129.70, 129.66, 128.81, 128.79, 128.66, 128.05, 127.92, 127.86, 127.51, 127.00, 126.50, 126.37, 125.92, 122.72, 119.52, 116.31, 104.08, 101.51, 98.18, 98.00, 83.29, 82.42, 81.41, 78.05, 75.77, 75.66, 69.86, 69.64, 69.49, 63.84, 63.18, 45.83, 44.97 ppm; IR (KBr): ν 3444 (O−H, N−H), 2918 (C−H), 2032 (CO), 1919 (CO), 1163 (CF3SO3−), 1030 cm−1 (CF3SO3−). Positive-ion ESI-MS: ion cluster at m/z 887 [M − CF3SO3−]+. Anal. Calcd for C40H32N4O12SF3Re· 2.5H2O: C, 44.44; H, 3.45; N, 5.18. Found: C, 44.28; H, 3.48; N, 4.99. D
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K. W.; Fung, K.-P. J. Cell. Biochem. 2004, 93, 1134. (c) Godoy, A.; Ulloa, V.; Rodrı ́guez, F.; Reinicke, K.; Yañez, A. J.; Garci, M. D.; Medina, R. A.; Carrasco, M.; Barberis, S.; Castro, T.; Martı ́nez, F.; Koch, X.; Vera, J. C.; Poblete, M. T.; Figueroa, C. D.; Peruzzo, B.; Perez, F.; Nualart, F. J. Cell. Physiol. 2006, 207, 614. (8) Levi, J.; Cheng, Z.; Gheysens, O.; Patel, M.; Chan, C. T.; Wang, Y.; Namavari, M.; Gambhir, S. S. Bioconjugate Chem. 2007, 18, 628. (9) Tanasova, M.; Plutschack, M.; Muroski, M. E.; Sturla, S. J.; Strouse, G. F.; McQuade, D. T. ChemBioChem 2013, 14, 1263. (10) Tatibouët, A.; Yang, J.; Morin, C.; Holman, G. D. Bioorg. Med. Chem. 2000, 8, 1825. (11) See: for example: (a) Fernández-Moreira, V.; ThorpGreenwood, F. L.; Coogan, M. P. Chem. Commun. 2010, 46, 186. (b) Zhao, Q.; Li, F.; Huang, C. Chem. Soc. Rev. 2010, 39, 3007. (c) Lo, K. K.-W.; Li, S. P.-Y.; Zhang, K. Y. New J. Chem. 2011, 35, 265. (d) Zhao, Q.; Huang, C.; Li, F. Chem. Soc. Rev. 2011, 40, 2508. (e) Lo, K. K.-W.; Choi, A. W.-T.; Law, W. H.-T. Dalton Trans. 2012, 41, 6021. (12) Amoroso, A. J.; Arthur, R. J.; Coogan, M. P.; Court, J. B.; Fernández-Moreira, V.; Hayes, A. J.; Lloyd, D.; Millet, C.; Pope, S. J. A. New J. Chem. 2008, 32, 1097. (13) Pierri, A. E.; Pallaoro, A.; Wu, G.; Ford, P. C. J. Am. Chem. Soc. 2012, 134, 18197. (14) (a) Lo, K. K.-W.; Tsang, K. H.-K.; Hui, W.-K.; Zhu, N. Inorg. Chem. 2005, 44, 6100. (b) Lo, K. K.-W.; Louie, M.-W.; Sze, K.-S.; Lau, J. S.-Y. Inorg. Chem. 2008, 47, 602. (c) Choi, A. W.-T.; Louie, M.-W.; Li, S. P.-Y.; Liu, H.-W.; Chan, B. T.-N.; Lam, T. C.-Y.; Lin, A. C.-C.; Cheng, S.-H.; Lo, K. K.-W. Inorg. Chem. 2012, 51, 13289. (15) We have recently reported the cellular uptake properties of two phosphorescent iridium(III) fructose complexes. Lo, K. K.-W.; Law, W. H.-T.; Chan, J. C.-Y.; Liu, H.-W.; Zhang, K. Y. Metallomics 2013, 5, 808. (16) Casey, J. R.; Grinstein, S.; Orlowski, J. Nat. Rev. Mol. Cell Biol. 2010, 11, 50. (17) Yde, C. W.; Issinger, O. G. Int. J. Oncol. 2006, 29, 1397. (18) (a) Gao, R.; Ho, D. G.; Hernandez, B.; Selke, M.; Murphy, D.; Djurovich, P. I.; Thompson, M. E. J. Am. Chem. Soc. 2002, 124, 14828. (b) Abdel-Shafi, A. A.; Bourdelande, J. L.; Ali, S. S. Dalton Trans. 2007, 2510. (c) Djurovich, P. I.; Murphy, D.; Thompson, M. E.; Hernandez, B.; Gao, R.; Hunt, P. L.; Selke, M. Dalton Trans. 2007, 3763. (d) Lai, S. W.; Liu, Y.; Zhang, D.; Wang, B.; Lok, C. N.; Che, C. M.; Selke, M. Photochem. Photobiol. 2010, 86, 1414. (e) Kastl, A.; Dieckmann, S.; Wähler, K.; Völker, T.; Kastl, L.; Merkel, A. L.; Vultur, A.; Shannan, B.; Harms, K.; Ocker, M.; Parak, W. J.; Herlyn, M.; Meggers, E. ChemMedChem 2013, 8, 924. (f) Li, S. P.-Y.; Lau, C. T.-S.; Louie, M.W.; Lam, Y.-W.; Cheng, S. H.; Lo, K. K.-W. Biomaterials 2013, 34, 7519. (19) Schztzschneider, U. Eur. J. Inorg. Chem. 2010, 1451. (20) (a) Ford, P. C.; Bourassa, J.; Miranda, K.; Lee, B.; Lorkovic, I.; Boggs, S.; Kudo, S.; Laverman, L. Coord. Chem. Rev. 1998, 171, 185. (b) Rimmer, R. D.; Pierri, A. E.; Ford, P. C. Coord. Chem. Rev. 2012, 256, 1509. (21) Wood, T. E.; Dalili, S.; Simpson, C. D.; Hurren, R.; Mao, X.; Saiz, F. S.; Gronda, M.; Eberhard, Y.; Minden, M. D.; Bilan, P. J.; Klip, A.; Batey, R. A.; Schimmer, A. D. Mol. Cancer Ther. 2008, 7, 3546. (22) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals; Pergamon: Oxford, U.K., 1997.
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