In-Cell Activation of Organo-Osmium(II) Anticancer Complexes

Article abstract of DOI:10.1002/anie.201610290

The family of iodido Os^IIarene phenylazopyridine complexes [Os(η⁶-p-cym)(5-R¹-pyridylazo-4-R²-phenyl))I]⁺(where p-cym=para-cymene) exhibit potent sub-micromolar antiproliferative activity towards human cancer cells and are active in vivo. Their chemical behavior is distinct from that of cisplatin: they do not readily hydrolyze, nor bind to DNA bases. We report here a mechanism by which they are activated in cancer cells, involving release of the I^?ligand in the presence of glutathione (GSH). The X-ray crystal structures of two active complexes are reported, 1-I (R¹=OEt, R²=H) and 2-I (R¹=H, R²=NMe₂). They were labelled with the radionuclide¹³¹I (β^?/γ emitter, t_1/28.02 d), and their activity in MCF-7 human breast cancer cells was studied. 1-[¹³¹I] and 2-[¹³¹I] exhibit good stability in both phosphate-buffered saline and blood serum. In contrast, once taken up by MCF-7 cells, the iodide ligand is rapidly pumped out. Intriguingly, GSH catalyzes their hydrolysis. The resulting hydroxido complexes can form thiolato and sulfenato adducts with GSH, and react with H₂O₂generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo-osmium complexes.

Full text of DOI:10.1002/anie.201610290

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201610290
German Edition: DOI: 10.1002/ange.201610290
Anticancer Agents
In-Cell Activation of Organo-Osmium(II) Anticancer Complexes
Russell J. Needham+, Carlos Sanchez-Cano+, Xin Zhang, Isolda Romero-Canelꢀn,
Abraha Habtemariam, Margaret S. Cooper, Levente Meszaros, Guy J. Clarkson,
Philip J. Blower, and Peter J. Sadler*
1
2
Abstract: The family of iodido OsII arene phenylazopyridine
complexes [Os(h6-p-cym)(5-R1-pyridylazo-4-R2-phenyl))I]+
(where p-cym = para-cymene) exhibit potent sub-micromolar
antiproliferative activity towards human cancer cells and are
active in vivo. Their chemical behavior is distinct from that of
cisplatin: they do not readily hydrolyze, nor bind to DNA
bases. We report here a mechanism by which they are activated
in cancer cells, involving release of the IÀ ligand in the presence
of glutathione (GSH). The X-ray crystal structures of two
active complexes are reported, 1-I (R1 = OEt, R2 = H) and 2-I
(R1 = H, R2 = NMe2). They were labelled with the radionuclide
131I (bÀ/g emitter, t1/2 8.02 d), and their activity in MCF-7
human breast cancer cells was studied. 1-[131I] and 2-[131I]
exhibit good stability in both phosphate-buffered saline and
blood serum. In contrast, once taken up by MCF-7 cells, the
iodide ligand is rapidly pumped out. Intriguingly, GSH
catalyzes their hydrolysis. The resulting hydroxido complexes
can form thiolato and sulfenato adducts with GSH, and react
with H2O2 generating hydroxyl radicals. These findings shed
new light on the mechanism of action of these organo-osmium
complexes.
and 2-I·PF6 (R = H, R = NMe2) show long Os I bonds
(2.6974(2) and 2.7083(2) ꢀ, respectively), and relatively flat
N,N-chelated phenylazopyridine ligands (Figure 1). Unlike
À
Figure 1. Complexes studied here, HPLC retention times, and ORTEP
diagrams for complexes 1-I and 2-I. Ellipsoids are shown at the 50%
probability level. H atoms, counter ions and solvent molecules are
omitted for clarity.
Organometallic complexes show promise as a new gener-
ation of anticancer drugs. These include cyclopentadienyl
complexes of FeII, RhIII and IrIII, and arene complexes of RuII,
OsII, RhIII and IrIII.[1] They offer the prospect of mechanisms
of action that differ from PtII complexes, which are currently
the most widely-used drugs in the clinic. Organometallic
drugs have the potential to expand the range of treatable
cancers, cause fewer side-effects, and provide activity against
Pt-resistance, a current clinical problem. OsII arene com-
plexes containing a chelated phenylazopyridine ligand, [Os-
(h6-p-cym)(5-R1-pyridylazo-4-R2-phenyl))I]+, possess typical
half-sandwich “piano-stool” structures. The X-ray crystal
structures of complexes 1-I·PF6·0.5EtOH (R1 = OEt, R2 = H)
cisplatin, 1-I and 2-I are relatively inert. They do not readily
hydrolyze nor bind to DNA in vitro.[2] However, 1-I and 2-I
exhibit activity that is equal to or greater than that of the
clinical drug cisplatin in a wide range of cancer cell lines,
despite having a contrasting profile of chemical reactivity
(Table 1), and are capable of overcoming resistance to clinical
platinum drugs.[2] Complex 2-I is 49 ꢁ more potent than
cisplatin in a panel of 809 cancer cell lines,[3] and active in
vivo.[4] We have shown that this drug-candidate is capable of
modulating the cellular redox balance, increasing dramati-
cally the production of reactive oxygen species (ROS) in
[*] R. J. Needham,[+] Dr. C. Sanchez-Cano,[+] X. Zhang,
Dr. I. Romero-Canelꢀn, Dr. A. Habtemariam, Dr. G. J. Clarkson,
Prof. Dr. P. J. Sadler
Table 1: Antiproliferative activity of complexes 1 and 2 towards A2780
Department of Chemistry, University of Warwick
Coventry, CV4 7AL (UK)
E-mail: p.j.sadler@warwick.ac.uk
human ovarian and MCF-7 breast cancer cells.
Complex
IC50 [mm]
A2780
MCF-7
Dr. M. S. Cooper, Dr. L. Meszaros, Prof. Dr. P. J. Blower
Division of Imaging Sciences and Biomedical Engineering
King’s College London
1-I
1-Cl
1-OH
2-I
2-Cl
0.92Æ0.02
15.1Æ0.5
0.27Æ0.02
0.15Æ0.02[a]
1.8Æ0.3[a]
1.2Æ0.2
1.2Æ0.2
n.d.
14.3Æ0.3
0.20Æ0.01[a]
1.1Æ0.8[a]
7.4Æ0.2
St. Thomas Hospital, London, SE1 7EH (UK)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201610290.
cisplatin
[a] Ref. [2].
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cancer cells, and has enhanced potency when used in
combination with low doses of l-buthionine sulfoximine (l-
BSO), which depletes cellular levels of glutathione (GSH, g-
l-Glu-l-Cys-Gly).[5] GSH is an important cellular antioxidant
that plays a key role in the detoxification of ROS[6] and
platinum drugs.[7] The organo-Ru analogue of 2-I binds to
GSH and catalyzes its oxidation to GSSG, probably through
redox mediation by the azo group.[8] Furthermore, the Ru–SG
thiolate adduct formed from chlorido RuII arene ethylenedi-
amine complexes can be oxidized to Ru-SOG sulfenate
species in the presence of O2; these reactive adducts facilitate
the interaction between the Ru complexes and guanine/
DNA.[9] Other Ru complexes can also be activated by GSH.[10]
Additionally, the coupling of anticancer activity to redox
reactions of metals and ligands in organometallic complexes
provides intriguing possibilities for novel mechanisms of
action, as is illustrated especially by the ferrociphen series of
complexes.[11] We show here that, surprisingly, the antioxidant
GSH not only promotes activation of iodido OsII arene
azopyridine complexes through aquation, but also forms
sulfenate adducts.
Figure 2. Release of free 131I into the supernatant of cell culture
medium at various times after incubation with 1-[131I] ( ) or 2-[131I]
^
(&), in the absence (dashed lines) or presence (solid lines) of MCF-7
breast cancer cells. Percentages were determined by HPLC peak
integrals.
Initially, we used the bÀ/g emitter 131I (t1/2 8.02 d) as
a radiotracer to label 1-I and 2-I and study their cell uptake
and efflux. Complexes 1-[131I] and 2-[131I] were synthesized by
exchange of ClÀ in 1-Cl and 2-Cl (Figure 1), by reacting
a large excess of complex with Na131I. The exchange was
complete in 2 h for 1-Cl, but required 18 h for 2-Cl. Reactions
were followed by radio-TLC chromatograms (Figure S1 in the
Supporting Information), and reverse-phase HPLC with
simultaneous detection at 254 nm and g-emission (Figure S2).
Os-OH, Os-Cl and Os-I species were identified using LC-MS,
and the formation of Os-131I was confirmed by performing the
radio-labelling in presence of 0.5 mol equiv of cold NaI
(Figures 1 and S2). Complexes 1-[131I] and 2-[131I] were
purified via preparative HPLC to remove residual chlorido
complex, diluted in PBS to pH 6–7, then frozen immediately
and stored at 193 K to minimize decomposition until
required.
Figure 3. Cellular accumulation of 131I in MCF-7 breast cancer cells at
various times after incubation with 2-[131I].
Both 1-[131I] and 2-[131I] exhibited good stability after 24 h
at 310 K in human blood serum (ca. 25%, and 11% iodide
released, respectively), and cell culture medium (ca. 27%,
and 14%, Figure S3). However, when MCF-7 breast cancer
cells were treated with the tracer-complexes, we observed
a rapid release of free 131I into the supernatant. After 24 h,
97% and 99% of 1-[131I] and 2-[131I], respectively, lost the
radioactive iodide ligand, the rate of loss being greater for 2-
readily under either intracellular (23 mm) or intranuclear
(4 mm) levels of chloride (Figure S5), and therefore the
observed loss of the iodido ligand might arise from interaction
with intracellular biomolecules.
These surprising results led us to study the reactions
between 1-I or 2-I (75 mm) and GSH (1 mol. equiv) using
HPLC. Surprisingly, these experiments showed that the
À
hydrolysis of the Os I bond is promoted by GSH: a new set
[
131I] (Figure 2). Interestingly, the maximum amount of intra-
of peaks identified as 1-OH and 2-OH by LC-MS began to
appear after 3 h of incubation and no GSH adducts were
detected. The extent of hydrolysis was greater for 1-I (71%)
than for 2-I (33%) after 24 h (Figure 4 and S7). In contrast,
less than 1% of 1-OH and 2-OH was observed when 1-I and
2-I were incubated under the same conditions in the absence
of GSH (Figure S8), indicating that hydrolysis is induced by
the presence of the thiol-containing tripeptide. The pKa of 1-
OH2 was determined by NMR titration to be 4.55 Æ 0.01,
indicating that the more stable Os-OH species will predom-
inate at physiological pH values (ca. 7.4) over the more labile
Os-OH2 species (Figure S9). Furthermore, incubation of 1-I
or 2-I with a large excess of GSH (100 mol. equiv) accelerated
cellular 131I was observed after only 5 min for both 1-[131I] and
2-[131I] (0.8% and 1.8% of total 131I/106 cells, respectively).
After this time, the level of accumulated 131I declined steadily
(Figure 3 and S4).
We have shown previously that significant amounts of
complex 2-I are taken up by cancer cells within the first
30 min and the amount of Os accumulated increases with
longer incubation times.[12] Thus the free iodide detected here
might arise from the efflux of 131I, perhaps via chloride
transport channels.[13] In general, iodide transport mecha-
nisms appear to be little studied apart from cells in the
thyroid. However, complex 1-I was found not to hydrolyze
2
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Figure 4. HPLC separation of products from reactions of complexes with GSH in 7.5 mm phosphate buffer (pH 7.4) at 310 K for various times.
A) 1 mm 1-OH with 1 mol. equiv GSH in 0.1m phosphate buffer. B) 75 mm 1-I with 1 mol equiv GSH, and C) 75 mm 1-I with 100 mol equiv GSH.
their hydrolysis rates dramatically (complete in 3 h for 1-I and
6 h for 2-I; Figures 4 and S7). Moreover, the formation of
thiolato (GSÀ) and sulfenato (GSOÀ) adducts of 1-I and 2-I
were observed (Figures 4 and S7), and confirmed by LC-MS
(Figure S10 and Table S1). This appears to be the first report
of OsII–sulfenato adducts. Similar adducts were observed
when 1-OH was incubated with just 1 mol. equiv of GSH,
À
suggesting that hydrolysis of the Os I bond is essential for
GSH binding to 1-I and 2-I. Complexes 1-Cl and 2-Cl behaved
in a similar way, but showed faster rates of hydrolysis and
GSH binding, indicating greater reactivity than their Os-I
analogues (Figure S11). Similar results were observed when
1 mol. equiv N-acetyl-l-cysteine (NAC) or ascorbic acid (also
reducing agents) were used instead of GSH (Figures S12 and
S13). Interestingly, the presence of 30%v/v acetone almost
completely hindered the reaction of 2-I with NAC and
hydrolysis of 2-I (Figure S14), accounting for our previous
observation of a lack of reaction between 2-I and NAC.[2]
GSH-mediated hydrolysis of 1-I and 2-I can therefore
generate Os species that are more reactive than the parent
iodido complexes. When the reaction of 2-I (75 mm) and GSH
(0.08–7.5 mm) was repeated in the presence of an intracellular
concentration of NaCl (25 mm), a new peak corresponding to
2-Cl was observed after 24 h incubation with GSH concen-
trations up to ca. 2 mm. Incubations at higher GSH concen-
trations led to the formation of 2-OH, thiolato and sulfenato
adducts only (Figure S15).
Complexes 1-I and 2-I and their Cl and hydroxido
analogues react with H2O2, a ROS overproduced in cancer
cells, to generate hydroxyl radicals detected by EPR spec-
troscopy using the spin-trap 5-diethoxyphosphoryl-5-methyl-
1-pyrroline N-oxide (DEPMPO, Figures 5 and S16). The
efficiency of OHC radical generation followed the trend Os-
OH > Os-Cl > Os-I. This is the same reactivity trend
observed for reactions with GSH, and suggests that intra-
cellular hydrolysis of 1-I and 2-I might be a key activation step
for their biological activity. Additionally, the low reactivity of
iodido complexes 1-I and 2-I compared to 1-Cl and 2-Cl might
explain why chlorido derivatives are 10 ꢁ less active in
inhibiting the proliferation of cancer cells than their iodido
analogues (Table 1). The chlorido complexes might undergo
side-reactions more readily, leading to detoxification before
reaching target sites. Interestingly, 1-OH is more active than
Figure 5. X-band EPR spectra showing A) trapping of OH radicals by
the spin-trap DEPMPO (6 mm) from reaction of H2O2 (10 mm) with 1-
OH (1 mm) in 75 mm phosphate buffer, pH 7.4, and B) quenching in
presence of ethanol (10 mm). The EPR parameters of the trapped
radical are typical of trapped HOC (g: 2.01, aNNO: 14.02 G, aP: 47.01 G,
aHb: 13.22 G).[14]
1-I in A2780 but not MCF-7 cells. This might be due to higher
levels of GSH in MCF-7 compared to A2780 cells (ca. 40
versus 30 nmol GSH/mgÀ1 protein, respectively)[15] but other
factors may also play a role.
In conclusion, we show that, in contrast to platinum
anticancer drugs, GSH can provide a route for intracellular
activation of osmium prodrugs 1-I and 2-I (Figure S17). This
À
involves hydrolysis of the Os I bond, most probably via redox
mediation by the azo group and transformation into more
reactive hydroxido forms 1-OH and 2-OH, releasing the IÀ
ions from the cell in the process. Such Os-OH complexes can
bind to ClÀ ions or GSH, forming chlorido, thiolato and also
Os-sulfenato adducts, and can also catabolize H2O2 generat-
ing OHC radicals. The facile ability of GSH to form sulfenato
adducts (compared to NAC) was especially notable. Organo-
osmium complexes can cause dramatic changes in the redox
state of cancer cells[5] and these new insights into their
activation mechanism pave the way for furthering our under-
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standing of their target sites, which might involve attack by
osmium on proteins in the cytoplasm and mitochondria.
[1] a) A. M. Pizarro, A. Habtemariam, P. J. Sadler, Top. Organomet.
Chem. 2010, 32, 21 – 56; b) C. G. Hartinger, P. J. Dyson, Chem.
Soc. Rev. 2009, 38, 391 – 401; c) G. Gasser, I. Ott, N. Metzler-
Nolte, J. Med. Chem. 2011, 54, 3 – 25; d) S. S. Braga, A. M. S.
Silva, Organometallics 2013, 32, 5626 – 5639; e) Z. Liu, P. J.
Sadler, Acc. Chem. Res. 2014, 47, 1174 – 1185; f) S. J. Lucas,
R. M. Lord, A. M. Basri, S. J. Allison, R. M. Phillips, A. J.
Blacker, P. C. McGowan, Dalton Trans. 2016, 45, 6812 – 6815;
g) W. Kandioller, E. Balsano, S. M. Meier, U. Jungwirth, S.
Gçschl, A. Roller, M. A. Jakupec, W. Berger, B. K. Keppler,
C. G. Hartinger, Chem. Commun. 2013, 49, 3348 – 3350; h) M.
Gras, B. Therrien, G. Sꢃss-Fink, A. Casini, F. Edafe, P. J. Dyson,
J. Organomet. Chem. 2010, 695, 1119 – 1125; i) M. Streib, K.
Krꢄling, K. Richter, X. Xie, H. Steuber, E. Meggers, Angew.
Chem. Int. Ed. 2014, 53, 305 – 309; Angew. Chem. 2014, 126, 311 –
315; j) S. Chatterjee, S. Kundu, A. Bhattacharyya, C. G. Har-
tinger, P. J. Dyson, J. Biol. Inorg. Chem. 2008, 13, 1149 – 1155.
[2] Y. Fu, A. Habtemariam, A. M. Pizarro, S. H. van Rijt, D. J.
Healey, P. A. Cooper, S. D. Shnyder, G. J. Clarkson, P. J. Sadler,
J. Med. Chem. 2010, 53, 8192 – 8196.
[3] J. M. Hearn, I. Romero-Canelꢅn, A. F. Munro, Y. Fu, A. M.
Pizarro, M. J. Garnett, U. McDermott, N. O. Carragher, P. J.
Sadler, Proc. Natl. Acad. Sci. USA 2015, 112, E3800 – E3805.
[4] S. D. Shnyder, Y. Fu, A. Habtemariam, S. H. Van Rijt, P. A.
Cooper, P. M. Loadman, P. J. Sadler, MedChemComm 2011, 2,
666 – 668.
[5] I. Romero-Canelꢅn, M. Mos, P. J. Sadler, J. Med. Chem. 2015, 58,
7874 – 7880.
[6] G. K. Balendiran, R. Dabur, D. Fraser, Cell Biochem. Funct.
2004, 22, 343 – 352.
[7] L. Galluzzi, L. Senovilla, I. Vitale, J. Michels, I. Martins, O.
Kepp, M. Castedo, G. Kroemer, Oncogene 2012, 31, 1869 – 1883.
[8] a) S. J. Dougan, A. Habtemariam, S. E. McHale, S. Parsons, P. J.
Sadler, Proc. Natl. Acad. Sci. USA 2008, 105, 11628 – 11633;
b) H. Petzold, P. J. Sadler, Chem. Commun. 2008, 4413 – 4415;
c) H. Petzold, J. Xu, P. J. Sadler, Angew. Chem. Int. Ed. 2008, 47,
3008 – 3011; Angew. Chem. 2008, 120, 3050 – 3053.
[9] F. Wang, J. Xu, A. Habtemariam, J. Bella, P. J. Sadler, J. Am.
Chem. Soc. 2005, 127, 17734 – 17743.
[10] G. Jaouen, A. Vessieres, S. Top, Chem. Soc. Rev. 2015, 44, 8802 –
8817.
[11] a) M. Matczuk, M. Przadka, S. S. Aleksenko, Z. Czarnocki, K.
Pawlak, A. R. Timerbaev, M. Jarosz, Metallomics 2014, 6, 147 –
153; b) A. M. Palmer, B. PeÇa, R. B. Sears, O. Chen, M.
El Ojaimi, R. P. Thummel, K. R. Dunbar, C. Turro, Philos.
Trans. R. Soc. London Ser. A 2013, 371, 20120135.
Experimental Section
Synthesis of 1-I·PF6: [Os(h6-p-cym)I2]2 (100 mg, 86.5 mmol) was
dissolved in ethanol (10 mL), and a solution of 2-(phenylazo)-5-
ethoxypyridine (41.3 mg, 181.6 mmol) in ethanol (5 mL) was added
drop-wise. The mixture was stirred for 18 h at ambient temperature,
and ammonium hexafluorophosphate (140.9 mg, 0.86 mmol) was
added. The mixture was concentrated under reduced pressure to ca.
3 mL and placed in a freezer overnight. The dark crystalline
precipitate was collected via vacuum filtration, washed with ice-cold
ethanol (2 ꢁ 1 mL) and diethyl ether (2 ꢁ 5 mL), and dried overnight
1
in a vacuum desiccator. Yield: 119.6 mg (84%). H NMR (CD3OD):
d = 9.07 (d, 1H, J = 2.6 Hz), 8.84 (d, 1H, J = 9.1 Hz), 8.04–8.01 (m,
2H), 7.94 (dd, 1H, J = 9.1, 2.6 Hz), 7.73–7.63 (m, 3H), 6.47–6.46 (m,
1H), 6.16–6.15 (m, 1H), 6.03–6.02 (m, 1H), 5.96–5.95 (m, 1H), 4.50–
4.38 (m, 2H), 2.70 (s, 3H), 2.45 (sept., 1H, J = 6.9 Hz), 1.55 (t, 3H, J =
7.0 Hz), 0.94–0.92 ppm (2x d, 6H, J = 6.9 Hz). ESI-MS calculated for
C23H27IN3OOs+: m/z 680.1. Found: 679.9. CHN analysis: Found: C,
33.30%; H, 3.26%; N, 4.98%. Calculated for C23H27F6IN3OOsP: C,
33.54%; H, 3.30%; N, 5.10%.
Radiolabelling: 50 mL of 1-Cl·PF6 or 2-Cl·PF6 in methanol
(5 mgmLÀ1) was transferred into a 2 mL plastic sealable tube and
combined with Na131I (30–70 MBq) in 0.1 mm NaOH solution.
Further water was added to give a water:methanol (1:1, v/v) solvent
matrix, then the mixture was heated for 18 h at 333 K with 300 rpm
stirring. The radio-labelled complexes were purified by preparative
radio-HPLC and diluted with three parts phosphate buffered saline
(PBS) and stored at 193 K.
Acknowledgements
We thank the ERC (Grant No. 247450), Science City (AWM/
ERDF), EPSRC (Grant No. EP/F034210/1), the Wellcome
Trust (Grant No. 107691/Z/15/Z) for support, Dr. Florian
Kampmeier and Putthiporn Charoenphun (KCL) for assis-
tance with cell culture, and members of EC COST Action
CM1105 for stimulating discussions. Research at Kingꢂs
College London was supported by Bloodwise (L.M.), the
Centre of Excellence in Medical Engineering funded by the
Wellcome Trust (Grant No. WT088641/Z/09/Z), EPSRC, the
Kingꢂs College London and University College London
Comprehensive Cancer Imaging Centre funded by CRUK
and EPSRC in association with the MRC and DoH (England)
(M.S.C.), and the National Institutes for Health Research
(NIHR) Biomedical Research Centre based at Guyꢂs and St.
Thomasꢂ NHS Foundation Trust and Kingꢂs College London.
[12] S. H. van Rijt, I. Romero-Canelꢅn, Y. Fu, S. D. Shnyder, P. J.
Sadler, Metallomics 2014, 6, 1014 – 1022.
[13] K. J. Long, K. B. Walsh, Methods Cell Sci. 1997, 19, 207 – 212.
[14] a) J. Vꢆsquez-Vivar, B. Kalyanaraman, P. Martꢆsek, N. Hogg,
B. S. Siler Masters, H. Karoui, P. Tordo, K. A. Pritchard, Jr.,
Proc. Natl. Acad. Sci. USA 1998, 95, 9220 – 9225; b) C. Frejaville,
H. Karoui, B. Tuccio, F. le Moigne, M. Culcasi, S. Pietri, R.
Lauricella, P. Tordo, J. Chem. Soc. Chem. Commun. 1994, 1793 –
1794.
[15] a) S. Okuno, H. Sato, K. Kuriyama-Matsumura, M. Tamba, H.
Wang, S. Sohda, H. Hamada, H. Yoshikawa, T. Kondo, S. Bannai,
Br. J. Cancer 2003, 88, 951 – 956; b) A. Ozkan, K. Fiskin, Exp.
Oncol. 2006, 28, 86 – 88.
Conflict of interest
The authors declare no conflict of interest.
Keywords: anticancer agents · bioinorganic chemistry ·
glutathione · metallodrugs · organo-osmium complexes
Manuscript received: October 20, 2016
Final Article published: && &&, &&&&
4
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Communications
II
À
Anticancer Agents
Os I bond activation: Iodido Os arene
phenylazopyridine complexes show
R. J. Needham, C. Sanchez-Cano,
X. Zhang, I. Romero-Canelꢁn,
A. Habtemariam, M. S. Cooper,
L. Meszaros, G. J. Clarkson, P. J. Blower,
promising anticancer properties both in
vitro and in vivo. Surprisingly they can be
activated in cells by hydrolysis of their
À
Os I bond in the presence of glutathione
P. J. Sadler*
&&&& — &&&&
(GSH). The newly formed hydroxido
complexes are more reactive and can
form chlorido, thiolato and sulfenato
adducts with GSH, and react with H2O2,
generating hydroxyl radicals.
In-Cell Activation of Organo-Osmium(II)
Anticancer Complexes
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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