Journal of Organometallic Chemistry 839 (2017) 5e14

Contents lists available at ScienceDirect

Journal of Organometallic Chemistry

journal homepage: www.elsevier.com/locate/jorganchem

Advances in the design of organometallic anticancer complexes

Pingyu Zhang, Peter J. Sadler*
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK

a r t i c l e i n f o a b s t r a c t

Article history: Organometallic complexes containing ligands such as CO, carbenes, alkyls, phenyls, p-bound alkynes,
Received 10 February 2017 alkenes, cyclopentadienyls and arenes possess properties which have often been exploited in areas such
Received in revised form as catalysis and materials chemistry. They also offer opportunities for the design of new drugs with novel
12 March 2017
mechanisms of action. Here we focus on anticancer drugs which might complement successful platinum
Accepted 21 March 2017
drugs in the clinic by widening the spectrum of activity, reducing side-effects and combatting resistance.
Available online 23 March 2017
The early clinical trials of titanocene dichloride highlighted the need to understand the aqueous solution
chemistry of organometallic complexes and to identify their target sites in cancer cells. More recently
Keywords:
Bioorganometallic chemistry
organometallic Cp complexes of Fe(II), Rh(III) and Ir(III), and arene complexes of Ru(II) and Os(II), have
Metallodrugs been shown to target the redox balance in cancer cells, in contrast to DNA which is the target of cisplatin
Anticancer and related platinum drugs. The activity of both catalytic and photoactive organometallic compounds is
being explored. Target recognition and activity are highly dependent not only on the metal and its
oxidation state, but also the other coordinated ligands, the coordination number and geometry. In
general, organometallic complexes are pro-drugs which undergo activation in vivo (by ligand exchange
or redox reactions), and the ligands themselves may be active components of the drug. A major challenge
is to elucidate the chemistry of organometallic complexes directly in cells. The design of organometallic
complexes for therapeutic and diagnostic applications in cancer and other areas of medicine present new
and exciting research opportunities.
2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).

1. Introduction potential therapeutic and diagnostic applications but also in other

Organometallic complexes can contain a wide variety of C-
bound ligands and have wide potential applications in medicine
(Table 1), although there are relatively few examples of clinical use.
Here we focus on organometallic anticancer compounds. The suc-
cessful introduction of cisplatin as an anticancer drug in the early
1980s led not only to new generations of platinum drugs (carbo-
platin and oxaliplatin) but also to clinical trials of several other
platinum compounds and to exploration of the anticancer activity
of complexes of other transition metals. A landmark investigation
was that of Ko pf and Ko
pf-Maier who tested a wide range of met-
allocene complexes [1], resulting in clinical trials of titanocene
dichloride in the 1990s [2]. It was evident that this complex has a
different mechanism of action to the platinum drugs and that DNA
may not be the major target. Since then interest in the new eld of
bioorganometallic chemistry has rapidly increased, for not only for
* Corresponding author.
E-mail address: P.J.Sadler@warwick.ac.uk (P.J. Sadler).
areas of biotechnology [3e10].
Carbon-bound, p-bound arenes and cyclopentadienyl ligands
can provide control of the hydrophilicity and hydrophobicity of the
faces of the coordination complex (which inuences cell uptake
and targeting) [11,12]. Most metallodrugs are prodrugs, and control
over ligand substitution is vital if the complex is to reach and react
with its target site. In this respect, low-spin d6 complexes are
attractive for drug design since they are often kinetically inert.
Inertness increases from the rst-to second-to third-row transition
metals.
Recently, our laboratory and others have attempted to design
new generations of organometallic anticancer complexes that
might overcome clinical problems with platinum drugs, notably
resistance, the limited spectrum of activity, and side effects [11e15].
We have applied the design concepts discovered for Ru(II) and
Os(II) arene complexes to organometallic Rh(III) and Ir(III) Cp*
complexes. The rate of hydrolysis, acidity of the aqua adducts, in-
teractions with nucleobases, hydrophobicity and cell accumulation
have been studied for these organometallic complexes
[11,12,69e74,85].

http://dx.doi.org/10.1016/j.jorganchem.2017.03.038
0022-328X/ 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
6 P. Zhang, P.J. Sadler / Journal of Organometallic Chemistry 839 (2017) 5e14

Table 1
Some examples of organometallic fragments and their applications, or potential applications in medicine.

Hapticity/Fragment Example Application Ref

h1/M-CO [Ru(II)(Gly)(CO3)Cl] Inammation, vascular dysfunction, tissue ischaemia, organ rejection [20e22]
[Mn(CO)3X&(polymer)]
(CORMs, Photo-CORMs)
M-CN Na2[Fe(CN)(NO)] Vasodilator (Nipride), anti-hypertension [23]
M-alkyl Methyl cobalamin Vitamin B12 derivative [24]
Me2As(SG)(Darinaparsin) Anticancer [25]
M-phenyl Phenylmercuric nitrate Antiseptic [26]
M-carbene Ag(I)(N-heterocyclic carbene) Antibacterial, anticancer [27,28]
M-alkynyl [Pd(C^N^C)(C^CPh)] PF6 Photo-cytotoxic [29]
[Pt (C^N^C)(C^C-L)] CF3SO3 DNA binding [30]
h4/M-diene Ir(COD)(acac) Anticancer [31]
h5/M-Cp Ferroquine Antimalarial [32]
Ferrocifens Anticancer [33,34]
(Cp*)Rh(III)/Ir(III) Anticancer [12,35]
h6/M-arene Ru(II), Os(II) arenes Anticancer [36-40,77,91,100]
Antimalerial

Although metallodrugs offer the prospect of agents with novel
mechanisms of action, their progress towards clinical approval re-
quires that their target sites and mechanisms of action are better
understood at the molecular level and that the side effects often
associated with heavy metals are minimized. New methods for
monitoring the temporal and spatial speciation of metallodrugs in
cells at physiologically relevant concentrations are likely to play
crucial roles in such progress, as are modern proteomics and ge-
nomics which might eventually guide the use of metallodrugs in
personalized medicine [16e19]. In this focused review, we have
selected some of the major classes of organometallic complexes
(metal arene, cyclopentadienyl, carbene and cyclometalated com-
plexes) and we discuss recent progress in their design as anticancer
agents.
2. Organometallic complexes
2.1. Metallocenes
2.1.1. Ferrocenes
Ferrocene, Fe(h5-C5H5)2 (Fig. 1a), is relatively non-toxic; how-
ever, the ferrocenium cation, [Fe(h5-C5H5)2], exhibits toxicity to-
wards a variety of cancer cell lines [41]. The mechanism by which
[Fe(h5-C5H5)2] exerts its antiproliferative effect is not completely
understood, but since it has been shown to generate hydroxyl
radicals under physiological conditions, it is plausible that it
generates such radicals inside cancer cells, which leads to damage
of DNA and the cell membrane [42].
Substitution of one of the phenyl rings of tamoxifen with a
ferrocenyl group gives rise to so-called ferrocifen derivatives,
which can have improved activity [43,44]. Jaouen et al. have re-
ported a new generation of ferrocifen derivatives with strong
antiproliferative behavior in vitro [44]. In particular, the hydrox-
ypropyl derivative HO(CH2)3C(Fc) C(C6H4OH)2 (Scheme 1) ex-
hibits exceptional antiproliferative activity against test cancer cell
lines. Chemical oxidation of the ferrocifen derivative yields an un-
precedented tetrahydrofuran-substituted quinone methide (QM)
via internal cyclization of the hydroxyalkyl chain, whereas the
corresponding alkyl analogue CH3CH2-C(Fc) C(C6H4OH)2 merely
formed a vinyl QM. The ferrocenyl group in this complex plays a key
role, not only as an intramolecular reversible redox antenna, but
also as a stabilized carbenium ion modulator [44].
Behr et al. have designed a new ferrocenyl-iminosugar conju-
gate complex (Fig. 1b) with fucosidase inhibitory and anticancer
activity. The complex exhibited signicant anticancer activity on
MDA-MB-231 and SK-MEL28 cell lines [45]. Ferrocene-
functionalized guanidines have been reported as redox-active
precursors for the synthesis of heterometallic Pt(II)eguanidine
complexes with anticancer activity. Guanidine-containing FePt
complexes (Fig. 1c and d) are active in a range of human cancer cell
lines, with GI50 values of 1.4e2.6 mM, and are more cytotoxic than
cisplatin in the resistant T-47D and WiDr cell lines [46].

2.1.2. Titanocenes
Titanocene dichloride, [Ti(h5-C5H5)2Cl2] (Fig. 2a) was originally
explored as an anticancer complex because it contains a cis-
dichlorido motif that was expected to give rise to a GG crosslink
analogous to that formed by cisplatin [47]. Although the structure
of the molybdenum analogue bound to DNA was found to be
reminiscent of that established for cisplatin [48], there is little ev-
idence that [Ti(h5-C5H5)2Cl2] targets DNA bases. Clinical trials of

Fig. 1. The chemical structures of (a) ferrocene, (b) a ferroceneeiminosugar conjugate Scheme 1. Proposed mechanism for the formation of the novel heterocyclic ferrocenyl
complex and (c,d) ferroceneefunctionalized Pt(II)eguanidine complexes. QM species. Printed with permission from Ref. [44].
 P. Zhang, P.J. Sadler / Journal of Organometallic Chemistry 839 (2017) 5e14 7

up by transferrin which may therefore act as a delivery vehicle

[55e59].
Our research showed that Ti(IV) binds strongly to human serum
transferrin (hTF) in its specic Fe(III) binding sites [55]. This pro-
vides a route for delivery of Ti(IV) to cancer cells, which overexpress
transferrin receptors. Our studies on transferrin and the model
ligand EHPG suggested that at low pH ATP might act as an acceptor
for Ti(IV) from [Cp2TiCl2] in cells and that novel routes might exist
for the transfer of Ti(IV) onto DNA in vivo [56]. The high afnity of
Ti(IV) for phosphate groups might be important for its biological
activity. We also reported that Ti(IV) binds specically to bacterial
transferrin (FBP) and that Ti(IV) binding induces characteristic
structural changes in the protein. Importantly 1H NMR spectra
showed that the Cp* ligands are displaced from titanocene
dichloride during the reaction [59].

2.2. Metal arene complexes

2.2.1. Ruthenium arene anticancer complexes

Our work on ruthenium arene complexes began in Edinburgh in
1997 with a PhD student Robert Morris. We designed monofunc-
tional half-sandwich Ru(II) arene complexes which were not cross-
resistant with cisplatin. Even though, as with cisplatin, DNA was
Fig. 2. The molecular structures of (a) titanocene, (b) enantiopure chiral titanocenes,
R Et, Ar 2-MeOC6H4, (c) titanocene Y and (d) titanoceneeAu(I)ecarbene complex also the target, the ruthenium complexes caused different struc-
for inhibition of TrRx. tural lesions. Patents were led and licenced to Oncosense which
undertook preclinical development [60]. These complexes exhibi-
ted high activity towards a range of cancer cells, with low in vivo
titanocene dichloride were eventually abandoned after about 10 toxicity [61,62].
years and following phase II trials [48e50]. Its low water solubility We showed that the monofunctional Ru(II) complexes [(h6-ar-
and poor hydrolytic stability resulted in formulation problems that ene)RuII(en)X] (arene p-cymene or biphenyl;
eventually hampered its development. In addition, anti-cancer en ethylenediamine; X halide) are effective inhibitors of the
therapies based on titanocene are limited by low selectivity and growth of cancer cells and form strong monofunctional adducts
lack of understanding of its mode(s) of action. However, it is clear with DNA [63,64] (Fig. 3a). They are highly selective in their
that the mode of action of titanocene derivatives is quite distinct recognition of nucleic acid bases and the nature of the coordinated
from that of clinical platinum drugs and the continued exploration arene has a dramatic effect on the kinetics of binding. Simultaneous
of this class of organometallic complexes might lead to a useful direct coordination, intercalation, and stereospecic H-bonding to
clinical drug candidate. DNA can be incorporated into Ru(II) arene complexes. We studied
To address the problems, enantiopure titanocene complexes the kinetics and thermodynamics of hydrolysis reactions, which
(Fig. 2b) have been investigated by Bradshaw [51]. The in vitro anti- allowed prediction of species present in plasma and cells [65e67].
tumor activity of these complexes is selective for cancer cells; in We also discovered that Ru arenes not only can attack DNA, but
clonogenic assays. The (S, S)-complex is twice as effective at their mechanism of action can also involve unusual redox activity
inhibiting colony formation as the other stereoisomers after 24 h [68e70]. As expected, Ru arene complexes (Fig. 3b) form strong
exposure. Tacke et al. showed that the promising cytotoxic and complexes with thiols such as glutathione. Surprising though was
anti-angiogenic anticancer drug candidate Titanocene Y, which our observation that thiolato complexes readily undergo oxidation
exhibits good in vitro and in vivo activity [52]. They also compared to the sulfenate (RuS(O)G) and even sulnate (Ru-SO2G). The highly
the short-term effects of cisplatin and non-cross-resistant bis-[(p- reactive sulfenate is stabilized by binding to Ru(II) [68e70]. We
methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titano-
cene Y, Fig. 2c) on phosphorylation of 46 sites on a total of 38
signaling proteins in tumor-suppressor-protein-p53-wild-type
NCI-H526 SCLC cells [53].
Contel et al. have synthesized and characterized a novel heter-
ometallic titanoceneeAu(I)ecarbene complex (Fig. 2d) [54]. This
complex did not display a signicant interaction with plasmid
(pBR322) used as a model oligonucleotide. It was found to be highly
apoptotic and to inhibit TrRx in prostate PC3 cancer cell lines. The
work is the proof-of-concept that titanoceneeAu complexes may
have potential as cancer chemotherapeutics which can be further
modied.
The serum iron transport protein transferrin has a very high
afnity for Ti(IV) [55e59]. In blood this protein is only about one-
third saturated with Fe(III) and therefore has capacity to trans-
port other metal ions to cells. Metal-loaded transferrin is taken up
via specic transferrin receptors and rapidly-dividing cancer cells
have a higher density of such receptors on account of their high iron
requirement. Titanium from titanocene dichloride is readily taken Fig. 3. Chemical structures ofhalf-sandwichruthenium arene complexes.
8 P. Zhang, P.J. Sadler / Journal of Organometallic Chemistry 839 (2017) 5e14

further observed that the bound sulfenate is readily displaced by

guanine N7, and thus initial GSH binding can be followed by
transfer of Ru onto DNA. This appears to involve protonation of the
bound sulfenate [71]. Moreover we showed that cysteine thiols in
proteins and enzymes are susceptible to Ru arene-induced oxida-
tion to sulfenates and sulnates, for example serum albumin and
glutathione S-transferase [72,73].
Some of our Ru erene anticancer complexes have features
similar to Noyori-type transfer hydrogenation catalysts and we
demonstrated that they can act as catalysts for the reduction of
coenzyme NAD to NADH using formate as an hydride source [74].
Catalyst efcacy can be improved markedly by the choice of the
arene and by incorporating sulfonyl groups as diamine substituents
[75,76]. Moreover their antiproliferative activity towards cancer
cells can be enhanced by over an order-of-magnitude by treating
cells in combination with low non-toxic doses of formate [76]. The
reduction in NAD level in cells correlated with the dose of formate
suggesting that in-cell catalysis is possible with creation of reduc-
tive stress in cancer cells.
We discovered that the chelating ligand in Ru arene complexes
can have a dramatic effect on reactivity [77]. Replacing diamines
with phenylazopyridine derivatives (Fig. 3c and d) and choosing the
monodentate ligand as iodide led to inert complexes with redox
mechanisms of anticancer activity, which also seemed to involve Fig. 4. Chemical structures of some ruthenium arene anticancer complexes.
catalysis.
Some Ru(II) arenes are photoactive. For example, we have
designed Ru arene anticancer complexes (Scheme 2), which can be
activated towards DNA binding by visible light, potentially attrac-
tive for reducing unwanted side-effects of anticancer drugs. Their
specicity can be improved further by incorporation of cancer cell-
targetting peptides [78e80]. By incorporating carborane ligands,
Ru arene complexes become attractive for possible use in Boron
Neutron Capture Therapy (BNCT), as we have demonstrated in a
proof-of-principle study [81]. In BNCT, neutrons are captured by 10B
which degrades to high energy a-particles and high energy 7Li
which kill cancer cells. We also discovered that Ru arene can act as
radiosensitizers, enhancing the effect of radiation on colorectal
cancer cells [82].
There are many other interesting reports of the biological ac-
Fig. 5. Arene-ruthenium(II) PTA (1,3,5-triaza-7-phosphaadamantane) complexes with
tivity of ruthenium arene complexes. For example Dyson et al. have
chelated acylpyrazolones bearing aliphatic groups in the acyl side-chain which are
reported the synthesis of a range of RAPTA complexes (Fig. 4a) active towards A2780 human ovarian cancer cells. Printed with permission from
compounds and explored optimisation of their activity [83e85]. Ref. [86]. Copyright 2016 American Chemical Society.
Recently the complex [(arene)Ru(QR)(PTA)][PF6] (arene p-cym-
ene (cym) or hexamethylbenzene (hmb) containing 4-acyl-5-
pyrazolonate QR ligand, PTA 1,3,5-triaza-7- complex carrying a maleimide-functionalized N-phenyl-2-
phosphaadamantane) has been evaluated in vitro against human pyridinecarbothioamide (PCA) ligand allows covalent conjugation
ovarian carcinoma cells (A2780 and A2780cisR), as well as against to biological thiols (Fig. 4c). In vitro cytotoxicity studies revealed
nontumorous human embryonic kidney (HEK293) cells (Fig. 5) low potency, explained by the observed high reactivity of the
[86]. Some new ruthenium arene PTA type complexes have been maleimide to the thiol of L-cysteine (Cys), while the metal center
synthesized using substituted picolinamide derivatives as ancillary itself shows little afnity for amino acids of the model protein
ligands by Mukhopadhyay et al. (Fig. 4b). They found these com- lysozyme [88]. Complexes with 2-hydroxy- [1,4]-naphthoquinone-
plexes can strongly inhibit thioredoxin reductase [87]. derived ligands coordinated to {Ru(II)(h6-p-cymene)Cl} (Fig. 4d
With the aim of increasing the accumulation of Ru anticancer and e) are stable in aqueous solution and react with glutathione
agents in the tumor, a targeted delivery strategy based on a mal- and ascorbic acid but are not reduced. One-electron reduction with
eimide anchor for the biological vector human serum albumin pulse radiolysis revealed different behavior for the naph-
(HSA) has developed by Hartinger and co-workers. A Ru(h6-arene) thoquinone and nitroso-naphthalene complexes, also observed in
in vitro anticancer assays [89].
Wang et al. found that the ligation of {(arene)Ru(II)}2 frag-
ments with 4-anilinoquinazolines not only makes the target com-
plexes excellent EGFR inhibitors, but also confers high afnity to
bind in the minor groove of DNA while maintaining their reactivity
towards DNA bases, so conferring dual-targeting properties (Fig. 4f)
[90].
p53 is an important tumor suppressor gene involved in key
Scheme 2. Photo-induced ligand exchange on ruthenium(II) arene complexes. cellular processes and implicated in cancer therapy. Therrien et al.
 P. Zhang, P.J. Sadler / Journal of Organometallic Chemistry 839 (2017) 5e14
reported that hydrazinyl-thiazolo arene ruthenium complexes can
induce cell death via p53-dependent pathways (Fig. 4g and h) [91].
However, this pathwqay is inactivated in more than 50% of all
cancers due to mutation or overexpression of its negative regula-
tors. This leads to drug resistance and poor chemotherapeutic
outcome as most clinical drugs act via a p53-dependent mecha-
nism of action. Ang et al. showed some new Ru(II)-arene Schiff-base
complexes are able to induce p53-independent cytotoxicity (Fig. 4i)
[92]. An attractive strategy to circumvent this resistance would be
to identify new anticancer drugs that act via a p53-independent
mode of action.
2.2.2. Osmium arenes for anticancer complexes
When we started work on the design of Os(II) arene anticancer
complexes, we did not expect much success because the literature
gave the impression that all low-spin 5d6 Os(II) complexes are
relatively inert, although there had been relatively few studies on
their aqueous chemistry [93,94].
Our studies of piano-stool Ru(II) arenes had taught us how to
control their reactivity and we transferred this knowledge to Os(II)
arene complexes. The rates of hydrolysis, for example, are about
100x slower, and coordinated water about 1.5 pKa units more acidic.
The pKa of bound water can be lowered by changing from O,O to
O,N to N,N chelates, and especially to p-acceptors such as phenyl-
azopyridines [94]. This is important because M-OH bonds are often
less reactive than M-OH2 bonds. We discovered good activity
amongst e.g. reasonably reactive N,O-chelated picolinate com-
plexes that can attack DNA [95,96].
We discovered that Os(II) arene complexes with certain phe-
nylazopyridine ligands were even more potent and unreactive with
iodide as the monodentate ligand (Fig. 6a) [97,98]. They are not only
more potent than cisplatin in the NCI-60 cell line screen, but also
49x more potent on average in a Sanger panel of 809 cancer cell
lines, and active in vivo [98]. They kill cancer cells by redox
mechanisms of action, inducing rapid bursts of reactive oxygen
Fig. 6. Mononuclear and tetranuclear osmium(II) arene anticancer complexes. Radio-
labelling of the iodido ligand with b/g emitter 131I (t1/2 8.02 d) allows iodide release in
cells to be studied, The stability of the tetranuclear complexes depends on the length of
the linker.
9
species (ROS), and especially superoxide in cells. Recent studies of
the distribution of osmium in cancer cells treated with physiolog-
ically relevant doses of the complex in Fig. 6a using nano-focussed
x-ray uorescence shows localisation in specic areas of cells
resembling mitochondria (Fig. 7) [99]. These complexes are can-
didates for preclinical development.
Radiolabelling of iodido Os(II) azopyridine complexes with 131I
(Fig. 6b) has revealed that the iodide ligand is rapidly released from
Os(II) coordination once the complexes enter cells despite the
apparent inertness towards hydrolysis [100]. This activation may
involve attack by intracellular GSH which appears to catalyse hy-
drolysis and formation of the hydroxido adduct (pKa of bound
water ca. 5) (Fig. 8) [99]. Interestingly, bound GSH can also undergo
oxidation to the glutathione sulfenate in much the same way we
have observed for the Ru(II) arene complexes described previously.
The lower reactivity of transition metal M - OH bonds compared to
M - OH2 bonds is again notable.
Dinuclear trihydroxido-bridged osmiumearene complexes are
inert and biologically inactive, but we showed that linking
dihydroxido-bridged OsIIearene fragments by a bridging di-imine
to form a metallacycle framework results in strong anti-
proliferative activity towards cancer cells and distinctive knotting
of DNA (Fig. 6c and d). The shortened spacer length reduces bio-
logical activity and stability in solution towards decomposition to
biologically inactive dimers [101].
2.2.3. Iridium and rhodium cyclopentadienyl complexes
Our exploration of the design of organo-iridium anticancer
complexes began with Cp* Ir(III) N,N-chelated complexes with
chloride as the monodentate ligand (Fig. 9) [102e105]. Much to our
surprise, these low-spin 5d6 complexes turned out to be highly
labile toward aquation but were inactive anticancer agents, until
we appended one or two phenyl rings to the Cp*. Then, not only
could they bind directly to DNA (especially N7 of G), but also
intercalate via the extended Cp* between DNA bases, and showed
good potency towards cancer cells. Moreover we found that the Cp*
extension was not necessary if a chelated N,C ligand was used
suggesting a switch to a different mechanism of action [104,105].
Subsequently we have demonstrated that Cp* Ir(III) complexes
can have redox mechanisms of action [106e114]. Particularly
Fig. 7. X-ray uorescence map of a section of an A2780 human ovarian cancer cell
treated for 24 h with 1 mM of the iodido azopyridine Os(II) arene complex in Fig. 6a,
showing the localised cellular distribution of osmium in organelles resembling mito-
chondria (red with yellow outline), as well as the distribution of the natural elements
Zn and Ca. Reproduced with permission from Ref. [99]. (For interpretation of the ref-
erences to colour in this gure legend, the reader is referred to the web version of this
article.)
10 P. Zhang, P.J. Sadler / Journal of Organometallic Chemistry 839 (2017) 5e14
Fig. 8. Possible pathways which link intracellular activation of iodido azopyridine
Os(II) arene anticancer complexes with Ca mobilization, mitochondrial dysfunction,
ROS generation and cell death. Reproduced with permission from Ref. [99].
Fig. 9. Chemical structures of half-sandwich organometallic Ir(III) anticancer
complexes.
intriguing is the ability of these complexes to accept hydride
directly from coenzyme NADH (Fig. 10), a reaction that can be used
to carry out catalytic hydrogenation of substrates like ketones,
quinones and protons (to generate H2). Moreover, such complexes
can increase the ratio of NAD/NADH in cancer cells and cause
oxidative stress [106,107]. We detect bursts of superoxide in cancer
cells analogous to those seen for Os(II) arene azopyridine com-
plexes, and again do not see such bursts in normal cells. This may be
related to the altered function of mitochondria in cancer cells
(mitochondrial DNA mutations). There is much novel chemistry
still to be explored for these complexes, including the ability of
hydrides to generate peroxide, and of glutathione adducts to un-
dergo oxidation to the sulfenate and sulnate adducts, potentially
important in cells. Reducing the chemical reactivity by
Fig. 10. Reactions of IrIII pyridine and its Cl analogue and possible pathways for gen-
eration of H2O2. Adapted from Ref. [12]. Copyright 2014 American Chemical Society.
incorporating monodentate pyridine ligands produces complexes
with higher potency than cisplatin or carboplatin in the NCI-60 cell
line screen [108]. We have characterized hydrosulde adducts
which may play a role in biological activity [114]. Perhaps such
adducts could be formed in cells by attack on ferredoxins.
We also investigated Rh(III) complexes of general formula [(Cpx)
Rh(N,N0 )(Cl)] (Fig. 11) [115]. These complexes can reduce NAD to
NADH using formate as a hydride source under biologically-
relevant conditions. The efciency of the transfer hydrogenation
reactions was highly dependent on the nature of the chelating
ligand and the Cpx ring. Competition reactions between NAD and
pyruvate for reduction by formate catalyzed showed a preference
for reduction of NAD.
2.3. Metal-carbene complexes
Metal complexes with N-heterocyclic carbene (NHC) ligands
were initially studied for their antimicrobial properties and sub-
sequently as antiproliferative agents against cancer cells [116e122].
Indeed, cytotoxic AgeNHC complexes have been shown to have
promising antibacterial activity [123] and in vivo anticancer activity
in an ovarian cancer xenograft model [122]. Various Au(I)eNHC
complexes have been reported to inhibit the enzyme thioredoxin
reductase (TrxR) leading to cancer cell death [123,124]. TrxR con-
tains a redox-active Cys/Se-Cys pair of amino acids. Gold(I) has a
high afnity for thiolate and selenolate ligands.
In view of the facile reduction of Au(III) to Au(I), Che and co-
workers developed a class of Au(III) complexes bearing NHC li-
gands that can dually serve as uorescent thiol probes and anti-
cancer agents (Fig. 12aec) [116]. These Au(III) complexes, through
the formation of Au(I)eNHC upon reduction, can inhibit cellular
TrxR activity and are cytotoxic to several cancer cell lines. Further
in vivo studies reveal that treatment with the complex in Fig. 12c
can signicantly suppress tumor growth in mice bearing HeLa xe-
nografts (76% inhibition) with no mouse death or bodyweight loss
[116].
The rationale is as follows: (1) Au(III) is four-coordinate while
Au(I) is usually two-coordinate, hence the reduction of Au(III) to
Au(I) would be accompanied by the release of two ligands; (2)
Au(III) complexes are usually non-emissive due to the relatively low
energy orbitals, if the ligand is uorescent, Au(III) to Au(I) reduction
should switch on the ligand emission; (3) NHC ligands (similarly to
phosphine ligands) are well known to stabilize Au(I) against
reduction to Au(0), and Au(I)eNHC complexes are also known to be
anticancer-active. These Au(III)eNHC complexes are sensitive to
thiols that cause reduction of Au(III) to Au(I) with the release of the
uorescent H2N^N^N ligand (Scheme 3), and therefore can act as a
Fig. 11. Organometallic half-sandwich Rh(III) anticancer complexes studied for the
reduction of NAD by transfer hydrogenation from formate.
 P. Zhang, P.J. Sadler / Journal of Organometallic Chemistry 839 (2017) 5e14
Fig. 12. The chemical structures of (aec) Au(III)-NHC, and (def) Au(I)eNHC complexes.
switch-on probe for thiols in biological systems. Fluorescence mi-
croscopy studies show that the blue uorescence of the H2N^N^N
ligand is switched on within 10 min after treatment of HeLa cells
with one of these Au(III) complexes. The uorescence is mainly
located in mitochondria, where the potential molecular target
enzyme TrxR resides [116].
Ott and co-workers have described a series of Au(I)eNHC
complexes as potent TrxR inhibitors. Au(I)eNHC complexes
increased ROS formation, inhibited mitochondrial respiration,
induced apoptosis, and strongly affected cellular metabolism [125].
Systematic investigation of [Au(NHC)L] (L Cl, NHC, or PR3) com-
plexes (Fig. 12def) using atomic absorption spectrometry (AAS)
revealed that the binding reactions with serum albumin followed
the order: [Au(NHC)Cl] > [Au(NHC)(PR3)]I > [Au(NHC)2]I. The TrxR
inhibition activity of these gold complexes followed the same order
with EC50 values being 0.36, 0.66, 4.89 mM, respectively [126]. The
reactivity of [Au(NHC)(PR3)]I with different substituents on the
phosphine ligand, was compared [127]. The AueP(PPh3) bond in
[Au(NHC)(PPh3)]I was found to be more reactive than the
AueP(PR3) (R alkyl) bond in the [Au(NHC)(PR3)]I complexes.
Palladium(II) NHC complexes are generally reactive toward
substitution/reduction, and their biological applications are seldom
explored. A new series of palladium(II) complexes that are stable in
the presence of biological thiols has been reported (Fig. 13). The
representative complex displayed potent antiproliferative toward
cancer cell lines but is less cytotoxic toward a normal human
broblast cell line. In vivo anticancer studies revealed that the Pd(II)
complexes signicantly inhibit tumor growth in a nude mice model
[128].
Scheme 3. Reduction of [AuIII(IPI)(NHC)]OTf by GSH leads to the formation of free
H2IPI ligand and [AuI(NHC)(SG)]. Adapted from Ref. [116].
11
Fig. 13. Chemical structures of palladium(II) NHC complexes.
2.4. Cyclometalated complexes
Singlet oxygen (1O2) can be produced effectively from ground
state triplet oxygen (3O2) by cyclometalated Ir(III) complexes on
irradiation with light, and can induce cell death [129e133]. Mao
and co-workers have reported a series of cyclometalated Ir(III)
complexes which inhibit histone deacetylase (HDAC) [132]
(Fig. 14a). Treatment of HeLa cells with these complexes leads to
an elevation in histone-acetylation levels. Further they designed
cyclometalated Ir(III) complexes with pH-responsive 1O2 produc-
tion and lysosome-specic imaging properties [133]. The pH-
responsive phosphorescence of these complexes can be utilized
to monitor the lysosomal integrity upon photodynamic therapy
(PDT). This provides a convenient method for in-situ monitoring of
therapeutic effects and real-time assessment of treatment
outcome.
Chao et al. have reported a cyclometalated Ru(II) complex,
[Ru(bpy)(phpy)(dppz)] (Fig. 14b) [134], which is rapidly taken up
by cancer cells, and selectively (ca. 90%) accumulated in the nuclei
after a 2 h incubation (Scheme 4). The anticancer activity of this
complex was screened against a panel of cancer cell lines. The
cyclometalated Ru(II) complex (CN) was more toxic to cancer cells
than the polypyridyl complex(NN). [Ru(bpy)(phpy)(dppz)] and
displayed potencies superior to cisplatin against 3D tumor spher-
oids. Further studies revealed that the high DNA binding afnity of
[Ru(bpy)(phpy)(dppz)] resulted in effective disruption of the
binding of transcription factor NF-kB to DNA sequences, thereby
inhibiting cellular transcription and leading to irreversible cancer
cell apoptosis. The work sheds new light on the biological in-
teractions and anticancer molecular mechanisms of DNA-specic
Ru(II) cyclometalated complexes. In addition to cyclometalated
Fig. 14. Chemical structures of octahedral cyclometalated (a) Ir(III), (b) Ru(II), and (c)
Os(II) complexes.
12 P. Zhang, P.J. Sadler / Journal of Organometallic Chemistry 839 (2017) 5e14
Scheme 4. The mechanism of action of cyclometalated Ru(II) complex
[Ru(bpy)(phpy)(dppz)] in cancer cells. Printed with permission from Ref. [134].
Copyright 2014 American Chemical Society.
Ru(II) and Ir(III) complexes, a cyclometalated Os(II) complex with N,
N, N- and N, C, N-chelator has been reported by Pfeffer and co-
workers [135] (Fig. 14c). The complex displays promising cytotox-
icity toward the human glioblastoma cell line A172 with IC50 values
in the high nM range. These examples illustrate that cyclometalated
complexes have exciting potential for exploration as novel anti-
cancer drugs.
Che et al. reported a series of luminescent cyclometalated Pt(II)
complexes [136,137]. The complexes [Pt(C^N^Npyr)(CNR)]
[HC^N^Npyr 2-phenyl-6-(1H-pyrazol-3-yl)-pyridine] contain pin-
cer type ligands having pyrazole groups (Fig. 15) [137]. These Pt(II)
complexes exert potent cytotoxicity to a panel of cancer cell lines
including primary bladder cancer cells and display strong phos-
phorescence that is highly sensitive to the local environment. The
self-assembly of these complexes is signicantly affected by pH of
the solution. The complexes were observed to self-assemble into
orange phosphorescent polymeric aggregates driven by intermo-
lecular Pt(II)ePt(II) and ligandeligand interactions in a low-pH
physiological medium. Importantly, their intracellular assembly
and dis-assembly are accompanied by a change of emission color
from orange to green. These complexes accumulated in the lyso-
somes of cancer cells, increased the lysosomal membrane perme-
ability and induced cell death.
3. Conclusions
We have summarized some recent advances in the design of
organometallic anticancer complexes. Notable is the wide variation
in target sites, dependent on the metal, its oxidation state, the types
and numbers of coordinated ligands. The mechanisms of their
anticancer activities vary from attack on DNA, proteins and en-
zymes, ROS generation and disturbance of the redox balance in
cells. The establishment of structure-activity relationships for
organometallic complexes is important. It is clear that small
changes in their structures can have dramatic effects on activity.
The wide range of C-binding ligands available, both neutral and
charged, s-donors p-acceptors/donors, in organometallic com-
plexes provide much scope for rational drug design with potential
for tuning their properties to maximise selective targeting and
minimize unwanted side-effects. The transfer of concepts well
Fig. 15. Chemical structures of luminescent cyclometalated Pt(II) complexes.
known in organometallic chemistry into the eld of bio-
organometallic chemistry is likely to produce new paradigms for
the design of novel drugs of the future. The progress of organo-
metallic complexes towards clinical trials will improve the accep-
tance of organometallic complexes by the pharmaceutical industry
and support further research into anticancer metallodrugs.
Acknowledgements
This research was supported by the ERC (grant no. 247450),
EPSRC (grant no. EP/F034210/1 to P.J.S.), Wellcome Trust (grant no.
107691/Z/15/Z) and Royal Society (Newton International Fellow-
ship for P.Z.). PJS thanks all his co-workers for their important
contributions and members of EU COST Actions for stimulating
discussions. This short review is not comprehensive. Many other
workers are making important contributions to this area of
research. It is based on a lecture by PJS to the 8th International
Symposium on Bioorganometallic Chemistry, in September 2016.
Appendix
References
pf-Maier, W. Wagner, H. Ko pf, Cancer Chemother. Pharmacol. 5 (1981)
[1] P. Ko
237.
[2] P. Ko pf-Maier, Eur. J. Clin. Pharmacol. 47 (1994) 1.
[3] R.H. Fish, G. Jaouen, Organometallics 22 (2003) 2166.
[4] C.G. Hartinger, P.J. Dyson, Chem. Soc. Rev. 38 (2009) 391.
[5] N. Chavain, C. Biot, Curr. Med. Chem. 17 (2010) 2729.
[6] G.S. Smith, B. Therrien, Dalton. Trans. 40 (2011) 10793e10800.
[7] A.L. Noffke, A. Habtemariam, A.M. Pizarro, P.J. Sadler, Chem. Commun. 48
(2012) 5219.
[8] G. Gasser, N. Metzler-Nolte, Curr. Opin. Chem. Biol. 16 (2012) 84.
[9] G. Jaouen, M. Salmain, Print ISBN: 9783527335275.
[10] B. Albada, Chem. Rev. 116 (2016) 11797.
[11] I. Romero-Canelo n, P.J. Sadler, Inorg. Chem. 52 (2013) 12276.
[12] Z. Liu, P.J. Sadler, Acc. Chem. Res. 47 (2014) 1174.
[13] R.P. Miller, R.K. Tadagavadi, G. Ramesh, W.B. Reeves, Toxins 2 (2010) 2490.
[14] D. Screnci, M.J. McKeage, J. Inorg. Biochem. 77 (1999) 105.
[15] S.R. McWhinney, R.M. Goldberg, H.L. McLeod, Mol. Cancer Ther. 8 (2009) 10.
[16] C.G. Hartinger, N. Metzler-Nolte, P.J. Dyson, Organometallics 31 (2012) 5677.
[17] L. Cuesta, J.L. Sessler, Chem. Soc. Rev. 38 (2009) 2716.
[18] G. Suss-Fink, Dalton Trans. 39 (2010) 1673.
[19] G. Gasser, N. Metzler-Nolte, Curr. Opin. Chem. Biol. 16 (2012) 84.
[20] R. Motterlini, B.E. Mann, R. Foresti, Expert Opin. Investig. Drugs 14 (2005)
1305.
[21] A.C. Kautz, P.C. Kunz, C. Janiak, Dalton Trans. 45 (2016) 18045.
[22] M.A. Wright, J.A. Wright, Dalton Trans. 45 (2016) 6801.
[23] D.G. Hottinger, D.S. Beebe, T. Kozhimannil, R.C. Prielipp, K.G. Belani,
J. Anaesthesiol.Clin. Pharmacol. 30 (2014) 462.
 P. Zhang, P.J. Sadler / Journal of Organometallic Chemistry 839 (2017) 5e14
[24] K. Gruber, B. Puffer, B. Kra utler, Chem. Soc. Rev. 40 (2011) 4346.
[25] K.K. Mann, B. Wallner, I.S. Lossos, W.H. Miller Jr., Expert Opin. Investig. Drugs
18 (2009) 1727.
[26] I.P. Kaur, S. Lal, C. Rana, S. Kakkar, H. Singh, Cutan. Ocul. Toxicol. 28 (2009)
93.
[27] J.C. Garrison, W.J. Youngs, Chem. Rev. 105 (2005) 3978.
[28] R.A. Haque, A.W. Salman, S. Budagumpi, A.A. Abdullah, A.M. Majid, Metal-
lomics 5 (2013) 760.
[29] F.F. Hung, S.X. Wu, W.P. To, W.L. Kwong, X. Guan, W. Lu, K.H. Low, C.M. Che,
Chem. Asian J. 12 (2017) 145.
[30] P. Wang, C.H. Leung, D.L. Ma, R.W. Sun, S.C. Yan, Q.S. Chen, C.M. Che, Angew.
Chem. Int. Ed. 50 (2011) 2554.
[31] T. Giraldi, G. Sava, G. Mestroni, G. Zassinovich, D. Stolfa, Chem. Biol. Interact.
22 (1978) 231.
[32] Ferroquine clinical trials. Clinical Trials. gov Identier: NCT02497612.
[33] G. Jaouen, A. Vessie res, S. Top, Chem. Soc. Rev. 44 (2015) 8802.
[34] P. Govender, T. Riedel, P.J. Dyson, G.S. Smith, Dalton Trans. 45 (2016) 9529.
[35] Y. Geldmacher, K. Splith, I. Kitanovic, H. Alborzinia, S. Can, R. Rubbiani,
M.A. Nazif, P. Wefelmeier, A. Prokop, I. Ott, S. Wo l, I. Neundorf,
W.S. Sheldrick, J. Biol. Inorg. Chem. 17 (2012) 631.
[36] A.A. Nazarov, D. Gardini, M. Baquie , L. Juillerat-Jeanneret, T.P. Serkova,
E.P. Shevtsova, R. Scopelliti, P.J. Dyson, Dalton Trans. 42 (2013) 2347.
[37] E. Paunescu, S. McArthur, M. Soudani, R. Scopelliti, P.J. Dyson, Inorg. Chem.
55 (2016) 1788.
[38] W. Kandioller, E. Balsano, S.M. Meier, U. Jungwirth, S. Go schl, A. Roller,
M.A. Jakupec, W. Berger, B.K. Keppler, C.G. Hartinger, Chem. Commun. 49
(2013) 3348.
[39] B. Biersack, Mini Rev. Med. Chem. 16 (2016) 804.
[40] E. Ekengard, L. Glans, I. Cassells, T. Fogeron, P. Govender, T. Stringer,
P. Chellan, G.C. Lisensky, W.H. Hersh, I. Doverbratt, S. Lidin, C. de Kock,
P.J. Smith, G.S. Smith, E. Nordlander, Dalton Trans. 44 (2015) 19314.
[41] P. Kopf-Maier, H. Ko pf, E.W. Neuse, H. Ko pf, Angew. Chem. Int. Ed. 96 (1984)
446.
[42] M. Salmain, N. Metzler-Nolte, Wiley: Chichester, U.K., (2008) 499.
[43] P. Govender, T. Riedel, P.J. Dyson, G.S. Smith, Dalton Trans. 45 (2016) 9529.
[44] Y. Wang, P. Pigeon, S. Top, M.J. Mcglinchey, G. Jaouen, Angew. Chem. Int. Ed.
54 (2015) 10230.
[45] A. Hottin, A. Scandolera, L. Duca, D.W. Wright, G.J. Davies, J.B. Behr, Bioorg.
Med. Chem. Lett. 26 (2016) 1546.
[46] D. Nieto, S. Brunea, A.M. Gonzalez-Vadillo, J. Perles, F. Carrillo-Hermosilla,
A. Antineolo, J.M. Padro n, G.B. Plata, I. Cuadrado, Organometallics 34 (2015)
5407.
[47] A. Korfel, M.E. Scheulen, H.J. Schmoll, O. Grndel, A. Harstrick, M. Knoche,
Clin. Cancer Res. 4 (1998) 2701.
[48] L.Y. Kuo, M.G. Kanatzidis, M. Sabat, A.L. Tipton, T.J. Marks, J. Am. Chem. Soc.
113 (1991) 9027.
[49] M.M. Harding, G. Mokdsi, Curr. Med. Chem. 7 (2000) 1289.
[50] K. Mross, P. Robben-Bathe, L. Edler, J. Baumgart, W.E. Berdel, H. Fiebig,
C. Unger, Onkologie 23 (2000) 576.
[51] M. Cini, H. Williams, M.W. Fay, M.S. Searle, S. Woodward, T.D. Bradshaw,
Metallomics 8 (2016) 286.
[52] G. Lally, A. Deally, F. Hackenberg, J. Quinn, M. Tacke, Lett. Drug. Des. Discov.
10 (2013) 675.
[53] U. Olszewski, A. Deally, M. Tacke, G. Hamilton, Neoplasia 14 (2012) 813.
[54] Y.F. Mui, J. Fernandez-Gallardo, B.T. Elie, A. Gubran, I. Maluenda, M. Sanau,
O. Navarro, M. Contel, Organometallics 35 (2016) 1218.
[55] H. Sun, H. Li, R.A. Weir, P.J. Sadler, Angew. Chem. Int. Ed. 37 (1998) 1577.
[56] M. Guo, P.J. Sadler, J. Chem. Soc. Dalton Trans. (2000) 7.
[57] M. Guo, H. Sun, H.J. McArdle, L. Gambling, P.J. Sadler, Biochemistry 39 (2000)
10023.
[58] M. Guo, Z. Guo, P.J. Sadler, J. Biol. Inorg. Chem. 6 (2001) 698.
[59] M. Guo, I. Harvey, D.J. Campopiano, P.J. Sadler, Angew Chem. Int. Ed. 45
(2006) 2728.
[60] R. Morris, P. J. Sadler, H. Chen, D. Jodrell, PCT/GB00/04144. (2000) Int. Pub.
No. WO 01/30790.
[61] R.E. Morris, R.E. Aird, P. del Socorro Murdoch, H. Chen, J. Cummings,
N.D. Hughes, S. Parsons, A. Parkin, G. Boyd, D.I. Jodrell, P.J. Sadler, J. Med.
Chem. 44 (2001) 3616.
[62] R.E. Aird, J. Cummings, A.A. Ritchie, M. Muir, R.E. Morris, H. Chen, P.J. Sadler,
D.I. Jodrell, Br. J. Cancer 86 (2002) 1652.
[63] H. Chen, J.A. Parkinson, S. Parsons, R.A. Coxall, R.O. Gould, P.J. Sadler, J. Am.
Chem. Soc. 124 (2002) 3064.
[64] H. Chen, J.A. Parkinson, R.E. Morris, P.J. Sadler, J. Am. Chem. Soc. 125 (2003)
173.
[65] F. Wang, H. Chen, S. Parsons, I.D.H. Oswald, J.E. Davidson, P.J. Sadler, Chem.
Eur. J. 9 (2003) 5810.
[66] O. Novakova, H. Chen, O. Vrana, A. Rodger, P.J. Sadler, V. Brabec, Biochemistry
42 (2003) 11544.
[67] F. Wang, A. Habtemariam, E.P.L. van der Geer, R. Ferna ndez, M. Melchart,
R.J. Deeth, R. Aird, S. Guichard, F.P.A. Fabbiani, P. Lozano-Casal, I.D.H. Oswald,
D.I. Jodrell, S. Parsons, P.J. Sadler, Proc. Natl. Acad. Sci. U. S. A. 102 (2005)
18269.
[68] F. Wang, J. Xu, A. Habtemariam, J. Bella, P.J. Sadler, J. Am. Chem. Soc. 127
(2005) 17734.
[69] H. Petzold, J. Xu, P.J. Sadler, Angew. Chem. Int. Ed. 47 (2008) 3008.
13
[70] T. Sriskandakumar, H. Petzold, P.C.A. Bruijnincx, A. Habtemariam, P.J. Sadler,
P. Kennepohl, J. Am. Chem. Soc. 131 (2009) 13355.
[71] F. Wang, J. Xu, K. Wu, S.K. Weidt, C.L. Mackay, P.R. Langridge-Smith,
P.J. Sadler, Dalton Trans. 42 (2013) 3188.
[72] W. Hu, Q. Luo, X. Ma, K. Wu, J. Liu, Y. Chen, S. Xiong, J. Wang, P.J. Sadler,
F. Wang, Chem. Eur. J. 15 (2009) 6586.
[73] Y. Lin, Y. Huang, W. Zheng, F. Wang, A. Habtemariam, Q. Luo, X. Li, K. Wu,
P.J. Sadler, S. Xiong, J. Inorg. Biochem. 128 (2013) 77.
[74] Y.-K. Yan, M. Melchart, A. Habtemariam, A.F.A. Peacock, P.J. Sadler, J. Biol.
Inorg. Chem. 11 (2006) 483.
[75] J.J. Soldevila-Barreda, P.C.A. Bruijnincx, A. Habtemariam, G.J. Clarkson,
R.J. Deeth, P.J. Sadler, Organometallics 31 (2012) 5958.
[76] J.J. Soldevila-Barreda, I. Romero-Canelo n, A. Habtemariam, P.J. Sadler, Nat.
Commun. 6 (2015) 6582.
[77] S.J. Dougan, A. Habtemariam, S.E. McHale, S. Parsons, P.J. Sadler, Proc. Natl.
Acad. Sci. U. S. A. 105 (2008) 11628.
[78] S. Betanzos-Lara, L. Salassa, A. Habtemariam, P.J. Sadler, Chem. Commun. 43
(2009) 6622.
[79] F. Barraga n, P. Lopez-Senn, L. Salassa, S. Betanzos-Lara, A. Habtemariam,
V. Moreno, P.J. Sadler, V. March an, J. Am. Chem. Soc. 133 (2011) 14098.
[80] S. Betanzos-Lara, L. Salassa, A. Habtemariam, O. Nova kova, A.M. Pizarro,
G.J. Clarkson, B. Liskova, V. Brabec, P.J. Sadler, Organometallics 31 (2012)
3466.
[81] I. Romero-Canelo n, B. Phoenix, A. Pitto-Barry, J. Tran, J.J. Soldevila-Barreda,
N. Kirby, S. Green, P.J. Sadler, N.P.E. Barry, J. Organomet. Chem. 796 (2015)
17.
[82] R. Carter, A. Westhorpe, M. Romero, A. Habtemariam, C. Gallevo, Y. Bark,
N. Menezes, P.J. Sadler, R. Sharma, Sci. Rep. 6 (2016) 20596.
[83] A. Ratanaphan, T. Nhukeaw, K. Hongthong, P.J. Dyson, Anticancer Agents
Med. Chem. 17 (2017) 212.
[84] A. Weiss, R.H. Berndsen, M. Dubois, C. Mller, R. Schibli, A.W. Grifoen,
P.J. Dyson, P.N. Sliwinska, Chem. Sci. 5 (2014) 4742.
[85] W.H. Ang, A. Casini, G. Sava, P.J. Dyson, J. Organo. Chem. 696 (2011) 989.
[86] J. Palmucci, F. Marchetti, R. Pettinari, C. Pettinari, R. Scopelliti, T. Riedel,
B. Therrien, A. Galindo, P.J. Dyson, Inorg. Chem. 55 (2016) 11770.
[87] P. Mandal, N. Malviya, M.F. Guedes da Silva, S.S. Dhankhar, C.M. Nagaraja,
S.M. Mobin, S. Mukhopadhyay, Dalton Trans. 45 (2016) 19277.
[88] M. Hanif, S. Moon, M.P. Sullivan, S. Movassaghi, M. Kubanik, D.C. Goldstone,
T. Sohnel, S.M. Jamieson, C.G. Hartinger, J. Inorg. Biochem. 165 (2016) 100.
[89] M. Kubanik, W. Kandioller, K. Kim, R.F. Anderson, E. Klapproth, M.A. Jakupec,
A. Roller, T. So hnel, B.K. Keppler, C.G. Hartinger, Dalton Trans. 45 (2016)
13091.
[90] Y. Zhang, W. Zheng, Q. Luo, Y. Zhao, E. Zhang, S. Liu, F. Wang, Dalton Trans. 44
(2015) 13100.
[91] A. Grozav, O. Balacescu, L. Balacescu, T. Cheminel, I. Berindan-Neagoe,
B. Therrien, J. Med. Chem. 58 (2015) 8475.
[92] M.J. Chow, M.V. Babak, D.Y. Wong, G. Pastorin, C. Gaiddon, W.H. Ang, Mol.
Pharm. 13 (2016) 2543.
[93] A.F.A. Peacock, A. Habtemariam, R. Ferna ndez, V. Walland, F.P.A. Fabbiani,
S. Parsons, R.E. Aird, D.I. Jodrell, P.J. Sadler, J. Am. Chem. Soc. 128 (2006) 1739.
[94] A.F.A. Peacock, S. Parsons, P.J. Sadler, J. Am. Chem. Soc. 129 (2007) 3348.
[95] H. Kostrhunova, J. Florian, O. Novakova, A.F.P. Peacock, P.J. Sadler, V. Brabec,
J. Med. Chem. 51 (2008) 3635.
[96] A.L. Noffke, A. Habtemariam, A.M. Pizarro, P.J. Sadler, Chem. Commun. 48
(2012) 5219.
[97] 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. 53 (2010) 8192.
[98] J.M. Hearn, I. Romero-Canelo  n, A.F. Munro, Y. Fu, A.M. Pizarro, M.J. Garnett,
N. Ultan McDermott, O. Carragher, P.J. Sadler, Proc. Natl. Acad. Sci. U. S. A. 112
(2015) E3800.
[99] C. Sanchez-Cano, I. Romero-Canelo n, Y. Yang, I.J. Hands-Portman, S. Bohic,
P. Cloetens, P.J. Sadler, Chem. Eur. J. 23 (2017) 2512.
[100] R.J. Needham, C. Sanchez-Cano, X. Zhang, I. Romero-Canel, A. Habtemariam,
M.S. Cooper, L. Meszaros, G.J. Clarkson, P.J. Blower, P.J. Sadler, Angew. Chem.
Int. Ed. 19 (2017) 1017.
[101] Y. Fu, M.J. Romero, L. Salassa, X. Cheng, A. Habtemariam, G.J. Clarkson,
I. Prokes, A. Rodger, G. Costantini, P.J. Sadler, Angew. Chem. Int. Ed. 55 (2016)
8909.
[102] Z. Liu, A. Habtemariam, A. Pizarro, S. Fletcher, A. Kisova, O. Vrana, L. Salassa,
P. Bruijnincx, G. Clarkson, V. Brabec, P.J. Sadler, J. Med. Chem. 54 (2011) 3011.
[103] Z. Liu, L. Salassa, A. Habtemariam, A.M. Pizarro, G.J. Clarkson, P.J. Sadler,
Inorg. Chem. 50 (2011) 5777.
[104] Z. Liu, A. Habtemariam, A.M. Pizarro, G.J. Clarkson, P.J. Sadler, Organome-
tallics 30 (2011) 4702.
[105] A.J. Millett, A. Habtemariam, I. Romero-Canelo  n, G.J. Clarkson, P.J. Sadler,
Organometallics 34 (2015) 2683.
[106] S. Betanzos-Lara, Z. Liu, A.M. Pizarro, B. Qamar, A. Habtemariam, P.J. Sadler,
Angew. Chem. Int. Ed. 51 (2012) 3897.
[107] Z. Liu, R.J. Deeth, J.S. Butler, A. Habtemariam, M.E. Newton, P.J. Sadler, Angew.
Chem. Int. Ed. 52 (2013) 4194.
[108] J. Hearn, I. Romero-Canelo n, B. Qamar, Z. Liu, I. Hands-Portman, P.J. Sadler,
ACS Chem. Biol. 8 (2013) 1335.
[109] Z. Liu, I. Romero-Canelo n, B. Qamar, J.M. Hearn, A. Habtemariam, N.P.E. Barry,
A.M. Pizarro, G.J. Clarkson, P.J. Sadler, Angew. Chem. Int. Ed. 53 (2014) 3941.
[110] Z. Liu, P.J. Sadler, Acc. Chem. Res. 47 (2014) 1174.
14 P. Zhang, P.J. Sadler / Journal of Organometallic Chemistry 839 (2017) 5e14

[111] V. Novohradsky, L. Zerzankova, J. Stepankova, A. Kisova, Z. Liu, J. Kasparkova, M. Stefanopoulou, Y. Geldmacher, W.S. Sheldrick, G. Wolber, A. Prokop,
P.J. Sadler, V. Brabec, Metallomics 6 (2014) 1491. S. Wo l, I. Ott, J. Med. Chem. 53 (2010) 8608.
[112] Z. Liu, I. Romero-Canelo n, A. Habtemariam, G.J. Clarkson, P.J. Sadler, Organ- [126] R. Rubbiani, S. Can, I. Kitanovic, H. Alborzinia, M. Stefanopoulou,
ometallics 33 (2014) 5324. M. Kokoschka, S. Mo nchgesang, W.S. Sheldrick, S. Wo l, I. Ott, J. Med. Chem.
[113] Z. Liu, P.J. Sadler, Inorg. Chem. Front. 1 (2014) 668. 54 (2011) 8646.

[114] P. Starha, A. Habtemariam, I. Romero-Canelo  n, G.J. Clarkson, P.J. Sadler, Inorg. [127] R. Rubbiani, L. Salassa, A. de Almeida, A. Casini, I. Ott, ChemMedChem 9
Chem. 55 (2016) 2324. (2014) 1205.
[115] J.J. Soldevila-Barreda, A. Habtemariam, I. Romero-Canelo n, P.J. Sadler, J. Inorg. [128] T.T.-H. Fong, C.-N. Lok, C.Y.-S. Chung, Y.-M.E. Fung, P.-K. Chow, P.-K. Wan, C.-
Biochem. 153 (2015) 322. M. Che, Angew. Chem. Int. Ed. 55 (2016) 11935.
[116] T. Zou, C.T. Lum, S.S.Y. Chui, C.M. Che, Angew. Chem. Int. Ed. 52 (2013) 2930. [129] R. Gao, D.G. Ho, B. Hernandez, M. Selke, D. Murphy, P.I. Djurovich,
[117] I. Ott, Coord. Chem. Rev. 253 (2009) 1670. M.E. Thompson, J. Am. Chem. Soc. 124 (2002) 14828.
[118] A. Bindoli, M.P. Rigobello, G. Scutari, C. Gabbiani, A. Casiniand, L. Messori, [130] S.P.Y. Li, C.T.S. Lau, M.W. Louie, Y.W. Lam, S.H. Cheng, K.K.W. Lo, Biomaterials
Coord. Chem. Rev. 253 (2009) 1692. 34 (2013) 7519.
[119] M. Stallings-Mann, L. Jamieson, R.P. Regala, C. Weems, N.R. Murray, [131] S. Moromizato, Y. Hisamatsu, T. Suzuki, Y. Matsuo, R. Abe, S. Aoki, Inorg.
A.P. Fields, Cancer Res. 66 (2006) 1767. Chem. 51 (2012) 12697.
[120] S.J. Berners-Price, C.K. Mirabelli, R.K. Johnson, M.R. Mattern, F.L. McCabe, [132] R.R. Ye, C.P. Tan, L. He, M.H. Chen, L.N. Ji, Z.W. Mao, Chem. Commun. 50
L.F. Faucette, C.M. Sung, S.M. Mong, P.J. Sadler, S.T. Crooke, Cancer Res. 46 (2014) 10945.
(1986) 5486. [133] L. He, Y. Li, C.P. Tan, R.R. Ye, M.H. Chen, J.J. Cao, L.N. Ji, Z.W. Mao, Chem. Sci. 6
[121] S. Tian, F.M. Siu, S.C.F. Kui, C.N. Lok, C.M. Che, Chem. Commun. 47 (2011) (2015) 5409.
9318. [134] H.Y. Huang, P.Y. Zhang, B. Yu, Y. Chen, J.Q. Wang, L.N. Ji, H. Chao, J. Med.
[122] S. Patil, A. Deally, B. Gleeson, H. Muller-Bunz, F. Paradisi, M. Tacke, Metal- Chem. 57 (2014) 8971.
lomics 3 (2011) 74. [135] B. Boff, C. Gaiddon, M. Pfeffer, Inorg. Chem. 52 (2013) 2705.
[123] D.A. Medvetz, K.M. Hindi, M.J. Panzner, A.J. Ditto, Y.H. Yun, W. Youngs, J. Met. [136] T. Zou, J. Liu, C.T. Lum, C. Ma, R.C.-T. Chan, C.-N. Lok, W.-M. Kwok, C.-M. Che,
Based Drugs (2008) 384010. Angew. Chem. Int. Ed. 53 (2014) 10119.
[124] G.F. Rush, P.F. Smith, G.D. Hoke, D.W. Alberts, R.M. Snyder, C.K. Mirabelli, [137] J.L.L. Tsai, T. Zou, J. Liu, T. Chen, A.O.Y. Chan, C. Yang, C.M. Che, Chem. Sci. 6
Toxicol. Appl. Pharmacol. 90 (1987) 391. (2015) 3823.
[125] R. Rubbiani, I. Kitanovic, H. Alborzinia, S. Can, A. Kitanovic, L.A. Onambele,