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Accepted Article
Title: Introducing Metallosalens to Biological Studies: The Renaissance
of Traditional Coordination Complexes

Authors: Hao-Yan Yin, Juan Tang, and Jun-Long Zhang

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European Journal of Inorganic Chemistry 10.1002/ejic.201700695

MICROREVIEW
Introducing Metallosalens to Biological Studies: The Renaissance
of Traditional Coordination Complexes
Hao-Yan Yin,[a] Juan Tang,[a] and Jun-Long Zhang*[a]

Dedicated to Professor Chi-Ming Che on the occasion of his 60th birthday

Abstract: Metal complexes attracted great attention in biological application because of their attractive structures and intriguing physico-
chemical properties. Combinations of the skeleton structures of salen ligands and various metal ions provide many possibilities for incorporation
of diverse biological functionalities, which is unachievable for conventional small organic molecules. The past decade has witnessed remarkable
advances for metallosalens; we herein present a microreview of recent progress of their biological application. This microreview is divided into
4 categories, namely, DNA binding, fluorescent imaging, magnetic resonance imaging, and drugs. Each approach is described with
representative examples. The fundamental principles for the relationship between structures and biological behaviors of metallosalens are
featured, bearing in mind the current opportunities and challenges applying metallosalens to biology.

1. Introduction are explicitly called ‘salophen (o-phenylenediamine)’, ‘salpn (1,2-

propylenediamine)’ and ‘salompen (4,5-dimethyl-1,2-
N, N’-bis(salicylidene)ethylenediamine based ligands are a class phenylenediamine)’ and in this microreview, all the salen-type
of most studied tetradentate ligands in coordination chemistry. ligands are broadly depicted as ‘salen’ (Figure 1). Since Pfeiffer
They are often abbreviated to ‘salen’, named after the et al. reported the first series of metal (Ni, Cu, Fe, and Mn) salen
condensation of two parts of salicylaldehyde and complexes in 1933,[1] salen coordination chemistry has drawn
ethylenediamine. According to different diamine moieties, they considerable attention for the easy synthesis and tunable
chemical and electronic structures, allowing the formation of
metal complexes with most of the transition metals and main
[a] Beijing National Laboratory for Molecular Sciences, State Key group metals in periodic table.[2] More importantly, for the similar
Laboratory of Rare Earth Materials Chemistry and Applications, planar structures to metalloporphyrins, various metallosalens
College of Chemistry and Molecular Engineering, Peking University,
Beijing 100871, P. R. China.
have been extensively explored as catalysts (including
E-mail: [email protected]; Fax: +86-10-62767034 asymmetric catalysis) in atom transfer reactions such as
http://www.chem.pku.edu.cn/zhangjl/ epoxidation of olefins, ring opening polymerization,

Hao-Yan Yin received his B.S. degree in Peking University in 2015, and since then he has been a Ph. D. student in Prof. Jun-Long Zhang's
group in Peking University. Currently, his research focuses on studying cellular events using fluorescent imaging with luminescent metal
complexes and mechanism of action for metallodrugs.

Juan Tang received her B.S. degree in Wuhan University in 2012. She started her chemistry in Prof. Haibing Zhou’s group in 2010 and
mainly focused on synthesis of selective estrogen receptor modulators. After graduation, she went Peking University and started her
graduate studies in Prof. Jun-Long Zhang’s group. During the last five years, her research has focused on probing the activities of
synthesized metal complexes in the cellular milieu through fluorescent imaging and other chemical/biological techniques, with an aim to
provide insight on metabolism of inorganic drugs.

Jun-Long Zhang received his BSc from Sichuan University (1997) and his MSc from Chengdu Institute of Organic Chemistry, CAS (2000).
In 2005, he obtained his PhD degree in the University of Hong Kong under the supervision of Prof. Chi-Ming Che. After 3 years postdoctoral
research with Prof. Yi Lu in University of Illinois at Urbana-Champaign, he was selected in “100 scientists” Program in Peking University
started his independent research career as PI of bioinorganic chemistry since 2008. He is now associate professor with tenure, College of
Chemistry and Molecular Engineering, Peking University. His research interests include porpholactone chemistry, molecular imaging using
luminescent metal complexes and biomimetic inorganic chemsitry. He was selected as the Early Career Series for ChemPlusChem, (2015)
Emerging Investigator in Bioinorganic Chemistry (American Society of Chemistry, 2016) and awarded Peking University Luye Eminent
Young Scholar Fellowship (2011) and Young Scientist Award by Chinese Society of Rare Earth (2017).

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European Journal of Inorganic Chemistry 10.1002/ejic.201700695

MICROREVIEW

Figure 1. General structure of salen type ligands. The N2O2 coordination pocket
is available for various metals and the extensive modification methods brings
about multiple application possibilities.

Figure 2. X-ray crystal structure of Ni(salen) binding to G-quadruplex DNA. (A)

cyclopropanation, sulfoxidation and so on.[3] Along with the Two quadruplexes interact at their 3’ end G-quartet faces and are separated by
advances of supramolecular chemistry and coordination polymers salen ligands and a pair of water-bridged thymine bases. (B) Topview of the
in last century, metallosalens have been further employed as metallosalen-quadruplex stacking mode. Reprinted with permission from
literature 10. Acknowledgment of copyright 2012, American Chemical Society.
molecular building blocks of new coordination polymeric materials
with magnetic, photophysical and catalytic properties, based on
various coordination modes.[4] These works significantly and organelle distribution; 4) easy synthesis and modification,
promoted the development of metallosalen chemistry by allowing further ingenious design by combination with the
combination of their intriguing photophysical, magnetic, electronic sophisticated chemistry to generate diverse biological functions.
and catalytic properties and several excellent reviews have been For instance, as shown in Figure 1, by modifying the R1 ~ R5
published in recent years.[2c, 3d, 3f, 3i, 4c] positions, not only the conjugated structure but also their
In contrast to tremendous progress made in the last century, lipophilicity and electron density can be adjusted, and more
applications of metallosalens in biological studies has been much functional groups can be appended. Therefore, since the turn of
less reported, and most of them are used to investigate the the century, biological studies of metallosalens with various metal
interaction between metal complexes and biomolecules such as ions as well as ligand derivations start to boom, bringing a
proteins and DNA. Prominently, metallosalens could be used as renaissance to these “century” compounds.
non-native cofactors to replace heme in some metalloproteins In this paper, we provide a microreview of biological
and construct artificial catalytic metalloenzymes, demonstrating applications of metallosalens, summarizing advances from recent
the biocompatibility of metallosalens and the potential to researches. Up to date, metallosalens have displayed important
specifically bind proteins.[5] With the rapid development of functions in binding biomolecules, biological fluorescent imaging,
chemical biology, coordination compounds gradually rise to the magnetic resonance imaging, protecting normal cells and killing
equal place as organic molecules, which stimulates new cancer cells. Each application is described with representative
applications in cell biology and even medicinal studies.[6] In the examples, and noteworthy features of metallosalens are
last decade, metallosalens attracted much attention for their discussed. We expect that this review would raise interest in
unique features, including 1) tunable coordination spheres and gaining fundamental understanding and assist in the judicious
well-established structural relationship between the intriguing design and construction of metallosalens for biological application.
photophysical properties, rendering them potential molecular
imaging reagents; 2) rich reactivity, especially intrinsic redox
properties, facilitating to induce catalytic reaction in living cells 2. Metallosalens bind to DNA
and regulate intracellular molecular events or signals such as
oxidative stress; 3) the square planar structure tending to
aggregate and form stable stacking oligomers in aqueous media,
which has different biological behaviors such as cellular uptake

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European Journal of Inorganic Chemistry 10.1002/ejic.201700695

MICROREVIEW

Figure 3. Metallosalens with DNA-binding ability.

Metallosalens are well-studied DNA-binding complexes, with a skeleton also participate in the interaction with the grooves and
wide range of metal centers including Pd, Pt, Cu, Zn, V, Al, and loops of G-quadruplex (Figure 2). Thomas et al. found that
so on.[7] Burrows et al. demonstrated Ni(salen)s to bind to duplex Ni(salen)s strongly interacted with human telomeric sequence
DNA.[8] The coordinated Ni(II) center triggers redox chemistry that when modified with alkylimidazolium side chains, stablizing the
is ligand-centered, and generates a reactive intermediate which telomeric G-quadruplex structure.[11] Computational studys
coupled with nucleobases and formed a covalent adduct. Fe and confirmed that the aromatic rings of Ni(salen)s were involved in
Co(salen) complexes conjugated with ammonium and distamycin π-π stacking and the alkylimidazolium side chains inserted into
like moieties showed efficient DNA minor groove binding affinity opposite grooves. By changing the length, number, and position
along with DNA cleavage capacities, reported by Bhattacharya et of the alkylimidazolium side chains, the optimized Ni(salen)
al.[9] These metallosalens showed cytotoxicity to various cancer significantly inhibited telomerase activity with low IC50 value of 70
cell lines and induced cell death following apoptotic pathway. nM. Further studies show that not only Ni(II) but also other
Besides, metallosalens also have binding affinity to G- metallosalens with square planar and square pyramidal
quadruplex with high selectivity towards duplex DNA. Vilar et al. configurations have similar binding activity.[7b, 7c, 12] The X-ray
reported Ni(salen)s as excellent G-quadruplex DNA stabilizers.[10] crystal structures showed the end-stacking binding modality and
The planar structures stack on the top of the guanine tetrads, and the metal in each case was in line with the central potassium ion
the protonated piperidine groups extended from the salen channel.[12] Thus, the metallosalens were potential inhibitors of
telomerase activity and showed antibacterial and anticancer
ability.
Fluorescent DNA-binding metallosalens were potential
candidates for theranostic agents. Che et al. reported the
luminescent Pt(salen) as G-quadruplex probe.[13] Pt(salen)
exhibits enhanced fluorescence upon binding to G-quadruplex,
and could effectively down-regulate the expression of c-myc, a
human oncogene containing quadruplex sequence, in human
hepatocarcinoma cells (Figure 4). Rodríguez et al. evaluated a
series of o-phenylenediamine derived Zn(salen)s with binding
affinity to DNA. These compounds enter the cells but did not show
any inhibition ability to DNA expression, which might be due to
localizing in cytoplasm as revealed by confocal microscopy
results.[14] Substituted by nitro groups in 5, 5’-positions of
salicylaldehyde moieties, Zn(salen) showed enhanced interaction
with DNA, and the complex could enter the nucleus. However, the
nitro-substituted Zn(salen) still did not show any cytotoxicity.[15]

Figure 4. (A) Structure of the G-quadruplex binding Pt(salen). (B) Emission 3. Metallosalens for fluorescence molecular
spectra Pt(salen) in Tris/KCl buffer with increasing concentration of the G-
quadruplex. (C) The expression of c-myc in Pt(salen) treated HepG2 cells. (D) imaging
Relative c-myc mRNA level. Reprinted with permission from literature 13.
Acknowledgment of copyright 2009 Wiley-VCH Verlag GmbH&Co. KGaA, Metallosalens (M = Ni, Pd, Pt, Fe, Zn and Al) have been reported
Weinheim.
as intracellular fluorescent probes. The involved metals could be

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European Journal of Inorganic Chemistry 10.1002/ejic.201700695

MICROREVIEW

Figure 5. (A) Structure of nuclear staining Pt(salen). (B) Confocal imaging of

HeLa cells incubated with Pt(salen). Reprinted with permission from literature
16. Acknowledgment of copyright 2014 Royal Society of Chemistry.

Figure 6. (A) Structure of Fe(salen) with axial coumarin hydroxamate ligand.

(B~C) Fluorescent imaging pictures of A2780 cells. Reprinted with permission
from literature 18. Acknowledgment of copyright 2009 Royal Society of
Chemistry.

classified into three types according to their electron

configurations: open-shell diamagnetic, open-shell paramagnetic
and closed-shell. Figure 7. (A) the orthogonality between function of R1 and R2 substitution. (B~F)
Confocal imaging of HeLa cells using fluorescent Zn(salen)s with different R1
For open-shell divalent group 10 metals with d8 electronic
and R2. Reprinted with permission from literature 21. Acknowledgment of
configuration, the strong planar square ligand field of salen gives copyright 2014 Royal Society of Chemistry.
rise to diamagnetic. The luminescence of these compounds was
generated from excited states formed by metal-to-ligand charge
transfer and ligand-centered transitions. Vilar et al. carried out Fe(salen) probes could be functionalized by an extra fluorescent
fluorescent microscopy imaging of two emissive Pt(salen)s in four appendant. Fe(salen) with an axial coumarin hydroxamate ligand
different cell lines.[16] They found that the two compounds has negative reduction potential and the intracellular fluorescence
localized at different organelles. Pt(salen) with less hydrophilicity increases along with the axial ligand release, possibly via a
exhibited a characteristic nucleus staining (Figure 5), and the reduction process of the metal center.[18] It is noteworthy that while
other one with sulfonic acid group substitutions was less cell the free coumarin ligand displays non-specific distribution, the
permeable, displaying dim fluorescence that could be observed in Fe(salen) complex shows lysosomal accumulation of the
the discrete region of the cytoplasm in most cases. Bhattacharya coumarin fluorescence (Figure 6). This approach is instructive for
et al. synthesized Ni(salen)s and Pd(salen)s with readily available drug delivery. Fe(salen)s were also used for selective
fluorescein-derived salicylaldehyde as the backbone to provide fluorescence turn-on detection of endogenous pyrophosphate in
an extended aromatic surface.[17] These complexes exhibited mitochondria following a disassembly approach.[19] The probe has
human telomeric G-quadruplex DNA affinity and inhibition of good biocompatibility and membrane permeability, as well as the
telomerase activity, leading to significant cancer cell cytotoxicity. possibilities for further modification.
Confocal microscopy showed the subcellular localization of To circumvent the potential toxicity of heavy metals,
Ni(salen) and Pd(salen) in the nucleus and mitochondria, causing bioavailable Zn(II) was chosen as the metal center and Zn(salen)s
G1-phase arrest and inducing cell death via apoptotic pathway. were systematically studied as fluorescent imaging probes[20].
The open-shell paramagnetic metals, such as Fe(III), could Zn(II) is a closed-shell metal, and fluorescence of Zn(salen) are
quench the ligand-centered luminescence and thus Fe(salen) ligand-centered. It can stabilize the ligand structure and improve
could not directly be used as fluorogenic probes. However, the rigidity of the molecule, thus enhances the photo-stability and

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European Journal of Inorganic Chemistry 10.1002/ejic.201700695

MICROREVIEW

Figure 8. (A) Photooxidation of the thioether-functionalized Zn(salen). (B) Confocal imaging of the photoactivation process in L6 myoblasts. (C) Intracellular
fluorescence intensity plot. Reprinted with permission from literature 22. Acknowledgment of copyright 2012 Royal Society of Chemistry. (D) Structure of the
mitochondria super-resolution imaging Zn(salen) probe. (E) STORM imaging in COS7 cells. Reprinted with permission from literature 24. Acknowledgment of
copyright 2016 Royal Society of Chemistry.

the fluorescence quantum yield, compared to the corresponding Zn(salen) with myeloperoxidase (MPO), the membrane-
free ligands. Zhang et al. demonstrated the use of luminescent permeable adduct can work as lysosome-specific H2O2
Zn(salen)s as subcellular organelles imaging probes through one- fluorescent “turn-on” probe in acidic conditions, with both high
and two-photon fluorescent microscopy in living cells.[20] These region- and substrate-selectivity and sensitivity.[23] Moreover, the
complexes share 2, 3-diaminomaleonitrile as electron- photoactivation property of the thioether Zn(salen) was also
withdrawing unit and salicylaldehyde with different 4-amino demonstrated in super-resolution imaging.[24] By incorporating
substitutions as electron-donating unit. The donor-π-acceptor propargyl groups to the thioether Zn(salen), Zhang et al. reported
structures make the emission bathochromic shift to 618-635 nm the first example for luminescent metal complexes as super-
with fluorescence quantum yields of 0.34-0.69, as well as high resolution imaging probe of mitochondria with a ca. 12 nm
two-photon absorption cross-sections. The Zn(salen)s exhibit localization precision (Figure 8).
good chemo- and photo-stability and low cytotoxicity. Autophagy is an important biological process that refers to
Through constructing a fluorescent Zn(salen) library of 48 digestion of worn-out organelles by the cell’s own lysosomes. D-
complexes, the relationship between the molecular structures, the Glucose-attached Zn(salen) can be used as specific and
photophysical properties, and the subcellular distribution of quantitative autolysosome tracker for monitoring later stages of
Zn(salen)s were carefully studied.[21] Experimental and theoretical autophagy by one- or two-photon fluorescent microscope.[25] This
results demonstrated that changes of the diamine moieties could probe only exhibits 'turn-on' fluorescence upon starvation- or
effectively modulate the photophysical properties of Zn(salen)s. chemical agent-induced autophagy, with the autolysosome or
The subcellular localizations are highly related to the lipophilicity, possible late endosome/lysosome networks localization. The
which is correlated to the N-substituents at the 4-position of introduced glucose groups adjust the lipophilicity of the molecule,
salicylaldehyde (Figure 7). Thus, the orthogonality between the contributing to the subcellular distribution and the selective ‘turn-
fluorescent properties and the subcellular localizations of the on’ fluorescence in hydrophobic environment. Compared to the
Zn(salen)s, which is regulated by discrete moieties, makes them generally used autophagy probe LC3-GFP, this fluorescent
suitable fluorophores for the modular design of bioprobes in living Zn(salen) probe can be used to quantify autophagy at a single
cell imaging. point without transfection process or false positive signals
Besides tuning the subcellular localization, modification on because of protein aggregation. This is the first example of using
salicylaldehyde moieties renders Zn(salen) photoactivatable transition metal complex to monitor autophagy process.
fluorescence. Thioether moieties derived in the 3, 3’-positions Furthermore, experiments carried out with the Zn(salen) probe
could quench the emission of Zn(salen) through a photo-induced verified the quantitative relationship between Zn2+ ions and
electron transfer (PET) process.[22] Under one- or two-photon autophagy, and this probe can be used for high-throughput
irradiation, the thioethers can be oxidized to sulfoxides, changing screening of autophagy inducers by non-invasive fluorescence
the frontier molecular orbital energy, perturbing the PET process, detection as well.
restoring the fluorescence (Figure 8). By combining thioether

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European Journal of Inorganic Chemistry 10.1002/ejic.201700695

MICROREVIEW

Figure 10. Luminescent Zn(salen) probes avoiding self-aggregation. (A) The

cryptand tri-Zn(salen) complexes. (B) Sulfonium-functionalized Zn(salen)s.

fluorescence, in contrast to no fluorescence of corresponding

monomer in PLGA.
Then, cationic sulfonium groups were incorporated to the salen
skeleton at its 3, 3’- and 5, 5’- positions, furnishing water-soluble
Zn(salen)s to avoid intermolecular Zn···O coordination (Figure
10).[29] The sulfonium functionalization provides positive charges
to enhance electrostatic repulsion, as well as increases the steric
Figure 9. (A) Aggregation and deaggregation forms of triphenyl phosphonium hindrance, rendering Zn(salen)s water soluble as monomers in
derived Zn(salen) underwent different cellular uptake pathways and different aqueous media. Compared to their thioether analogues, these
subcellular localizations. (B) Colocalization study in HeLa cell. In the presence Zn(salen)s display “switched-on” fluorescence due to the
of pyridine, Zn(salen) colocalized with MitoTracker Green; in the absence of
pyridine, Zn(salen) colocalized with LysoTracker® Green DND-26. Reprinted
perturbation of the PET process by the electron-withdrawing
with permission from literature 27. Acknowledgment of copyright 2015 Royal sulfonium moieties. Imaging experiments showed that modulation
Society of Chemistry. of the number or the alkyl substituents of sulfonium moieties could
tune the cell-permeability of these fluorescent Zn(salen)s.
Alternative approach to prevent the intermolecular interaction is
Zn(salen)s tend to aggregate through axial intermolecular
to change Zn to Al, a +3 charged metal ion, forming Al(salen)s
Zn···O coordination.[26] Zhang et al. demonstrated that this self-
with one positive charge and avoiding self-aggregation through
aggregation process exerted great influence on the subcellular
electrostatic repulsion.[30] A comparative study with Zn(salen)
behaviors of Zn(salen) probes with a triphenyl phosphonium
showed that Al(salen) displayed higher intracellular fluorescence
derived complex.[27] Experiments including photophysical studies,
and lower cytotoxicity. Moreover, Al(salen) holds enhanced
transmission electron microscopy and dynamic light scattering
fluorescence intensity as well as lifetime along with increasing
results suggested the existence of Zn(salen)’s self-aggregation
viscosity. It can be used as intracellular fluorescent microviscosity
mainly induced by intermolecular Zn···O coordination in
probe, under both intensity imaging and lifetime imaging modes.
(semi-)aqueous environment. Adding pyridine as external ligands
dissociate the aggregates to monomers. Comparative cell uptake
studies of the aggregates and monomers revealed that the
aggregates underwent cellular uptake by caveolae-mediated
4. Metallosalens as MRI contrast agents
endocytosis and entered endosomal and lysosomal
Other than fluorescent imaging, there are several examples using
compartments, while the monomers were internalized by
metallosalens, especially Fe(salen)s, as magnetic resonance
membrane potential dependent passive diffusion and localized in
imaging (MRI) contrast agents. This is due to the intrinsic
mitochondria (Figure 9). The above results pointed to
magnetic character of metal centers. Ishikawa et al. showed that
“intermolecular metal-ligand interaction” as an overlooked fact in
the transport of Fe(salen) could be influenced and guided by
designing fluorescent metallosalen probes.
magnet.[31] The accumulation of Fe(salen) in tumor can be
To modulate the intermolecular metal-ligand coordination of
visualized by MRI. In addition, the accumulation of Fe(salen) at
Zn(salen)s, cryptand type tri-Zn(salen) complexes were designed,
tumorous position causes apparent decrease of the tumor size
in which the 3D-cryptand structure efficiently helped restrict the
(Figure 11). While encapsulating the Fe(salen) into the
intermolecular Zn···O interaction (Figure 10).[28] However, this
polypyrrole (PPy)-b-polycaprolactone (PCL) smart diblock
probe is very hydrophobic and can not be used solely in aqueous
copolymers, the magnetic properties of Fe(salen) nanoparticles
media. When encapsulated in PLGA nanoparticle, the tri-
are dramatically enhanced, and magnetic field-triggered release
Zn(salen) complexes enter the live cells and display intracellular
of Fe(salen) molecules is realized under acidic conditions.[32]

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European Journal of Inorganic Chemistry 10.1002/ejic.201700695

MICROREVIEW

Figure 11. (A) ORTEP diagram of dinuclear [Fe(salen)]2O crystal structure. (B). Sagittal slice of photos (upper row) and T2*-weighted magnetic resonance images
(bottom row) at the mice tail. (C). Effect of Fe(salen) to mice leg tumors size with (bottom row) or without (upper row) magnet application. (D). Tumors volume
statistics with treatment of Fe(salen) and magnet. Reprinted with permission from literature 31. Acknowledgment of copyright 2015 Nature Publication.

protect normal tissue from diseases.[34] This activity has been well
summarized by several reviews[35] and their protective effects on
5. Metallosalens as predrugs lung, liver, kidney and radiation-induced mucositis have been
reported.[36] EUK compounds realize their bioactivity and prevent
Metallosalens with a wide range of metal centers are studied for apoptosis mainly by inhibiting the ROS, up-regulating Bcl-2 and
their bioactivities for a long time. Up to date, anticancer activity of down-regulating Bax.[37] The effects of antioxidant treatment
metallosalens with metal centers from group 3 to group 15 have include not only inhibition of proliferation that reduces tumor
been examined since the pioneering work of cytotoxic Co(salen)s burden, but also promoting programmed cell death of acute
reported by Sommer et al. at 2004.[33] Among all these metals, myeloid leukemia through suppressing the ROS signal.[38]
biological activities of two groups of metallosalens are most Mn(salen)s also show relatively high cytotoxicity as apoptosis
systematically studied. inducers through mitochondria pathway, thus not relevant to their
Mn(salen)s, also called eukarion (EUK) compounds (Figure 12), antioxidative properties.[39] The bioactivity of Mn(salen)s is a
are a class of superoxide dismutase catalase mimetics known to double-edged sword with pretty different pharmacological
functions from case to case.
Fe(salen)s are representative complexes for cytotoxicity
studies of metallosalens. Mandal et al. first reported that
Fe(salen)s affected cell viability by nuclear fragmentation and
caspase activation (characteristics of apoptosis).[40] Remarkably,
the apoptosis-inducing ability of Fe(salen)s is not certainly related
to their DNA binding and cleavage activities, and apoptosis is
initiated via mitochondria pathway. Treatment of Fe(salen)s
results in cytochrome c release and mitochondrial membrane
potential decrease, with an IC50 as low as 2.0 μM. Some
Fe(salen)s show cytotoxicity specific to tumor cells while normal
cells remain unaffected.[41] Furthermore, Fe(salen)s are also used
for drug delivery[18] and magnetic resonance imaging[31-32] as
mentioned above, making them candidates for multi-functional
theranostic agents.
Besides, metallosalens can also work as enzyme inhibitors,
allowing them to be potential drugs. For example, oxovanadium
Figure 12. Representative EUK complexes with antioxidant activity.
salens are known for their insulin-like effect against

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European Journal of Inorganic Chemistry 10.1002/ejic.201700695

MICROREVIEW
under aqueous solution. Our recent work about Zn(salen)
provided a clear clue to demonstrate the importance of
aggregation on the cellular uptake and subcellular distribution.
Thus, to systematically reveal the relationship between structure
and biological activity of metallosalens, more characterization
techniques are expected, which enables one to disclose the basic
properties comprehensively including the lipophilicity, charge
state, electrostatic potential and morphology in an identical
biological environment.
Metallosalens have been demonstrated to be catalytically
Figure 13. (A) Structure of Cu(salen) as proteasome inhibitor. (B) Conformation
active in various chemical reactions even in aqueous media. It is
of Cu(salen) in proteasome β2 subunit simulated with Autodock. Reprinted with
permission from literature 43. Acknowledgment of copyright 2016 Elsevier Ltd. noticeable that biological applications are much behind the
catalytic studies, which provide opportunities to introduce the
reactivity of metallosalens to adjust or interfere the metabolism of
hyperglycemic level, which might be due to the inhibition of protein living cells. Despite of proof-of-concept investigations on such
tyrosine phosphatase activity.[42] Recently Xu et al. screened a reactivity-based metal complex probes reported, there is no report
series of Cu(salen) as selective proteasome β2 subunit inhibitors, for metallosalens up to date. Previous studies for molecular
and the optimized Cu(salen) structure showed IC50 of 0.89 μM for imaging revealed the perspective on intracellular delivery of
proteasome inhibition.[43] Autodock was used for predicting the metallsalens. Hence, special attention should be paid to the
bonding mode between Cu(salen) and proteasome β2 subunit. design of reactive metallosalen probes, which is important to
The result showed that Cu(salen) embedded deep in β2 subunit further extend their application to pharmaceutics from the
with adequate hydrogen bonds between Cu(salen) and protein, standpoint of cell biology. Perhaps there is still a long way to go,
which explained the selective inhibition to some degree (Figure but we expect a bright future in fulfilling biological applications of
13). Following the similar method, another series of Co(salen) metal complexes including metallosalens, which will be
were screened, and the selected one showed high MEK1 binding adequately exploited in the coming years.
affinity with IC50 71 nM, which is so far the best result for metal
complexes.[44]

Acknowledgements
6. Summary and outlook
We acknowledge financial support from the National Key Basic
Increasing attention is given to metal complexes in biological
Research Support Foundation of China (Grant 2015CB856301)
studies because of their attractive structures and intriguing
and the National Scientific Foundation of China (Grants 21571007,
physico-chemical properties. For metallosalens, remarkable
21271013, 21321001).
progress has been made in biological imaging and disease
treatment as fluorescent probes, MRI probes, antioxidants and
apoptosis inducers especially in the past decade, making it Keywords: coordination chemistry, metal complex, molecular
become an exciting research area. It is noteworthy that metal imaging, biological application, metallosalen
coordination renders metallosalens more flexibility in synthesis
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MICROREVIEW
Renaissance: Metallosalen*
Metallosalens are
Hao-Yan Yin, Juan Tang,
traditional metal
and Jun-Long Zhang*
complexes since last
century, and recently
Page No. – Page No.
found the new
applications in diverse Title
biological studies, Introducing Metallosalens
including DNA binding, to Biological Studies: The
fluorescent imaging, MRI Renaissance of Traditional
contrast agent, and
Coordination Complexes
potential drugs.

*one or two words that highlight the emphasis of the paper or the field of the study

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Key Topic*

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Title

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