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Cite this: Chem. Soc. Rev., 2013,
42, 1601
Recent advances in the development of
1,8-naphthalimide based DNA targeting binders,
anticancer and fluorescent cellular imaging agents†
Swagata Banerjee, Emma B. Veale, Caroline M. Phelan, Samantha A. Murphy,
Gillian M. Tocci, Lisa J. Gillespie, Daniel O. Frimannsson, John M. Kelly* and
Thorfinnur Gunnlaugsson*
The development of functional 1,8-naphthalimide derivatives as DNA targeting, anticancer and cellular
imaging agents is a fast growing area and has resulted in several such derivatives entering into clinical trials.
This review gives an overview of the many discoveries and the progression of the use of 1,8-naphthalimides as
such agents and their applications to date; focusing mainly on mono-, bis-naphthalimide based structures, and
their various derivatives (e.g. amines, polyamine conjugates, heterocyclic, oligonucleotide and peptide based,
and those based on metal complexes). Their cytotoxicity, mode of action and cell-selectivity are discussed and
compared. The rich photophysical properties of the naphthalimides (which are highly dependent on the nature
and the substitution pattern of the aryl ring) make them prime candidates as probes as the changes in
spectroscopic properties such as absorption, dichroism, and fluorescence can all be used to monitor their
binding to biomolecules. This also makes them useful species for monitoring their uptake and location within
cells without the use of co-staining. The p hotochemical properties of the compounds have also been exploited,
for example, for photocleavage of nucleic acids and for the destruction of tumour cells.
1. Introduction
In the area of anticancer research, the development of small
molecules capable of binding to deoxyribonucleic acid (DNA) and
exhibiting anticancer activities has received enormous attention in
recent times.
1
Amongst these it has been shown that 1,8-naphtha-
limides (benz[de]isoquinolin-1,3-diones) possess high antitumour
activity towards various human and murine cells
2
and the aim of
this review is to highlight their use as potential anticancer agents.
Naphthalimides are conveni ently synthesised from the corres-
ponding 1,8-naphthalic anhydrides by reaction with an amine
(Scheme 1). This allows the production of a large family of
derivatives (as will be well illustrated by the range of molecules
presented below – including Bis-naphtha limides, polyamine and
amino-acid derivatives). Additionally the naphthalimide ring can be
substitu ted, for example , at the 3- or 4-position by amino or nitro
groups, e.g. 1 and 2. This not only allows the introduction of other
functional groups, which can be used for targeting biomolecules,
but can have a major effect on the electr onic properti es with a
consequent influence on the chemical, photochemical and spectro-
scopic properties. Another fruitful approach for controlling the
Scheme 1 General synthetic route and numbering of 1,8-naphthlimide.
School of Chemistry, Centre for Synthesis and Chemical Biology and Trinity
Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street,
Dublin 2, Ireland. E-mail: jmkelly@tcd.ie, gunnlaut@tcd.ie; Tel: +353 1 896 1947,
+353 1 896 3459
† Part of the centenary issue to celebrate the Nobel Prize in Chemistry awarded to
Alfred Werner.
Received 15th November 2012
DOI: 10.1039/c2cs35467e
www.rsc.org/csr
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properties of naphthalimides is to extend the aromatic ring system
to create aromatic- or heteroaromatic-fused derivatives, as will be
outlined in Sections 2.4 and 2.5.
As mentioned above the optical and photophysical proper-
ties of 1,8-naphthalimides are very sensitive to substitution in
the aromatic ring. For example functionalisation with an amino
function at the 3, 4, 5 or 6 position of the ring (see numbering
in Scheme 1) produces compounds which possess internal
charge transfer (ICT) transitions. The resultant band in the
absorption spectrum is shifted to the visible and shows a
marked solvatochromic effect.
3a
Many of the compounds are
also strongly fluorescent, with a marked Stokes shift, Fig. 1.
This emission is often in the green part of the electro-
magnetic spectrum and can be directed further towards the
red by altering the nature of the ring substituent or that of
the imide. This yields particularly attractive derivatives since
they can partially overcome auto-fluorescence and light
scattering from any biological environments. These tuneable
photophysical properties thus make them excellent compounds
to probe the microenvironment of biological systems as
well as finding applications in the field of supramolecular
chemistry.
3
As will be illustrated below, these properties are
the basis for their use as dual therapeutic and fluorescent
imaging agents.
(top row) Swagata Banerjee, Emma Veale, Caroline Phelan,
Samantha Murphy; (bottom row) Gillian Tocci, Lisa Gillespie,
Daniel Frimannsson, John Kelly, Thorfinnur Gunnlaugsson
Swagata Banerjee completed her BSc (Chemistry Hons) from
Presidency College (University of Calcutta) and MSc in Biophysics
and Molecular Biology from the University of Calcutta. She
completed her PhD degree in 2012 under the joint supervision of
Prof. T Gunnlaugsson and Prof. J. M. Kelly from the School of
Chemistry, Trinity College Dublin, where her project focuses on the
development and photophysical studies of 1,8-naphthalimide
derivatives and their interactions with DNA.
Dr Emma B. Veale received her BSc Hon. from the National
University of Ireland, Maynooth, and a PhD in supramolecular
and medicinal chemistry from the School of Chemistry, Trinity
College Dublin. She has been a senior research fellow in the group
of Prof. Gunnlaugsson since 2007; working in the areas of medicinal
chemistry, anion recognition and sensing and lanthanide directed
supramolecular self-assembly formation.
Dr Caroline M. Phelan completed her BSc Hon. degree in Chemistry from University College Dublin before undertaking a PhD in
Chemistry from Trinity College Dublin in the area of naphthalimide anticancer agents. She has since then worked in various
pharmaceutical companies in Ireland; currently working as a Projects Operations Engineer at MSD Ireland, a subsidiary of Merck Ltd.
Dr Samantha A. Murphy completed her Moderatorship (BA Hon) in Medicinal Chemistry from Trinity College Dublin before undertaking
her PhD studies in the area of naphthalimide anticancer drugs at Trinity College Dublin, working on the development of bis-
naphthalimides functionalised Tro
¨
ger’s bases. She is currently employed by Intel Ireland Ltd. as process engineer.
Dr Gillian M. Tocci completed her Moderatorship (BA Hon) in Chemistry from Trinity College Dublin. She remained on for a short
postdoctoral fellowship within the group of Prof. Gunnlaugsson before undertaking a postdoctoral fellowship in the group of Dr Chris J.
Michejda at National Cancer Institute at Frederick, Maryland, USA. In the Molecular Aspects of Drug Design group at NCI, she carried out
research on glycopeptide derivatives of the anti-proliferative factor of interstitial cystitis. In 2006, Dr Tocci joined the Analytical Services
group at Particle Sciences, Bethlehem, Pennsylvania, USA.
Dr Lisa J. Gillespie completed her Moderatorship (BA Hon) in Chemistry from Trinity College Dublin. She undertook a PhD in the area of
naphthalimide conjugates as DNA targeting drugs and supramolecular chemistry with Prof. Gunnlaugsson. Since completing her
postgraduate training she has worked in publishing in London and as a writer; focusing on the writing of scientific literature and history.
Dr Daniel O. Frimannsson graduated from the University of Iceland with a BSc in Biochemistry before undertaking a PhD in chemistry
under the guidance of Prof. Gunnlaugsson and Prof. Mark Lawler at the Department of Haematology, focusing on the biological chemistry
of naphthalimides and anticancer agents. After completing his postgraduate studies he undertook a postdoctoral fellowship in the group of
Prof. Donal O’Shea at University College Dublin. He has since 2010 been a postdoctoral fellow in the Stanford Medical School.
Prof. John M. Kelly obtained his BSc from the University of Manchester in 1965, his MSc in organic photochemistry from McMaster
University (supervisor, John J. McCullough) and his PhD from the University of London (supervisor, George Porter) in 1970. After a
Leverhulme Teaching Fellowship at the University of the West Indies, Jamaica, he carried out postdoctoral work in Ernst Koerner von
Gustorf’s group at the Max Planck Institut fu
¨
r 1420 Strahlenchemie, Mu
¨
lheim. He joined Trinity College Dublin in 1973 and was the Head
of Department from 1994–2000. He is a Fellow of the Royal Society of Chemistry and a Member of the Royal Irish Academy (MRIA). His
research interests include the transient spectroscopy and photochemistry of DNA and metal containing compounds and the synthesis of
micro- and nanoparticles of metals and metal oxides for applications in electronic devices and biosensors.
Prof. Thorri Gunnlaugsson MRIA holds a Person Chair, Professor of Chemistry, in the School of Chemistry, Trinity College Dublin, and is
a PI at the Trinity Biomedical Science Institute. He undertook his PhD in Queen’s University Belfast under the supervision of Prof. A. P. de
Silva MRIA and postdoctoral work with Prof. David Parker FRS at Durham University before moving to the University of Dublin in
September 1998. He was elected as a Member of the Royal Irish Academy in 2011 and he is a recipient of the Bob Hay Lectureship of the
RSC Macrocyclic and Supramolecular Group. He has held several Honorary Professorships in Europe, Australia and New Zealand. He is
the author of over 150 publications in the areas of supramolecular and medicinal chemistry.
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Another feature of the naphthalimides is their ability to
target biomolecules and in particular nucleic acids. Indeed
many naphthalimides already form strong intermolecular
complexes with mononucleotides. The planar nature of the
aromatic core suggests that the molecule should intercalate
itself between the base-pairs of DNA and this behaviour has
been assumed in many cases. However, it should always be
borne in mind that small molecules can bind to DNA in a
number of ways – for example by binding to the grooves (most
often the minor one) or externally (especially if the molecules
show a propensity for stacking). Also it is possible that the
binding mode may depend on the DNA sequence. UV/visible
absorption and fluorescence spectroscopy are excellent techni-
ques for monitoring the binding to nucleic acids, e.g. Fig. 2.
Binding constants can then be determined by fitting the
changes, as illustrated in the inset of Fig. 2.
4a,b
However, other
methods are required to define the precise nature of the
binding sites. Ideally one would determine this through X-ray
crystallography, but to the best of our knowledge there are
currently no such reports for naphthalimides bound to DNA.
There are also few detailed NMR studies, probably because of
the problems of exchange processes. Excellent methods for
distinguishing intercalation from other DNA binding modes
include dichroism spectroscopies (especially linear dichroism),
hydrodynamic studies, such as viscometry, or biophysical
measurements such as topoisomerisation
4c
and such studies
have been carried out in a number of cases.
The uses of the 1,8-naphthalimide core extend beyond their
application as DNA-binding motifs and anticancer agents. They
have been extensively used within the field of supramolecular
chemistry (such as in anion sensing), and they have found
their applications as fluorescent brighteners, fluorescent bio-
probes,
5a
as solar energy collectors,
5b,c
and in laser dyes.
5d,e
Recently attention has focused on sulfonated derivatives of
1,8-naphthalimides and it has been reported that these
compounds can act as antiviral agents with selective in vitro
activity against the human immunodeficiency virus, HIV-1.
5f
1,8-Naphthalimides brominated at the 3 and 4 positions of the
ring have been proposed as good candidates for the photo-
chemotherapeutic inhibition of enveloped viruses in blood
and in blood products.
5g–i
Moreover, the 1,8-naphthalimides
are powerful photo-reagents, which can induce lesions in
DNA molecules and, as such, possess the ability to kill
cells when photoactivated.
5j
This opens up possible
applications in photo-therapy. Finally it should again be
emphasised that an important feature of 1,8-naphthalimides
is that they are relatively easy to synthesise in high purity on a
large scale.
2. 1,8-Naphthalimides as anticancer agents
The 1,8-Naphthalimides constitute a class of DNA-binding
agents developed initially by Bran
˜
a and co-workers.
2
Fabrica-
tion of these early naphthalimide derivatives was achieved by
the incorporation of the structural elements from various
known anticancer agents into a single structure, for example
the b-nitronaphthalene of aristolochic acid, basic side chain from
tilorone and morpholine b-thalidomide and the glutarimide unit
of cycloheximide.
Two leading members of this family amonafide, 1 (a 3-amino-
1,8-naphthlimide), and mitonafide, 2 (a 3-nitro-1,8-naphthalimide),
have entered into phase II clinical trials. Clinical studies showed
both exhibit high antitumour activity with IC
50
values (the concen-
tration of a drug required to inhibit a given biological/biochemical
process by 50%) of 0.47 mMand8.80mM, respectively, against HeLa
cell lines.
2,6a
The dihydrochloride salt of 1 developed by ChemGenex
Pharmaceuticals has successfully entered into phase II clinical trials
for prostate cancer under the generic name of Quinamed
s
,also
known as amonafide.
6b
These compounds have also been found to
stabilise double stranded DNA against heat denaturation.
6
Further-
more, 1 has been found to induce DNA strand breaks and
Fig. 1 The absorption, excitation and emission spectra of a 4-aminonaphthalimide
derivative in 10 mM phosphate buffer at pH 7.0 (for structure 68 discussed in
Section 2.9).
Fig. 2 (a) Changes in the UV-vis spectra of a 4-amino-1,8-naphthalimide
derivative in the presence of increasing concentration of salmon testes
(st)-DNA in 10 mM phosphate buffer (pH 7.0); inset: plot of r/C
f
vs. r (’) and
the best fit of the data (—) using the McGhee–von Hippel model. (b) Changes in
the steady state emission of a 4-amino-1,8-naphthalimide derivative in the
presence of increasing concentration of st-DNA (l
ex
= 480 nm) in 10 mM
phosphate buffer (pH 7.0); inset: plot of I/I
0
vs. DNA nucleotide phosphate/
ligand (P/D) (for structure 68 discussed in Section 2.9).
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protein–DNA crosslinking in cultured mammalian cells
7
and can
inhibit nucleic acid synthesis at a concentration where protein
synthesis is generally unaffected.
6a
The 3-nitro derivative 2 can
cause unwinding of closed circular DNA and increases the viscosity
of sonicated DNA.
8
Both 1 and 2 can bind to DNA via intercalation
and inhibit topoisomerase II activity by interfering with the
breakage–rejoining step of the enzymatic cycle and stabilise the
enzyme–DNA cleavage complex.
9
Earlier structure–activity relationship (SAR) studies have
pointed out some crucial parameters, which influence the
anticancer property of this kind of naphthalimide (i.e. related
to structures 1 and 2). The presence of a basic terminal group in
the side chain and of two or three methylene units separating
the terminal nitrogen of the side chain from the naphthalene
ring was shown to play a key role in their anticancer activity.
6a
Consequently, a large number of examples of such naphthal-
imides have been developed to date, but it is important to stress
that such SAR has been found to be highly dependent on the
nature of the group at the imide side of the naphthalimide
structure (see later discussion) but in the case of structures
related to 1 and 2, the nature of the terminal amino nitrogen
has been shown to play an important role in determining
the anticancer activity of structures possessing two carbon
spacers. Similarly, for such structures, the 3-nitro substituted
1,8-naphthalimides have been found to exhibit better anti-
tumour activity compared to the 4-nitro analogues;
10
a pheno-
menon that is also dependent on the nature of the imide
substituent. In the case of derivatives based on 1 and 2
(and in fact many other systems) this is presumably because
of better stacking interactions between the 3-nitro-1,8-naphtha-
limides and DNA, where the nitro group can assume a coplanar
orientation with the imide ring. However, for the 4-nitro
derivative, the angular orientation of the nitro group with
respect to the imide plane destabilises the stacking interaction.
Zee-Cheng and Cheng reported the development of
N-(dialk ylaminoethyl) -derivat ives of 3,6-dinitro and 3,6-diamino-
1,8-naphthalimides as potential DNA binders.
11
These derivativ es
showed high anticancer activity against leukemia with IC
50
values
of 0.036 and 0.33 mM, respectively, and colonadenocarcinomacell
lines (IC
50
values of 0.041 and 0.68 mM respectively). These
compounds also exhib ited high anticancer activity in vitro against
the P388 leukemia model. Subsequently, Bran
˜
a and co-workers
reported the development of a series of 3-amino-6-nitro-1,8-
naphthalimide derivatives.
12
These compounds exhibited very
high cytotoxicity compared to 1 and 2 against human CX-1 colon
carcinoma and LX-1 lung carcinoma cell lines. However, the
presence of alkyne substitution at the 3- and 4-positions of the
naphthalene ring was found to decrease the cytotoxic activity of
these compounds.
13
The parent compound (ring unsubstituted) 3 has also
been used successfully developed for anticancer treatment
and derivatives of this structure have entered clinical trials.
Compound 3a, benzisoquinolinedione, which is also known as
Nafidimide, was also synthesised by Bran
˜
a et al. and was found
to show considerable activity in a series of animal tumours both
in vitro and in vivo.
6a
Nafidimide’s pronounced activity in vivo
against tumours in animal models facilitated its entry into
clinical phase I trials. An investigation was undertaken by
Andersson et al. to study its antileukemic activity in vitro,
cellular drug transport, and molecular mechanism of action
with DNA.
7a
Compound 3a was found to be cytotoxic against
human myeloid leukemia cells (KBM-3, HL-60). However the
drug also reduced the survival of normal human bone marrow
cells. Agarose gel electrophoresis of various topoisomers
produced by the relaxing action of topoisomerase I on super-
coiled DNA in the presence of 3a confirmed that 3a intercalates
into DNA. It was also found to behave as a topoisomerase II
inhibitor.
7a
Related to this structure is Scriptaid, 3b,
7b
another
unsubstituted ring naphthalimide structure, which possesses
a hexanoic acid hydroxamide unit at the imide site. This
structure was found to inhibit histone deacetylase and in
combination with 5-aza 2
0
-deoxycytidine, 3b was shown to
enhance the expression of estrogen receptor a in estrogen
receptor negative human breast cancer cells.
7c
3b has also been
approved by FDA, clearly demonstrating that even the most
simple naphthalimide structures have great potential for
clinical use.
Azonafide, 4, represents another important compound,
where an anthracene moiety is introduced in the place of the
naphthalene ring.
14
The derivative 4 showed significantly
enhanced antitumour activity in vitro compared to 1. Among
various derivatives of 4, basicity of the side chain nitrogen,
length of the side chain and size of the substituent on the
anthracene moiety were found to be important in determining
the antitumour activity.
15,16
It has also been shown that the
4-, 5-, 7- and 9-amino derivatives exhibited significantly higher
potency than the unsubstituted compound 4 against leukemia
cell lines.
16
In order to achieve improved affinity for DNA and increase
the cytotoxic potential several bis-1,8-naphthalimide derivatives
have been developed, and these will be discussed in the
following section.
2.1 Bis-naphthalimide based anticancer agents
Bis-naphthalimides, where two 1,8-naphthalimide moieties are
connected by a polyamine spacer to enhance the DNA binding
and antitumour activity, were initially developed by Bran
˜
a
and co-workers.
17
Generally the nitro/amino substituted
derivatives exhibited better antitumour activity.
18
However,
the bis-naphthalimide, elinafide (LU79553) 5a, developed by
Bran
˜
a et al. lacks any such substitution and was found to
exhibit high activity against a variety of human xenograft models
such as LX-1 (lung), CX-1 (colon), and LOX (melanoma).
19
The
bis-naphthalimide, 5a, has been shown to be a bis-intercalator,
as demonstrated by its ability to unwind and consequently alter
the viscosity of closed circular plasmid DNA, binding to DNA
along the major groove; interacting with DNA in a sequence
specific manner where it was found to exhibit preference for
alternating purine–pyrimidine dinucleotide steps.
5j
Using a combination of NMR spectroscopy and molecular
dynamics, Gallego and Reid showed that two naphthalimide
chromophores of 5a bisintercalate at TpG and CpA steps in the
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hexameric d(ATGCAT)
2
sequence.
20
NMR spectroscopy showed
that the binding of 5a with DNA involves a two-step interaction
with dissociation rates of 10
2
s
1
and 1–4 s
1
.
21
The sequences
flanking the tetra nucleotide binding site have been found to
influence the overall binding, particularly the intercalation
step. The interaction is strongly disfavoured in the presence
ofA-richtractatthe3
0
-end of the tetranucleoti de motif apparently
due to poor stacking interaction between the naphthalimide–DNA
and among the DNA basepairs.
An anthracene derivative, 5b (also known as Bibenoline), has
also been developed.
22
This compound had similar activity to
5a; the IC
50
values for HT-29 human colon cell lines being
reported as 0.004 and 0.014 mM for 5a and b, respectively.
Chen and co-workers reported the development of another
bis-naphthalimide DMP 840, 6a, that exhibited potent proliferative
activity against leukemia and various solid tumours in vitro.
18a
Mechanistic studies showed that 6a inhibits DNA and RNA bio-
synthesis by interfering with the incorporation of thymidine and
uridine respectively and by inducing DNA single strand breaks.
18b
Moreover, 6a can also act as a eukaryotic topoisomerase II poison
and stabilises the cleavage complex of topoisomerase II with DNA,
hence causing cell death.
18c
A series of compounds related to 6a have been synthesised,
differing in the type of chromophores at one end of the
molecule, but leaving one of the naphthalimides unchanged
from that of 6a.
23
The compounds were evaluated in vitro for
DNA binding (ethidium bromide displacement), and growth
inhibition (L1210 murine leukaemia). A particular example
from this family of structures is 6b; the incorporation of a
phenanthrene chromophore was found to be an efficient DNA
binder. However, it was established that electron donating and
withdrawing groups at position 6 of the phenanthrene neither
helped DNA binding nor inhibition. Compound 6b was found
to display excellent L1210 activity with an IC
50
of 0.035 mM,
which was similar to that reported for 5a (IC
50
= 0.034 mM).
In an interesting extension to the aforementioned bis-
naphthalimide derivatives, Gunnlaugsson et al. developed a
series of bis-naphthalimides 7–9 linked by the Tro
¨
ger’s base
(TB) moiety for DNA targeting.
24,25
The molecules 7 and 8 were
specifically designed such that the terminal nitrogen atom in
side chain of all three bis-naphthalimides is protonated at
physiological pH, thereby increasing their water solubility and
favouring electrostatic interactions with the negatively charged
phosphate backbone of DNA. These bis-naphthalimides were
found to bind to calf thymus (ct)-DNA with significantly high
affinity (B10
6
M
1
) and stabilise ct-DNA against thermal
denaturation to a great extent (DT
m
>151C).
24
The molecules
are taken up readily by HL-60 cells (leukaemia cell line) and
localised within the nucleus. This was shown by using confocal
florescence microscopy, exploiting the green emission from
their ICT excited states. It was also demonstrated that these
compounds are taken up into cells rapidly. Their localisation
was further confirmed by co-staining using commercially
available agents. Compounds 7a and 7b were found to have
significa ntly high cytotoxi city (LD
50
5.21 and 5.5 mM, respectively)
compared to their 4-amino substituted mononaphthalimide
precursors (27.7 and 80.9 mM, respectively).
24
As an extension to this work, the TB-derivatives 8a–c derived
from 3-amino-1,8-naphthalimide were also developed.
25a
These
derivatives were found to have lower fluorescence quantum
yields compared to their 4-substituted analogues 7a–c. Photo-
physical measurements showed that they bind to DNA with
similar affinity and display dual mode of binding with one
naphthalimide ring intercalated between DNA basepairs
while the second one is groove-bound. Several additional
TB-derivatives incorporating various amino acids and peptide
side chains e.g. 9 have been subsequently developed.
25a
Compound 9 is formed from synthons that possess amino acid
or peptide residues and have been shown by Gunnlaugsson
et al. to be highly active anticancer agents in resilient cancer
cell lines such as the CML based K562 cell line.
25b
Furthermore,
the development of alternative bis-intercalators where the two
naphthalimide units were spaced by an alkyl or (poly)-amino-
alkyl based spacer, conjugated via a peptide linkage to such
amino acid derived structures was also undertaken and shown
to give rise to highly active agents that could bind to DNA with
high affinity.
25c
To achieve sequence selective DNA binding Suzuki et al.
developed novel naphthalimidobenzamide derivatives 10a and
b and analysed their interaction with various DNA sequences
by ethidium bromide displacement assay.
26
The strength of
binding of 10b was approximately 350 times stronger to
GC-repeats than to AT and AA-repeating oligomers.
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