Fluorescence properties and antiproliferative effects of mono-, bis-, and tris- thiophenylnaphthalimides: Results of a comparative pilot study

Article abstract of DOI:10.1016/j.jphotobiol.2011.06.012

A series of mono-, bis- and trisnaphthalimides with different substituents on the naphthalimide ring system was prepared. For compounds containing a thiophenyl substituent fluorescence spectroscopic measurements were performed and unexpectedly showed an increase in fluorescence emission for the bis- and trisnaphthalimide derivatives in phosphate buffered saline. Additional fluorescence microscopic experiments indicated an efficient cellular uptake of the thiophenyl substituted compound 1c into cultured tumor cells. Experiments on the inhibition of tumor cell proliferation were performed in MCF-7 breast adenocarcinoma and HT-29 colon carcinoma cells and confirmed derivatives containing a nitro substituent as the most active compounds. Compound 1c demonstrated potential as photoinducable antitumor agent.

Full text of DOI:10.1016/j.jphotobiol.2011.06.012

Journal of Photochemistry and Photobiology B: Biology 105 (2011) 75–80
Contents lists available at ScienceDirect
Journal of Photochemistry and Photobiology B: Biology
journal homepage: www.elsevier.com/locate/jphotobiol
Fluorescence properties and antiproliferative effects of mono-, bis-, and tris-
thiophenylnaphthalimides: Results of a comparative pilot study
b
b,
Ingo Ott a,b, , Yufang Xu , Xuhong Qian
⇑
⇑
a Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstr. 55, 38106 Braunschweig, Germany
b Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology, Meilong Road 130, 200237 Shanghai, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 April 2011
Received in revised form 9 June 2011
Accepted 10 June 2011
Available online 13 July 2011
A series of mono-, bis- and trisnaphthalimides with different substituents on the naphthalimide ring sys-
tem was prepared. For compounds containing a thiophenyl substituent fluorescence spectroscopic mea-
surements were performed and unexpectedly showed an increase in fluorescence emission for the bis-
and trisnaphthalimide derivatives in phosphate buffered saline. Additional fluorescence microscopic
experiments indicated an efficient cellular uptake of the thiophenyl substituted compound 1c into cul-
tured tumor cells. Experiments on the inhibition of tumor cell proliferation were performed in MCF-7
breast adenocarcinoma and HT-29 colon carcinoma cells and confirmed derivatives containing a nitro
substituent as the most active compounds. Compound 1c demonstrated potential as photoinducable anti-
tumor agent.
Keywords:
Naphthalimides
Antitumor drugs
Photoinduced electron transfer
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
results of cell proliferation experiments in comparison to related
mono- and bisnaphthalimides are described.
Naphthalimide derivativeshave been investigatedintensively dur-
ing the last decades for their impressive spectroscopic properties and
antitumoral activities [1–3]. Amonafide andmitonafide(seeFig. 1)en-
tered the clinical trial stages for the use as anticancer chemotherapeu-
tics but failed as a consequence of unexpected side effects. Concerning
their mode of drug action multiple mechanisms have been observed
including DNA intercalation, topoisomerase inhibition, photoactiva-
tion or induction of lysosomal membrane permeabilization and apop-
tosis [4–9]. With the development of elinafide, which contains two
naphthalimide ring systems, the drug design concept of the ‘‘mono-
naphthalimides’’ amonafide and mitonafide was extended [1,2]. As a
consequence a great number of highly active ‘‘bisnaphthalimides’’
could be obtained and promising results as potential anticancer or
anti-infective drugs have been reported [10–15].
We have recently reported on a series of mononaphthalimides
containing thioether substituents on the naphthalimide ring sys-
tem, which exhibited interesting biological effects such as interca-
lative DNA interaction and photoactivation [6]. Here we report on
our recent attempts to extend these ongoing efforts on the new
class of ‘‘trisnaphthalimides’’, which contain three naphthalimide
centers in one molecule. The synthesis, fluorescence studies and
2. Experimental
2.1. General
Chemicals and reagents were purchased from Sigma, Aldrich
and Fluka. The preparation of 1a, 1b, 2a and 2b was previously de-
scribed and compounds were obtained accordingly [6,15–17]. PBS:
phosphate buffered saline pH 7.4; NMR spectra were recorded on a
400 MHz or a 500 MHz NMR spectrometer (Bruker); elemental
analysis: Perkin–Elmer 240C; MS spectra: CH-/A-Varian MAT; cell
culture: MCF-7 breast cancer and HT-29 colon carcinoma cells
were maintained by standard procedures at 37 °C in a humidified
atmosphere of 95% air and 5% CO2. The cell culture medium for
MCF-7 and HT-29 cells consisted of minimum essential medium
eagle supplemented with 2.2 g NaHCO3, 110 mg/L sodium pyru-
vate and 50 mg/L gentamycin sulfate and adjusted to pH 7.4. Prior
to use 10% (V/V) fetal calf serum were added.
2.2. Synthetic chemistry
2.2.1. 4-Thiophenyl-N-(N’,N’-dimethylaminoethyl)-1,8-naphthalimide
(1c)
107 mg 4-thiophenyl-1,8-naphthalic anhydride (0.35 mmol)
were suspended in 15 mL absolute ethanol, 0.20 mL N,N-dimethyl-
aminoethylamine (2.83 mmol) were added and the mixture was
heated under reflux conditions for 7 h. The solvent was removed
⇑
Corresponding authors. Addresses: Institute of Medicinal and Pharmaceutical
Chemistry, Technische Universität Braunschweig, Beethovenstr. 55, 38106 Braun-
schweig, Germany. Tel.: +49 531 391 2743; fax: +49 531 391 8456 (I. Ott); Shanghai
Key Laboratory of Chemical Biology, East China University of Science and Technol-
ogy, Meilong Road 130, 200237 Shanghai, China (X. Qian).
E-mail addresses: ingo.ott@tu-bs.de (I. Ott), xhqian@ecust.edu.cn (X. Qian).
1011-1344/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jphotobiol.2011.06.012

76
I. Ott et al. / Journal of Photochemistry and Photobiology B: Biology 105 (2011) 75–80
N
O
O
O
N
O
N
N
H
N
N
H
O
O
R
elinafide
R = -H: amonafide
R = -NO2: mitonafide
Fig. 1. 1,8-Naphthalimide lead compounds.
and the product was isolated by column chromatography over sil-
ica using ethylacetate/methanol mixtures. yield: 83 mg
(0.22 mmol, 63%) pale yellow powder, m.p.: 114 °C, 1H NMR
(CHCl3): (ppm) 2.36 (s, 6H, CH3), 2.65 (t, 2H, 3J = 7.0 Hz, CH2),
4.32 (t, 2H, 3J = 7.0 Hz, CH2), 7.25–7.30 (m, 1H, ArH), 7.45 (m, 3H,
ArH), 7,53 (m, 2H, ArH), 7.78 (dd, 1H, 4J = 0.9 Hz, 3J = 8.4 Hz, ArH),
8.36 (d, 1H, 3J = 7.9 Hz, ArH), 8.66 (m, 2H, ArH); MS(EI, 125 °C):
376.3(1.8%); CHN (% calc./found): C(70.19/70.26), H(5.35/5.46),
N(7.44/7.44).
2.2.6. tris(N-ethylene-(4’-thiophenyl-1,8-naphthalimide)amine (3c)
348 mg (1.14 mmol) 4-thiophenyl-1,8-naphthalic anhydride
and 30
lL (0.20 mmol) tris-(2-aminoethyl)amine 96% in 35 ml
dry ethanol, 25 h reflux; yield: 53 mg (0.05 mmol, 25%), yellow
crystals; 1H NMR (CDCl3): 2.97 (t, 6H, 3J = 5.5 Hz, CH2), 4.23 (t,
6H, 3J = 5.5 Hz, CH2), 7.08 (d, 3H, 3J = 7.8 Hz), 7.39–7.49 (m, 18H,
ArH), 7.52 (m, 3H, ArH), 7.57 (d, 3H, 3J = 7.8 Hz, ArH), 8.50 (dd,
3H, 4J = 1.0 Hz, 3J = 8.4 Hz); MS (ESI): 1011 (M+); CHN (% calc./
found): C(71.27/70.02), H(4.19/4.97), N(5.54/5.46).
2.3. Fluorescence spectroscopy and microscopy
2.2.2. General procedure for the synthesis of the bis- and tris-
naphthalimides
Procedure for fluorescence spectroscopic measurements: com-
pounds were prepared as stock solutions in DMSO and diluted
hundredfold with the indicated degassed solvents. Fluorescence
measurements were performed using a Hitachi F-4500 fluores-
cence spectrometer. Procedure for fluorescence microscopic stud-
ies: MCF-7 cells were grown in 6-well plates (Sarstedt) until at
least 70% confluence. The cell culture medium was replaced with
fresh medium containing the compounds in a concentration of
The respective naphthalic anhydride (1.14–3.08 mmol) and the
respective amine (0.37–0.87 mmol) were stirred under reflux con-
ditions in dry ethanol. The precipitated products were isolated by
hot filtration, washed with ethanol and dried.
2.2.3. Bis(N-ethylene-(4-thiophenyl-1,8-naphthalimide)amine (2c)
669 mg (2.18 mmol) 4-thiophenyl-1,8-naphthalic anhydride,
85 lL (0.87 mmol) bis-(2-aminoethyl)amine in 60 mL dry ethanol,
10
CO2/95% air athmosphere. The medium was removed, the cells
were washed with PBS and finally 500 L PBS were added to
each well. Fluorescence microscopy was performed using
lM (0.1% V/V DMSO) and incubated for 6 h at 37 °C in a 5%
6 h; yield: 426 mg (0.63 mmol, 72%), yellow crystals; 1H NMR
(CHCl3): (ppm) 1.24 (s, 1H, NH), 3.07 (t, 4H, 3J = 6.1 Hz), 4.29 (t,
4H, 3J = 6.1 Hz), 7.19 (d, 2H, 3J = 7.8 Hz), 7.45 (m, 6 H, ArH), 7.51
(m, 4H, ArH), 7.67 (dd, 2H, 4J = 1.0 Hz, 3J = 8.4 Hz, ArH), 8.10 (d,
2H, 3J = 7.9 Hz, ArH), 8.37 (dd, 2H, 4J = 1.0 Hz, 3J = 7.3 Hz, ArH),
8.59 (dd, 2H, 4J = 1.0 Hz, 3J = 8.5 Hz, ArH), MS(EI, 250 °C) 679
(0.3%);CHN (% calc./found): C(70.67/70.55), H(4.30/4.62), N(6.18/
5.82).
l
a
Axiovert 40 CFL microscope (Zeiss) equipped with a 50 W mer-
cury vapor short arc lamp and a Ex/Em 390 11/460 25 nm
filter.
2.4. Antiproliferative effects and phototoxicity
Experiments on proliferation inhibition and phototoxicity were
essentially performed as described in detail in a previous paper [6].
2.2.4. tris(N-ethylene-1,8-naphthalimide)amine (3a)
611 mg (3.08 mmol) naphthalic anhydride and 75 lL
(0.50 mmol) tris-(2-aminoethyl)amine 96%, in 50 mL dry ethanol,
7 h reflux; yield: 330 mg (0.48 mmol, 96%) pale white platelets;
1H NMR (CHCl3): (ppm) 3.03 (t, 6H, 3J = 6.0 Hz, 1H, CH2), 4.29 (t,
6H, 3J = 6.0 Hz, 1H, CH2), 7.51 (dd, 6H, 3J = 7.2 Hz, 3J = 8.0 Hz,
ArH), 7.81 (d, 6H, 3J = 7.2 Hz, ArH), 8.14 (d, 6H, 3J = 8.0 Hz, ArH);
MS(EI, 300 °C) 686 (0.2%); CHN (% calc./found): C(73.46/72.32),
H(4.40/5.13), N(8.16/7.56).
3. Results and discussion
3.1. Synthesis
Mono,- bis- and tris-naphthalimides were prepared by reacting
naphthalic anhydrides with appropriate amines (see Scheme 1).
Whereas the mononaphthalimide compounds were purified by
column chromatography the bis- and tris- derivatives could be iso-
lated after precipitation by filtration. The target compounds were
characterized by 1H NMR and MS spectroscopy as well as elemen-
tal analyses.
2.2.5. tris(N-ethylene-(3-nitro-1,8-naphthalimide)amine (3b)
520 mg (2.14 mmol) 3-nitronaphthalic anhydride and 54 lL
(0.37 mmol) tris-(2-aminoethyl)amine 96% in 50 mL dry ethanol,
7 h reflux; yield: 134 mg (0.16 mmol, 43%) pale yellow powder;
1H NMR (DMSO): 2.85 (m, 6H, CH2), 4.02 (m, 6H, CH2), 7.50 (d,
3J = 7.2 Hz, 1H, ArH), (dd, 3J = 7.6H, 3J = 7.9H Hz, 1H, ArH), 7.88 (d,
4J = 2.1 Hz, 1H, ArH), 8.71 (m, 1H, ArH), 9.42 (d, 4J = 2.1 Hz, ArH);
MS(ESI) 822 (M+); CHN (% calc./found): C(61.39/61.38), H(3.31/
3.12), N(11.93/11.28).
3.2. Fluorescence spectroscopy
Our previous studies on naphthalimides with thioether substit-
uents and also a number of literature reports described a signifi-
cant environmental sensitivity of the fluorescence emission of

I. Ott et al. / Journal of Photochemistry and Photobiology B: Biology 105 (2011) 75–80
77
O
R1
O
O
N
O
N
O
R2
R2
N
H
N
N
R2
R1
2a - 2c
R2
O
R1
O
1a - 1c
(a)
(b)
R1
O
O
N
O
O
O
(c)
O
R1
N
R2
N
R1
R2
N
O
a: R1, R2 = H
O
b: R1=-NO2, R2 = -H
R2
c: R1=H, R2= -S-Phe
R1
3a - 3c
Scheme 1. Synthesis of the target compounds; (a) N,N-dimethylaminoethylamine, reflux in ethanol, (b) bis-(2-aminoethyl)amine, reflux in ethanol, c) tris-(2-
aminoethyl)amine, reflux in ethanol.
naphthalimides concerning e.g. solvent polarity, pH or presence of
anions or metal ions [5,6,18–24]. Usually intense fluorescence
emission is obtained in apolar solvents whereas a strong decrease
in intensity as well as a red shift of the maxima is observed when
going to more polar environments. These effects are commonly
attributed to a perturbation of the photoinduced electron transfer
(PET) between the free electron pair of the side chain nitrogen and
the aromatic naphthalimide core. As thio-naphthalimides exhibit
especially strong emission properties it was of interest here to
study the emission properties of thioether-compounds 1c, 2c and
3c in more detail.
on–off of the PET effect it can be speculated that the influence of
the chemical environment (here a phosphate buffer system) is dif-
ferent for 2c and 3c compared to 1c. This may include the proton-
ation status of the side nitrogen, interaction with phosphate
anions, geometric or solubility effects [3].
3.3. Fluorescence microscopy
Fluorescence microscopy provides a powerful tool to study
the biodistribution of fluorescent compounds in living cells. Here
we used MCF-7 breast adenocarcinoma cells, which were ex-
Initially, fluorescence scans for all three compounds were per-
formed in CHCl3, DMSO and phosphate buffered saline pH 7.4
(PBS). When changing the solvent from the apolar CHCl3 to the
more polar DMSO the expected quenching of fluorescence emis-
sion was observed in all cases (see Fig. 2). As expected for 1c the
emission was almost lost in PBS. However, the bis- and trisnaph-
thalimides 2c and 3c showed a significantly enhanced and broad-
ened maximum in PBS.
In order to investigate this unexpected effect in more detail we
performed concentration dependent studies on 1c, 2c and 3c in PBS
(see Fig. 3). In good agreement with the above described results
these experiments showed a tremendous enhancement of lumi-
nescence emission upon going from the mononaphthalimide com-
pound 1c (almost no emission) over the bisnaphthalimide 2c to the
trisnaphthalimide 3c. Linear regression analysis of the emission
intensities at the maxima of 2c (at 490 nm) and 3c (520 nm) over
the concentrations showed that for 2c good linearity (r2 = 0.9936)
posed to 10 lM of 1c, 2c and 3c for 6 h. With cells exposed to
1c a significant cellular accumulation was observed. Analogous
experiments with 2c and 3c did not afford a detectable cellular
uptake as the compounds precipitated under the chosen condi-
tions (as obvious by the formation of blue fluorescent crystals,
not shown here). Based on the dependency of fluorescence emis-
sion on the solvent polarity it can be concluded that 1c may be
well detectable if present in an apolar environment such as cel-
lular membranes. Thus, by inspecting Fig. 4 it can be concluded
that 1c was taken up into the cells and that it trafficked mostly
to compartments located around the nuclei. Structurally similar
mononaphthalimides had shown a comparable pattern of biodis-
tribution, however, with a stronger emission directly from the
nuclei of the cells [6]. For bisnaphthalimides with amino substit-
uents the preferential biodistribution into the nuclei had been
observed after 24 h in HL-60 cells [25].
was found in the concentration range from 10 to 40
l
M and for
3.4. Antiproliferative effects
3c in the range of 10–30
l
M (r2 = 0.9867). The slope calculated
for 3c was approximately 3 times of that with 2c. These calcula-
tions show that in a short concentration range the fluorescence
characteristics could also be used for quantification purposes and
that the number of the napthalimide rings correlates with an
strong increase in fluorescence emission intensity. As the free elec-
tron pair of the side chain nitrogen is responsible for the switching
Experiments on proliferation inhibition were performed in
MCF-7 breast cancer cells and HT-29 colon carcinoma cells. By
inspecting the results displayed in Table 1 it can be concluded that
the most active examples within this series of investigated com-
pounds are clearly those containing the nitro substituent in posi-
tion 3 (1b–3b). Thus, the bisnaphthalimide 2b provided overall

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I. Ott et al. / Journal of Photochemistry and Photobiology B: Biology 105 (2011) 75–80
CHCl3
PBS
DMSO
1c
2c
3c
2c in CHCl3
2c in DMSO
2c in PBS
Fig. 2. Top: Contour plots of fluorescence scans of 50
lM of 1c–3c in various solvents, bottom: fluorescence emission of 50
l
M 2c in various solvents.
1600
1200
800
1600
1200
800
400
0
1600
1200
800
400
0
400
0
435 460 485 510 535 560 585
435 460 485 510 535 560 585
nm
nm
435 460 485 510 535 560 585
nm
Fig. 3. Fluorescence emission of 10–50 lM of 1c (left), 2c (middle) and 3c (right) in PBS (excitation at 400 nm); emission decreases with decreasing the concentrations.
the lowest IC50 values. Comparing the results obtained with the
respective mono-, bis- and trisnaphthalimides showed that for
the series without substituent (1a–3a) the mono- and bisnaphthal-
imides 1a and 2a triggered similar activity whereas 3a was com-
pletely inactive. For the series of nitro-derivatives (2a–2c) the
bisnaphthalimide 2b provided an optimum, in the thiophenyl ser-
ies (1c–3c) the mononaphthalimide 1c was the only one displaying
significant activity. The inactivity of 2c, 3a and 3c can be mostly

I. Ott et al. / Journal of Photochemistry and Photobiology B: Biology 105 (2011) 75–80
79
Fig. 4. MCF-7 cells exposed to 10 lM of 1c for 6 h. left: phase contrast picture, right: fluorescence microscopic picture.
Table 1
IC50 values (lM) obtained in MCF-7 and HT-29 cells (presented as mean error of repeated experiments); values for 1a are from Ref. [6].
1a
1b
1c
2a
2b
2c
3a
3b
3c
MCF-7
HT-29
4.5
3.5
0.51 0.11
0.23 0.08
4.7 0.3
4.0 0.3
5.2 1.8
1.3 0.1
0.071 0.021
0.015 0.001
>100
>100
>100
>100
3.0 2.1
4.4 3.6
>100
>100
correlated to their insufficient solubility in the biological media
(see fluorescence microscopy section above), which was also ob-
served during the preparation of dilutions for the proliferation
inhibition assay.
be considered for this purpose. Photoactivation experiments were
exemplarily performed with 1c and confirmed our previous results
on the photoinduced toxicity of certain thioether containing naph-
thalimides as the cytotoxic effects of 1c could be significantly en-
hanced by irradiation with UV light (365 nm).
In a recent paper we had reported on the photoactivation of
naphthalimides containing thioether functions on the naphthali-
mide ring system [6]. These studies overall pointed to a positive
influence of sulfur substituents with non fused aromatic rings. In
this context 1c was selected here for extended proliferation inhibi-
tion studies under irradiation conditions. In these experiments the
compounds were withdrawn after an initial 24 h exposure, the cells
were exposed to a short irradiation at 365 nm and then further incu-
bated under cell culture conditions. In analogous control experi-
ments the irradiation period was omitted [6]. In fact these
experiments confirmed our previous results as for MCF-7 cells the
Acknowledgement
Financial support by DFG – Deutsche Forschungsgemeinschaft
and BMBF/DLR (funding of international cooperation between Ger-
many and China) is greatfully acknowledged.
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