Synthesis, spectroscopic studies and biological evaluation of acridine derivatives: The role of aggregation on the photodynamic efficiency

Article abstract of DOI:10.1016/j.bmcl.2018.02.005

Two new photoactive compounds (1 and 2) derived from the 9-amidoacridine chromophore have been synthesized and fully characterized. Their abilities to produce singlet oxygen upon irradiation have been compared. The synthesized compounds show very differen

Full text of DOI:10.1016/j.bmcl.2018.02.005

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, spectroscopic studies and biological evaluation of acridine
derivatives: The role of aggregation on the photodynamic efficiency
Carles Felip-León a, Olga Martínez-Arroyo a,b, Santiago Díaz-Oltra a,c, Juan F. Miravet a,
Nadezda Apostolova b, , Francisco Galindo a,
⇑
⇑
a Universitat Jaume I, Departamento de Química Inorgánica y Orgánica, Avda. Sos Baynat s/n, 12071 Castellón, Spain
b Universitat de València, Departamento de Farmacología, Avda. Blasco Ibañez n.15-17, 46010 Valencia, Spain
c Universitat Jaume I, Departamento de Educación, Avda. Sos Baynat s/n, 12071 Castellón, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new photoactive compounds (1 and 2) derived from the 9-amidoacridine chromophore have been
synthesized and fully characterized. Their abilities to produce singlet oxygen upon irradiation have been
compared. The synthesized compounds show very different self-aggregating properties since only 1 pre-
sent a strong tendency to aggregate in water. Biological assays were conducted with two cell types: hep-
atoma cells (Hep3B) and human umbilical vein endothelial cells (HUVEC). Photodynamic therapy (PDT)
studies carried out with Hep3B cells showed that non-aggregating compound 2 showed photoxicity,
ascribed to the production of singlet oxygen, being aggregating compound 1 photochemically inactive.
On the other hand suspensions of 1, characterized as nano-sized aggregates, have notable antiprolifera-
tive activity towards this cell line in the dark.
Received 30 November 2017
Revised 25 January 2018
Accepted 2 February 2018
Available online xxxx
Keywords:
Self-aggregation
Organic nanoparticles
9-Amidoacridine
Photodynamic therapy
Singlet oxygen
Ó 2018 Elsevier Ltd. All rights reserved.
Introduction
acridine moiety in the structure, which improves the stacking to
the nucleic acids and hence potentiates the biological effect.6 Apart
Acridine derivatives are well known biologically active com-
pounds, widely used, for instance, as topical antibacterial and
antiparasitic agents.1 They have been used also as anticancer drugs
since the planar structure of this chromophore permits the interca-
lation into the major groove of DNA and hence disruption of the
replication process.2 Further understanding of their molecular
mode of action showed that this biological effect is not only due
to their intercalating ability but also can be explained by targeting
of overexpressed biomolecules in tumoral cells, such as telom-
erase, protein kinase and topoisomerases I and II.3 An abundant
collection of acridine-based antiproliferative compounds can be
found in the literature, with plethora of structural variants
designed to enhance not only their binding abilities at the site of
action but also the membrane crossing features and transportation
properties of the molecules through the cellular millieu.4 For
example, Delcros et al. have described a series of 9-substituted
aminoacridines and amidoacridines linked to polyamine chains
capable of inhibiting the growth of L1210 and CHO cells with
IC50 values in the micromolar range.5 One strategy followed to
enhance the DNA binding efficiency is the introduction of a second
from applications in oncology, acridines have also found utility in
other therapeutic fields, for instance as antimalarials7 and as cho-
linesterase inhibitors for Alzheimer’s disease therapy.8
In parallel with this conventional approach there is another
therapeutic strategy also using acridine-derived compounds and
light to inhibit the proliferation of cancerous cells9 and also to kill
microorganisms.10 Photodynamic therapy (PDT) is a clinical tool
that uses a photosensitizer in combination with visible or UV light
to produce cytotoxic reactive oxygen species (ROS) including
superoxide radical anion (OÅ2À) and singlet oxygen (1O2). Numerous
types of compounds have been employed so far for the generation
of 1O2, not only for photobiological applications,11,12 but also for
synthetic purposes.13
TheuseofacridinesinPDTdatesbacktotheveryoriginofthisdis-
cipline14 and currently there is a renewed interest in the develop-
ment of acridine derivatives for photodynamic applications. In
principle, acridine chromophore is an excellent candidate to develop
a bioactive photosentitizer, taking into account the very efficient
population of the triplet excited state upon irradiation.15 Energy
transfer to molecular triplet oxygen gives rise to very high yields of
1O2
(UD) both in polar and apolar medium. For instance, Ogilby
et al.16 have reported UD (benzene) = 0.84 and UD (acetonitrile) =
0.97. However, compared to the number of acridine derived com-
pounds reported as DNA binding agents, the number of PDT active
⇑
Corresponding authors.
E-mail addresses: nadezda.apostolova@uv.es (N. Apostolova), francisco.galindo@
uji.es (F. Galindo).
https://doi.org/10.1016/j.bmcl.2018.02.005
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Felip-León C., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.02.005

2
C. Felip-León et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
compounds based on this chromophore is relatively low. The aim of
thisstudyistocomparetheabilityoftwonew9-amidoacridinecom-
pounds (1 and 2 in Fig. 1) to generate 1O2 upon irradiation. The
hypothesis of this work is that the superstructure adopted by the
photosensitizing molecules affects dramatically their photobiologi-
cal efficiency, in such a way that aggregation can favour deactivation
pathways of the excited states, leading to quenching of the photo-
sensitizer (like molecule 1) and hence their invalidation as PDT
agents. In this regard, a simpler structure (like molecule 2) avoiding
this aggregation phenomenon would be more favourable for the
photogeneration of 1O2 in aqueous medium, and then their use for
clinical application more recommendable.
In acetonitrile, compounds 1 and 2 show the typical absorption
of the acridine chromophore at 360 nm, displaying optical features
appropriate for UVA excitation and weak fluorescence at 419 nm
(Fig. 2).17 In a polar solvent such as water, absorption maximum
undergoes opposed shifts (365 nm for 1 and 357 nm for 2) and flu-
orescence emission batochromic shifts (439 nm for 1 and 435 nm
for 2). The emission quantum yield in water is notably different:
very low for compound 1 and moderate for the mono-acridine
derivative 2. Summarized photophysical properties of the synthe-
sized compounds are shown in Table 1.
The generation of 1O2 upon irradiation was tested using a well-
known benchmark reaction like the oxygenation of 1,5-dihydroxy-
naphthalene (DHN) to juglone, depicted in Scheme 2.18 Com-
pounds 1 and 2 were irradiated in quartz cuvettes with light of
365 nm. The analysis of the reaction was performed by UV-vis
absorption measurements following the decreasing absorption of
DHN at 298 nm.
An illustrative example of the spectral changes occurring upon
irradiation of acridine derivatives in the presence of DHN can be
found in Fig. 3. As it can be seen, the absorption bands of DHN at
298 nm disappear when increasing the irradiation time and,
Compounds 1 and 2 were synthesized by coupling carbobenzy-
loxy-L-valine with the corresponding amine or diamine, as
depicted in Scheme 1, followed by deprotection of the Cbz group
and reaction with acridine-9-carbonyl chloride. Compounds were
purified by subsequent filtration and washing steps, and were fully
characterized by means of HRMS, 1H and 13C NMR spectroscopy
(see Supporting information).
1
100
50
0
0.5
0
300
400
500
600
Wavelength / nm
Fig. 2. Absorption and emission spectra of synthesized compounds in CH3CN. 1
continuous line, 2 dashed line.
Fig. 1. Synthesized compounds based on the 9-amidoacridine chromphore.
Scheme 1. Synthetic route for compounds 1 and 2 a) THF, Et3N ClCOOEt, r.t., 12 h b) CH3OH, Pd/C H2, r.t., 6 h c) for acridine-9-carboxylic acid activation: CH2Cl2, oxalyl
chloride, DMF(cat). For activated acid and amine coupling reaction: THF, Et3N, 16 h.
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C. Felip-León et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
Table 1
Photochemical properties of compounds 1 and 2.
Compd.
Solvent
kabs (nm)
kem (nm)
U F
U D
1
CH3CN
H2Oa
360
365
418
439
0.003 0.001
0.04 0.01
0.96 0.04
0.010 0.008
2
CH3CN
H2Oa
359
357
419
435
<0.001
0.32 0.06
0.97 0.01
0.263 0.004
a
Contains 1% CH3CN from a concentrated stock solution used to prepare the aqueous sample.
ence between them: whereas the larger compound 1 formed
nanostructures in suspension with an average diameter of 122
11 nm, monochromophoric acridine 2 did not form any detectable
colloidal species (Fig. 6(a)). Further experiments confirmed that 1
undergoes self-aggregation in different polar and apolar solvents.
0
2
4
6
C
CO
ln
0
d'
c'
-0,1
-0,2
-0,3
-0,4
-0,5
-0,6
Scheme 2. Photooxidation reaction of DHN. PS = Acridine photosensitizer; ISC =
Intersystem crossing; DHN = 1,5-dihydroxynaphthalene.
d
c
0.7
0.6
b’
a’
0.4
0.2
0
b
a
300
400
500
550
260
Wavelength / nm
Time / min
b
50% H2O Compound 2
b’ 50% H2O Compound 1
c
90% H2O Compound 2
90% H2O Compound 1
Fig. 3. Photooxidation of DHN by 1O2 induced by irradiation of
monitored by UV-Vis spectroscopy. [DHN] = 80 mM; [1] = 33 mM.
1
in CH3CN,
c‘
a
0% H2O Compound 2
d
d'
100% H2O Compound 2
100% H2O Compound 1
a’ 0% H2O Compound 1
concomitantly, the rise of a new absorption band takes place at
425 nm corresponding to the juglone photoproduct.
Fig. 4. Comparison of pseudo-first order linear fitting for the production of 1O2 by 1
and 2 in different media (CH3CN/H2O).
The initial kinetic points of the absorption bleaching of DHN
were fitted to a pseudo-first order model (ln C/C0 = Àkobs t, where
C is the concentration of DHN at a certain time t and C0 is the initial
concentration). The irradiations were performed in a series of
media with different water content, from acetonitrile to water.
The quantum yields for the 1O2 generation induced by irradiation
of 1 and 2 were determined by comparing the slopes of the above
mentioned fittings to the same reaction photosensitized by phena-
lenone, as a well-known photosensitizer standard (UD ꢀ 1),19 in
acetonitrile. All the fitted kinetics can be visualized in Fig. 4 (see
details in the Supporting information file).
As shown in Fig. 5 both mono- (2) and bis-acridine (1) com-
pounds generate very efficiently singlet oxygen upon irradiation
at 365 nm in acetonitrile, as expected, with UD = 0.97 and 0.96
respectively. However, upon addition of water to the medium, this
parameter falls dramatically, especially in the case of the bichro-
mophoric compound
1 (in water UD = 0.010). However the
decrease for monochromophoric derivative 2 is not so pronounced,
affording a moderate yield (in water UD = 0.263).
This differential behaviour prompted us to investigate the rea-
son for the absence of photo-reactivity in the case of bichro-
Fig. 5. 1O2 generation quantum yield (/ ) by compounds 2 and 1 in different media
mophoric compound 1. Aqueous samples of
1 and 2 were
D
analysed by dynamic light scattering (DLS) revealing a clear differ-
(CH3CN/H2O).
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Fig. 6. (a) Representative DLS analysis of 1 aggregates; (b) SEM analysis of 1 aggregates; (c) TEM analysis of 1 aggregates; (d) SEM micrograph of 1; (e) TEM micrograph of 1.
Aggregates of bis-acridine compound 1 were also observed by elec-
tron microscopy (SEM and TEM) with average diameters of 93 24
nm and 135 40 nm, respectively (Fig. 6b–e).
This finding suggests that, upon aggregation, a competing path-
way is favoured at the expense of energy transfer to triplet oxygen
to yield 1O2. This situation does not occur to the same extent in the
non-aggregated photosensitizer 2, which retains certain capacity
to generate 1O2 in aqueous medium.
Compounds 1 and 2 have also very different properties from the
photobiological viewpoint. When Hep3B cells incubated with the
compounds were irradiated with light of 365 nm, only 2 was cap-
able of inducing some PDT effect. As it can be seen in Fig. 7, Hep3B
cells were incubated for 1 h in the presence of 2 (10 mM) and then
irradiated for 3 min. Propidium iodide (PI) was used to test the
photodamage, monitored by means of confocal fluorescence laser
scanning microscopy (CLSM). Cells stained with PI after irradia-
tions would indicate dead or damaged cells. In the control cells
(no photosensitizer added) the number of damaged or dead cells
was very low (only several per field) meaning that the irradiation
per se was not deleterious. However, the number of PI-positive
cells was dramatically increased in the cell population that was
irradiated after up-take of 2, pointing to the existence of a partic-
ularly harmful effect on cell viability when the two stimuli (2 +
irradiation) were combined. The observed effect was confirmed
by the quantitative assessment of PI fluorescence using fluores-
cence microscopy coupled with static cytometry (see Supporting
information). While the presence of 2 without irradiation only
slightly enhances the number of PI+ cells (3.38% of the cells were
PI positive after exposure to 20 mM 2 in comparison to 1.25% of
the untreated cells), this number is notably higher when both stim-
uli are present and reaches the highest value with 20 mM of 2
(8.7%). For compound 1, no induced photodamage was detected
under the same experimental conditions. This observation con-
firms that aggregation must be avoided for photosensitizers based
on acridine, at the designing stage, since this process hampers the
generation of 1O2. The negative effect of aggregation on the PDT
activity is already well known for porphyrins and phthalocyanines,
and efforts are devoted to the design of photosensitizers circum-
venting this process.20 According to the observations here
reported, the same kind of considerations should be taken into
account when dealing with acridine-based photosensitizers.
Despite the lack of PDT activity of 1, this compound apparently
retains the DNA binding ability. MTT (3-4,5-dimethylthiazol-2-yl-
2,5-diprenyl tetrazolium bromide) assays showed that exposure
to 1 diminished cell viability in a concentration-dependent manner
while exposure of 2 had no effect. The primary cell line Human
umbilical vein endothelial cells (HUVEC) was slightly more suscep-
tible than hepatoma cells Hep3B which is in line with previous
reports of pharmacological toxicities using both cell models.21
After 3 h exposure to the highest concentration of 1 employed,
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C. Felip-León et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
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Fig. 7. CLSM images of Hep3B cells (30.000 cell/well) stained with propidium iodide used to mark damaged or dead cells (visualized in red color) (1 mM). Top row: Irradiated
set of wells in absence of 2 (10 mM); (a) bright field; (b) PI fluorescence, kex = 488 nm, kem = 500–700 nm; (c) merged channels. Bottom row: Irradiated control set of wells in
presence of 2; (d) bright field; (e) PI fluorescence, kex = 488 nm, kem = 500–700 nm; (f) merged channels. Irradiation performed with UV lamp at 365 nm, 6 W, for 3 min. (For
D
D
interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 8. CLSM images of Hep3B cells (30.000 cell/well) of 1 (10 mM) incubated for 1 h stained with Draq5 (1 mM). (a) Bright field; (b) Merged images of Draq5 fluorescence
(nuclei stained in red) and 1 fluorescence (blue) sequentially acquired (1 fluorescence, kex = 405 nm,
Dkem = 410–550 nm, Draq5 fluorescence, kex = 488 nm, Dkem = 600–700
nm). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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C. Felip-León et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
the calculated IC50 was 29.5 mM for Hep3B cells and 18.62 mM for
HUVEC. Of note, prolonged incubation (24 h) with 1 did not exac-
erbate the effect on cellular viability recorded after 3 h-exposure,
in Hep3B cells. In HUVEC cells, the prolonged incubation did have
a greater effect (46% and 27% vs control after 3 h- and 24 h-incuba-
tion respectively). Also, we observed the capacity of both cell lines
to recover from exposure to 1 and 2 (21 h recovery after the 3 h-
treatment, see Fig. S4 in the supporting information file). The cal-
culated IC50 value lies within the range of reported toxicities of
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