Disulfide-bridge dimeric porphyrin and their reference compounds for glutathione-based specific tumor-Activation

Article abstract of DOI:10.1142/S1088424617500961

The tumor micro-environment is rich in glutathione. To exploit this feature for tumor-Activatable porphyrin-based photosensitizers, a dimeric disulfide-bridged porphyrin has been designed and prepared, together with two reference derivatives, a non-cleava

Full text of DOI:10.1142/S1088424617500961

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2017; 21: 1–7
DOI: 10.1142/S1088424617500961
Published at http://www.worldscinet.com/jpp/
Disulfide-bridge dimeric porphyrin and their reference
compounds for glutathione-based specific tumor-activation
a
b
a ◊
Serkan Alpugan , Derya Topkaya and Fabienne Dumoulin *
a
Gebze Technical University, Department of Chemistry, 41400 Gebze, Kocaeli, Turkey
Dokuz Eylul University, Department of Chemistry, Faculty of Science, 35160 Tınaztepe, Izmir, Turkey
b
Received 20 December 2017
Accepted 22 December 2017
ABSTRACT: The tumor micro­environment is rich in glutathione. To exploit this feature for tumor­
activatable porphyrin­based photosensitizers, a dimeric disulfide­bridged porphyrin has been designed
and prepared, together with two reference derivatives, a non­cleavable dimer and a monomer. The three
compounds have been investigated from a photochemical and photophysical point of view. It appears that
the disulfide­bridged derivative exhibited intramolecular aggregation, but to an insufficient extent to induce
a satisfying self­quenching of its photoproperties. Unlike expected, the non­cleavable dimer behaved like
the monomeric derivative, due to the superior flexibility of the alkyl bridge over the disulfide bridge.
KEYWORDS: photodynamic therapy, porphyrin, tumor­activatable photosensitizer, disulfide, dimeric.
their temperature is higher [8], specific enzymes may
INTRODUCTION
be overexpressed [9] and intracellular sodium ion
Photodynamic therapy (PDT) is based on the
concentrationisalsosignificantlyhigher(uptothreetimes)
conversion of molecular oxygen into its singlet toxic
than normal tissues [10]. On the other hand, the electronic
form at the immediate vicinity of a photosensitizer
events leading to the generation of singlet oxygen upon
irradiated by appropriate wavelengths. The toxicity is,
irradiation of the photosensitizer are quenched if the
in theory, limited to the irradiated area (the tumor in the
photosensitizer is aggregated (self­quenching) or in the
case of anticancer PDT). Due to its elevated metabolism
presence of a quencher, including the protonable amine
compared to healthy tissues, the photosensitizer accumu­
function which exerts a PET quenching effect.
lates preferentially in the tumor. In any event, a varying
This led to the development of activatable triplet
proportion of the photosensitizer does not reach the
tumor and circulates in the patient body. To avoid
photosensitizers [11], also named smart photosensitizers
[12]. Dual or multiple activations may follow molecular
daylight­induced phototoxicity in healthy tissues with the
remaining photosensitizer, the patient must remain in the
dark until its complete excretion from the body. A way
to overcome this drawback is to enhance the tumor­
targeting of the photosensitizer [1], by conjugating it to
antibodies [2], vitamins [3], small peptidic units [4] or
more recently, to aptamers [5].
Another strategy, which is rapidly developing, takes
advantage of tumors’ distinctive features. In contrast
with healthy tissues, tumors are more acidic [6], com­
prise significantly higher amounts of glutathione [7],
logic gate principles. Their structure and activation
mechanismisschematicallyrepresentedinFig.1withsome
examples that can be classified as follows: photosensi­
tizer­quencher hybrids, covalent self­quenching dimeric
or multimeric photosensitizers, or non­covalent self­
assembled self­quenched photosensitizers: a self­assemb­
ling biarmed poly(ethylene glycol)­(pheophorbidea)
2
conjugate [13], a cell­selective glutathione­responsive
tris(phthalocyanine) [14], a silicon phthalocyanine sub­
stituted axially by a pyrene for an electronic energy
transfer quenching and a amino group with two methoxy­
+
(
triethylenoxy) axial chains [15], a pH and Na activatable
◊
SPP full member in good standing
BODIPY working as an AND logic gate [16], a pH
and glutathione­activatable SiPc [17], a self­assembling
hence self­quenching oligoethylene glycol dendronized
*
2
Correspondence to: Fabienne Dumoulin, tel: +90 262 605 30
2, fax: +90 262 605 30 05, email: fdumoulin@gtu.edu.tr.
Copyright © 2017 World Scientific Publishing Company

2
S. ALPUGAN ET AL.
Fig. 1. Schematic representation of some previously reported tumor­specific activation of photosensitizers
reduction­sensitive porphyrins [18], a caspase 3 activa­
table pyropheophorbide­a molecular beacon derivative
the best of our knowledge, no porphyrin has been used
for covalent self­quenching. This prompted us to explore
the relevance of a disulfite­bridged dimeric porphyrin
system.
[
19] and a g­glutamyltranspeptidase activatable selenor­
hodamine green [20]. Unlike for phthalocyanines, and to
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J. Porphyrins Phthalocyanines 2017; 21: 2–7

DISULFIDE-BRIDGE DIMERIC PORPHYRIN AND THEIR REFERENCE COMPOUNDS FOR GLUTATHIONE-BASED
3
Itreactswithbis­(tosylateethyl)disulfide5togive1,with
RESULTS AND DISCUSSION
1
,6­dibromohexane to yield 2, and with 1­bromopropane to
produce 3. One may note that unlike for reported procedures
23] and all our efforts, we managed to obtain 5 in very
Molecular design
[
The aim of this work is to assess the relevance of using
disulfide­bridged dimeric porphyrins for specific tumor­
activated photosensitizers, from the point of view of a
proof­of­concept. Besides, it is now known that rather
than making water­soluble derivatives, often more tedious
to synthesize and/or purify that hydrophobic derivatives,
good formulations allow to use of hydrophobic photo­
sensitizers for biological investigations [21]. Using the
most simple tetraphenylporphyrin core was therefore
decided, and the disulfide­bridged dimeric porphyrin
low yields (32% at best), and had to use it immediately
after its isolation as, in our hands, it quickly decomposed.
For each dimer, an excess of monohydroxylated porphyrin
was used. Nonetheless, 1 was obtained in rather low yield
(20%), attributed to the decomposition of 5 in the course of
the reaction. With similar reagent proportions, 2 was first
isolated in 10%, but could be isolated in 49% yield after
optimization of the stoichiometry. The use of an excess of
bromopropane for the preparation of 3 allowed its isolation
in high yield (93%). All final porphyrins have been
1
was designed. As often for such investigations, com­
1
characterized by MALDI­MS, IR and H NMR methods,
parison with a relevant reference compound is important,
and non­cleavable dimeric porphyrin 2 was designed,
together with the monomeric derivative 3. Their structures
are displayed in Fig. 2.
which confirmed the proposed structures.
Photophysics and photochemistry
All measurements have been performed in toluene and
the data are summarized in Table 1.
Synthesis and characterization
UV-vis absorption. The superimposed UV­vis spectra of
1, 2and 3in toluene are displayed in Fig. 3a. In order to have
the same amount of porphyrin core for each compound,
the concentration of 1 and 2 is 5 mM,
whereas the concentration of the monomeric
porphyrin 3 is 10 mM. Unlike expected, only
disulfide­bridged dimer 1 is aggregated as
evidenced by its less sharp and less intense
absorption bands. Non­cleavable dimer 2
and monomeric reference 3 have similar
absorptions, hence both are non­aggregated.
This is attributed to the higher flexibility of
the alkyl spacer of 2, which allows the two
porphyrin cores to move quite freely, whereas
the disulfide spacer is much more rigid [24],
thus enhancing the self­aggregation. Self­
quenching is confirmed by the linearity of
the Beer–Lambert law for all compounds
and in particular 1, with no influence of the
concentration (Fig. 3b). However, the self­
quenching is not as considerable as one could
expect for tumor specific activation, and the
molar extinction coefficient of 1 is only
slightly decreased compared to 2 and 3. This
was previously observed for ketal­linked
dimeric phthalocyanines [25].
Monohydroxylated porphyrin 4 [22] is the precursor
for each synthesis (Scheme 1).
NH
N
NH
N
N
S
O
O
S
N
HN
HN
1
NH
N
N
NH
N
N
O
O
HN
HN
2
Fluorescence. In order to follow
the cellular uptake and the subcellular
localization of a photosensitizer, a slight
fluorescence is useful, although it should
not be too important as this may induce a
lowered singlet oxygen generation (the total
sum of all quantum yields being 1, with
competing fluorescence and singlet oxygen
NH
N
N
O
HN
3
generation). The aggregation of disulfide­
bridge dimer 1 was not important enough to
Fig. 2. Schematic representation of tumor­specific activation of photosensitiser
and of the reference compounds 2 and 3
1
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J. Porphyrins Phthalocyanines 2017; 21: 3–7

4
S. ALPUGAN ET AL.
S
OTos
Table 1. Photophysical and photochemical data for 1, 2 and 3
TosO
S
5
1
2
3
1
2
3
4
20, 515,
420, 515,
420, 515,
lmax (nm)
5
50, 593, 648 551, 593, 649 551, 592, 649
e (at 420 nm)
5.36
0.15
0.56
5.80
0.15
0.81
5.48
0.15
0.77
OH
fF
fD
Br
N
Br
NH
HN
significantly lower fluorescence, and the quantum yields
of each compound are roughly the same. Fluorescence
lifetime is lower for 1 and roughly the same for 2 and 3.
Singlet oxygen generation. Singlet oxygen genera­
tion quantum yields are, again, roughly the same for 2
and 3 (0.81 and 0.77 respectively), and much lower for
the dimeric disulfide­bridged derivative 1 (Table 1 and
Fig. 4). Nonetheless, with a value of 0.56, the quenching
is quite weak, and unlikely to be suitable to limit the
photodynamic action to the tumor micro­environment.
N
4
Br
Scheme 1. Synthesis of porphyrins 1, 2 and 3
Fig. 3. (a) Superimposed UV­vis spectra of 1 (red, 5 mM), 2 (green, 5 mM) and 3 (blue, 10 mM). (b) UV­vis spectra of 1 at 0.5, 1, 2,
, 4 and 5 mM. (c) UV­vis spectra of 2 at 0.5, 1, 2, 3, 4 and 5 mM. (d) UV­vis spectra of 3 at 1, 2, 4, 6, 8 and 10 mM. All spectra have
been recorded in toluene. Abscissa: wavelength (nm). Ordinate: absorbance (a. u.)
3
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DISULFIDE-BRIDGE DIMERIC PORPHYRIN AND THEIR REFERENCE COMPOUNDS FOR GLUTATHIONE-BASED
5
1
eq.) and K CO (200 mg, 1.45 mmol, 20 eq.) were stirred
2 3
in DMF (5 mL) overnight at room temperature, then the
reaction mixture was poured into water. The resulting
precipitate was filtrated, recovered in dichloromethane,
dried over Na SO , and purified over silica gel column
2
4
chromatography (hexane/dichloromethane, 1/1). Dark
purple solid. Yield: 21% (20 mg). C H N O S , M. W.
9
2
66
8
2 2
­1
1
1
9
5
1
4
379.71 g/mol. FT­IR (u, cm ): 2963, 2925, 2854,
713, 1598, 1558, 1508, 1471, 1442, 1259, 1080, 1013,
66, 865, 792, 701, 660, 545 (S–S). H NMR (CDCl ,
1
3
00 MHz): d, ppm 8.88 (s, 4H), 8.84 (s, 12H), 8.21 (d,
2H), 8.11 (d, 4H), 7.76 (d, 18H), 7.28 (s, 4H), 4.33 (t,
H), 2.95 (t, 4H), ­2.76 (s, 4H). UV­vis (toluene): l, nm
1
Fig. 4. Phosphorescence emission intensities of O at 1270 nm
2
420, 515, 550, 593, 648.
vs. absorbance of 1 (red), 2 (green) and 3 (blue) in toluene
Synthesis of non-cleavable dimeric porphyrin
2
. Monohydroxylated porphyrin 4 (250 mg, 0.40
mmol, 4 eq.) and Cs CO (650 mg, 2 mmol, 20 eq.)
2
3
CONCLUSIONS AND OUTLOOK
were stirred in DMF (10 mL) for 30 min at 70°C.
1,6­dibromohexane (15 mL, 0.10 mmol, 1 eq.) was then
added and the stirring continued overnight at 70°C.
The cooled reaction mixture was poured into water.
The resulting precipitate was filtrated, recovered in
dichloromethane, dried over Na SO and purified over
In order to apply to porphyrin the glutathione­based
tumor­environment activation of the photodynamic
action, a dimeric disulfide­bridged porphyrin has been
designed and prepared, together with two reference
derivatives, a non­cleavable dimer and a monomer. The
dimeric disulfide­bridged porphyrin was partly self­
aggregated, whereasthenon­cleavabledimerdidnotshow
any self­aggregation, probably due to the flexibility of the
spacer. The intramolecular aggregation of the disulfide­
bridged dimer was not sufficient to induce a complete
self­quenching of the singlet oxygen generation. We plan
next to prepare multimers with higher porphyrin contents
which will be likely to exhibit better aggregation hence
self­quenching outside the tumor micro­environment.
This strategy was efficient with phthalocyanines [14] and
is also worthy of being implemented in future works.
2
4
silica gel column chromatography (elution gradient, from
1/1 dichloromethane/hexane to 4/1 dichloromethane/
hexane). Dark purple solid. Yield: 49% (49 mg).
C H N O , M. W. 1343.65 g/mol. MALDI­TOF­MS
9
4
70
8
2
+
(DHB): m/z 1344.93 (calcd. for [MH] 1344.65). FT­IR
(u, cm ): 3315, 3053, 2947, 2854, 1596, 1559, 1058,
1470, 1441, 1401, 1350, 1246, 1214, 1174, 1074, 1016,
­1
1
1001, 964, 877, 848, 796, 735, 702, 648, 578. H NMR
(CDCl , 500 MHz): d, ppm 8.93 (s, 4H), 8.86 (s, 12H),
3
8.23 (s, 12H), 8.15 (s, 4H), 7.76 (d, 18H), 7.33 (s, 4H),
4.35 (d, 4H), 2.13 (s, 4H), 1.85 (s, 4H), ­2.74 (s, 4H).
UV­vis (toluene): l, nm 420, 515, 551, 593, 649.
Synthesis of monomeric porphyrin 3. Monohydroxy­
lated porphyrin 4 (100 mg, 0.159 mmol, 1 eq.), 1­
bromopropane (72 mL, 0.793 mmol, 5 eq.) and K CO
EXPERIMENTAL
2
3
(
438 mg, 3.171 mmol, 20 eq.) were stirred in DMF (5 mL)
Synthesis
overnight at room temperature. The reaction mixture was
poured into water. The resulting precipitate was filtrated,
recovered in dichloromethane, and dried over Na SO . The
Materials and methods. Monohydroxylated porphy­
rin 4 [22] and bis(tosylate ethyl)disulfide 5 [23] were
prepared as reported. All reagents and solvents were of
synthetic grade and used as received. Column chromato­
graphies were carried out on silica gel Merck­60
2
4
productwaspurifiedoversilicagelcolumnchromatography
(1/1 dichloromethane/hexane). Dark purple solid. Yield:
93% (100 mg). C H N O, M. W. 672.83 g/mol. MALDI­
4
7
36
4
+
(
230–400 mesh, 60 A), and TLC on aluminum sheets
TOF­MS (DHB): m/z 672.93 (calcd. for [M] 672.83).
FT­IR (u, cm ): 3318, 2963, 2925, 2853, 1597, 1559,
1507, 1472, 1441, 1400, 1349, 1259, 1221, 1175, 1017,
­1
pre­coated with silica gel 60 F254 (E. Merck). FT­IR
­1
spectra were recorded between 4000 and 480 cm using
a PerkinElmer Spectrum 100 FT­IR spectrometer. NMR
spectrum were recorded in deuterated chloroform on a
Varian 500 MHz spectrometer at 298 K. Mass spectra
were recorded on a MALDI (matrix assisted laser
desorption ionization) BRUKER Microflex LT using
1
1016, 979, 965, 876, 846, 795, 730, 700, 658, 620. H
NMR (CDCl , 500 MHz): d, ppm 8.89 (s, 2H), 8.84 (s, 6H),
3
8.21 (d, 6H), 8.11 (d, 2H), 7.77 (d, 9H), 7.28 (d, 2H), 4.22
(t, 2H), 2.01 (m, 2H), 1.21 (t, 3H), ­2.76 (s, 2H). UV­vis
(toluene): l, nm 420, 515, 551, 592, 649.
2
,5­dihydroxybenzoic acid (DHB) as the matrix.
Synthesis of 5. 2­Hydroxyethyl disulfide (0.8 mL,
6.48 mmol, 1 eq.) and triethylamine (4 mL, 26 mmol,
4 eq.) were stirred in dichloromethane (20 mL) and cooled
by an ice bath. Tosyl chloride (3.71g, 19.5 mmol, 3 eq.) in
Synthesis of disulfide-bridged dimeric porphyrin 1.
Monohydroxylated porphyrin 4 (135 mg, 0.21 mmol,
eq.), bis(tosylate ethyl)disulfide 5 (32 mg, 0.07 mmol,
3
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6
S. ALPUGAN ET AL.
dichloromethane (10 mL) was then added drop by drop,
then the reaction mixture was allowed to reach room
temperature and further stirred overnight. The reaction
mixture was then washed by water, dried on Na SO and

Grad 
X
(
2)
(φ ) = (φ )
∆
X
∆
ST



Grad 
ST
2
4
quickly purified on silica gel column chromatography
eluent gradient from hexane to dichloromethane). Pale
Acknowledgments
(
waxy liquid. 960 mg (32%). The compound is used
Funding from the Scientific and Technological
ResearchCouncilofTurkey(TUBITAK)isacknowledged
(project 214Z099).
1
immediately after obtaining H NMR and FT­IR control.
­
1
C H O S , 462.61 g/mol. FT­IR (u, cm ): 2988, 2930,
1
8
22
6 4
1
595, 1351, 1175, 1096, 1002, 912, 815, 756, 659, 571.
H NMR (CHCl , d, ppm): 7.82 (d, 4H), 7.37 (d, 4H),
1
3
4
.13 (t, 4H), 3.32 (t, 4H), 2.47 (s, 6H).
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