The synthesis of new potential photosensitizers

Article abstract of DOI:10.1016/j.dyepig.2013.06.029

Abstract Several new derivatives of tetrakis(hydroxyphenyl)porphyrin were synthesized and their physicochemical data were established. These data were further assessed in terms of the synthesized compounds' usefulness as potential photosensitizers in anticancer photodynamic therapy. Absorption and fluorescence spectra, as well as triplet state lifetime were determined along with the compounds' stability and capacity to generate singlet oxygen. They obtained were compared to the corresponding data pertaining to a well-known and clinically admitted photosensitizing drug (Foscan).

Full text of DOI:10.1016/j.dyepig.2013.06.029

Dyes and Pigments 99 (2013) 627e635
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Dyes and Pigments
journal homepage: www.elsevier.com/locate/dyepig
The synthesis of new potential photosensitizers [1]. Part 2.
Tetrakis-(hydroxyphenyl)porphyrins with long alkyl chain
in the molecule
a
,
a
b
b
*
ꢀ
Marcin Rojkiewicz , Piotr Kus , Patrycja Kozub , Marta Kempa
a
Department of Chemistry, University of Silesia, 9, Szkolna Street, 40-006 Katowice, Poland
A. Chełkowski Institute of Physics, University of Silesia, 4, Uniwersytecka Street, 40-007 Katowice, Poland
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 April 2013
Received in revised form
Several new derivatives of tetrakis(hydroxyphenyl)porphyrin were synthesized and their physico-
chemical data were established. These data were further assessed in terms of the synthesized com-
pounds’ usefulness as potential photosensitizers in anticancer photodynamic therapy. Absorption and
fluorescence spectra, as well as triplet state lifetime were determined along with the compounds’ sta-
bility and capacity to generate singlet oxygen. They obtained were compared to the corresponding data
pertaining to a well-known and clinically admitted photosensitizing drug (Foscan).
Ó 2013 Elsevier Ltd. All rights reserved.
28 May 2013
Accepted 24 June 2013
Available online 4 July 2013
Keywords:
Photosensitizers
Porphyrins
Singlet oxygen
Fluorescence
Triplet state lifetimes
Photostability
1. Introduction
We based our search for novel photosensitizers on the structure
of Foscan which is a chlorine obtained on the basis of tetrakis(3-
PDT usefulness in anticancer treatment has been so far limited.
Undoubtedly, one of the reasons has been a small number of pho-
tosensitizers admitted for clinical use and capable of generating
singlet oxygen which would rapidly kill cancer cells in various body
locations [2]. Another problem is the delivery of photosensitizer to
the target site and availability of suitable methods is critically
important. The simplest approach is direct intratumoral injection of
such compound but this is not always feasible. Along with search for
novel photosensitizers also adequate methods of their transport in
the living organism are sought. Among known methods liposome
encapsulation has been used. Appropriate composition of lipo-
somes, besides assuring targeted delivery, can also assure resistance
of the transported photosensitizer against body defense mecha-
nisms. The drug (photosensitizer) can be liposome-encapsulated
and delivered intracellularly or it can be a part of liposomal lipid
bilayer which would ultimately lead to its integration with cellular
membrane. Destruction of cells follows their irradiation and can
occur both intracellularly and involving cell membrane.
hydroxyphenyl)-porphyrin. In his study, Bonnett determined bio-
logical activity of this compound and other similar hydroxyl de-
rivatives of tetrakisphenylporphyrin (especially para isomers). The
results were comparable to those of Photofrin, the first porphyrin
derivative admitted for clinical use. Tetrakis-(3-hydroxyphenyl)
porphyrin (1) turned out to be 25e30 times more active than the
earlier-studied HpD [3,4]. It did not, however, find use in PDT
photosensitizer. Two reduced derivatives of this porphyrin, namely
chlorin (2) and bacteriochlorin (3) proved to be better photosensi-
tizers owing to stronger absorption in the red part of visible light
spectrum compared to the starting porphyrin [5e8] (Fig. 1)
Since our goal was to obtain nontoxic porphyrin that could be
transported by liposomes we had to pay particular attention to its
hydrophobicehydrophylic properties. The manner in which
porphyrin is anchored in liposomes is of importance [8]. Literature
data suggest that hydrophilic porphyrins linked to long hydro-
phobic chains are incorporated much easier into micelle formed by
fatty substances. This process, and location of porphyrin in partic-
ular, is dependent on pH of the environment in which micelle are
formed and on porphyrin concentration [9e11]. These factors also
affect another feature, unfavorable from the perspective of PDT
*
Corresponding author. Tel.: þ48 32 359 1445.
E-mail address: marcin.rojkiewicz@us.edu.pl (M. Rojkiewicz).
0143-7208/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.dyepig.2013.06.029

628
M. Rojkiewicz et al. / Dyes and Pigments 99 (2013) 627e635
Fig. 1. Structures of 1, 2, 3.
application, namely porphyrin aggregation. Several aqueous
porphyrin solutions are prone to aggregation which causes their
precipitation from such solutions.
completely. Accordingly, we aimed at preparing porphyrins with less
“favorable” positioning of alkyl chain. The synthesized and charac-
terized compounds are shown in Fig. 3 and Table 1. They include
alkylporphyrins with ether bonds between alkyl and phenyl moi-
eties (the least favorable kind of bond from biological perspective),
as well as ester and amid derivatives. Another interesting group of
porphyrins are those with methoxy substituents. The latter, placed
in the vicinity of hydroxyl groups, decrease polarity of this fragment
of the molecule which translates into decisive effect upon hydro-
phobicehydrophylic properties of the whole molecule. Last but not
least is the length of the alkyl fragment attached to porphyrin. Our
earlier experience has shown that optimum length of this fragment
is that corresponding to 16 carbon atoms in the chain [13]. This is
why we used in the synthesis cetyl (hexadecyl) radicals or palmitic
acid fragments. The obtained compounds characterized in this study
are based on tetrahydroxyl porphyrin 1, and on several other starting
porphyrins shown below (5e7).
Using porphyrin 1 as a leading structure, we decided to modify it
in such a manner so that its derivatives were distinctly amphiphilic.
This feature allows porphyrin molecules to partially dissolve in less
polar liquids which can be of use in micellar or liposomal transport.
Vesicle formation has been observed for certain amphiphilic por-
phyrins which is not favorable for their incorporation into lipid
layers [12]. This phenomenon took place for porphyrins with three
pirydyl substituents. Encapsulating a very polar porphyrin mole-
cule inside a liposome is also possible albeit much less probable
than using a long amphiphilic fragment (such as porphyrin linked
to long alkyl chain) to co-form micelle or liposomes.
In line with our expectations, the best suited compound to
interact with lipid components of micelles or liposomes would be
porphyrin 4 with three hydroxyl groups in meta position and long
alkyl chain in para position (this is shown schematically in Fig. 2).
Alternative attachment of alkyl chain (in meta or orto position) might
cause spatial hindrance during porphyrin incorporation into semi-
permeable membranes of micelles or liposomes. However, micellar
incorporation of porphyrin with long alkyl chain attached in position
other than para position of the side phenyl ring cannot be ruled out
These compounds were obtained in one-stage direct synthesis
starting from appropriate hydroxybenzaldehydes. Earlier reports
describe synthesis of these compounds in two stages. First, suitable
methoxy or acetyloxyphenylporphyrins are obtained and then
protecting groups are removed [4].
The most relevant photophysical data are presented inTables 2e4.
Fig. 2. Structure of 4.

M. Rojkiewicz et al. / Dyes and Pigments 99 (2013) 627e635
629
Fig. 3. Structures of investigated compounds.
An important parameter characterizing PDT usefulness of por-
phyrins is their ability to generate singlet oxygen. Determination of
quantum yield of singlet oxygen production by all synthesized
derivatives was carried out by laser flash photolysis. As a reference,
we used tetrakisphenylporphyrin with a known quantum yield of
singlet oxygen generation (0.62) [14]. Quantum yields of all the
obtained compounds show very similar values.
flow injection system. UVeVis spectra were recorded in chloroform
or methanol solutions using Genesys 6 (ThermoSpectronic) spec-
trophotometer. Fluorescence spectra were made with a Fluores-
cence Spectrophotometer Eclipse Cary Varian in the range 550e
800 nm using 420 nm excitation wavelength and 1.0 nm the sam-
pling interval for all compounds. Transient tripletetriplet absorp-
tion spectra were observed with an Applied Photophysics LKS 60
2
. Experimental
Table 2
Porphyrins 1, 2, 4e19 Soret band and Q bands wavelengths (l nm) and log of molar
NMR spectra were obtained with a 400 MHz Bruker spectrom-
extinction coefficients (log ).
3
3 6
eter in CDCl or DMSO-d , and chemical shifts are reported in ppm
downfield from TMS. ESI mass spectra were recorded on a Varian
MS 500 or LCQ DUO FINNINGAN THERMOQUEST instruments using
Porphyrin
Soret
(log
Q
y
(1e0)
Q
y
(0e0)
Q
x
(1e0)
Q
x
(0e0)
l
3 )
l
(log
3 )
l
(log
3 )
l
(log
3 )
l
(log
3 )
1
2
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
415 (5.66)
416 (5.28)
422 (5.54)
420 (5.63)
423 (5.59)
424 (5.61)
423 (5.52)
419 (5.60)
419 (5.55)
419 (5.51)
426 (5.56)
424 (5.53)
427 (5.54)
428 (5.39)
420 (5.55)
421 (5.56)
423 (5.51)
419 (5.58)
514 (4.25)
516 (4.03)
517 (4.16)
517 (4.21)
518 (4.18)
519 (4.19)
519 (4.11)
517 (4.15)
517 (4.16)
519 (4.17)
520 (4.18)
519 (4.19)
520 (4.20)
520 (4.14)
518 (4.13)
518 (4.15)
519 (4.09)
517 (4.21)
549 (3.81)
544 (3.87)
553 (3.81)
554 (3.90)
550 (3.80)
551 (3.77)
556 (3.91)
550 (3.79)
554 (3.88)
553 (3.90)
558 (3.94)
558 (3.89)
557 (3.87)
556 (3.84)
549 (3.84)
549 (3.83)
556 (3.81)
554 (3.82)
590 (3.62)
597 (3.65)
593 (3.66)
592 (3.65)
592 (3.65)
591 (3.71)
594 (3.63)
591 (3.62)
592 (3.68)
595 (3.61)
593 (3.69)
594 (3.59)
594 (3.70)
594 (3.72)
594 (3.69)
593 (3.67)
592 (3.69)
593 (3.63)
650 (3.67)
651 (4.41)
651 (3.70)
651 (3.72)
651 (3.65)
650 (3.55)
651 (3.67)
647 (3.66)
648 (3.71)
652 (3.69)
651 (3.68)
650 (3.61)
650 (3.58)
650 (3.61)
649 (3.53)
651 (3.54)
649 (3.62)
651 (3.66)
Table 1
Composition of compounds 8e19.
Compound
R
1
R
2
R
3
R
4
R
5
R
6
8
9
OC16
H
OCOC15
H
H
33
H
OC16
H
H
H
H
H
H
H
OCH
OCH
H
OH
H
OH
H
OH
OH
OH
OH
OCH
OCH
OCH
OH
H
OH
H
OH
OCH
OCH
OCH
OCH
H
H
H
H
H
H
H
OCH
OCH
H
H
33
10
11
12
13
14
15
16
17
18
19
H
31
OCOC15
H
31
OC16
OCOC15
OC16
H
33
OCH
OCH
OCH
OCH
H
H
H
H
3
3
3
3
3
3
3
3
H
31
H
33
3
3
3
3
OCOC15
NHCOCH
H
31
3
3
3
3
NH
2
H
H
H
H
H
H
H
H
H
NHCOC15
NHCOC15
H
H
31
31

630
M. Rojkiewicz et al. / Dyes and Pigments 99 (2013) 627e635
Table 3
Fluorescence spectra of compounds 1, 2, 4e19: values for Q(0e0), Q(0e1), fluores-
cence quantum yields (420 nm) and Stokes shifts between the Q(0e0) and Q (0e
column with dichloromethane-methanol (30:1, v/v) mixture as
eluent to give 1.11 g (9%) of 1.
F
F
x
1
6
H NMR (400 MHz, DMSO-d ): d(ppm): 10.00 (s, 4H, OH), 8.88
0) band.
(
(
s, 8H,
b
H), 7.66e7.56 (m, 12H, ArH), 7.27e7.21 (m, 4H, ArH), ꢀ3.02
Porphyrin
Q(0e0)
max (nm)
Q(0e1)
max(nm)
F
F
Stokes shift (nm)
þ
s, 2H, NH); ESI MS (m/z): 680.1 [M þ H] .
l
l
Tetrakis-5,10,15,20-(3-hydroxyphenyl)chlorine (2) was obtained
according to [15].
1
2
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
654
651
651
656
656
657
657
648
653
650
657
655
659
658
655
654
655
652
719
715
717
721
724
725
720
713
718
713
726
724
723
725
721
721
723
721
0.098
0.210
0.096
0.123
0.126
0.120
0.126
0.086
0.114
0.092
0.128
0.125
0.118
0.121
0.117
0.119
0.118
0.121
4
0
0
5
5
7
6
1
5
2.2. 5-(4-Hexadecyloxyphenyl)-10,15,20-tris(3-hydroxyphenyl)
porphyrine (4) (C60
62 4 4
H N O
¼ 903.159)
3-Hydroxybenzaldehyde (3.66 g, 0.03 mol), 4-hexadecyloxy-
benzaldehyde (3.46 g, 0.01 mol) were dissolved in 100 mL of pro-
pionic acid and heated to reflux. Pyrrole (2.8 mL, 0.04 mol) was
added and the resulting mixture was heated under reflux for 1.5 h.
0
1
2
3
4
5
6
7
8
9
ꢀ2
6
50 mL of propionic acid was removed by distillation. 200 mL of
5
9
8
6
3
6
1
water was added to the rest of cooled mixture. Propionic acid was
neutralized by solid sodium carbonate. Precipitated organic com-
pounds were dissolved in dichloromethane (500 mL), washed with
water (5 ꢁ 100 mL) and dried with anhydrous Na
2 4
SO . Dichloro-
methane was evaporated and the residue was chromatographed on
silica gel with chloroformeethyl acetate (3:1, v/v) mixture as
eluent. Yield: 0.34 g (w4%).
1
H NMR (400 MHz, DMSO-d
H), 8.05 (d, 2H, J ¼ 7.2 Hz, ArH), 7.67e7.55 (m, 8H, ArH), 7.33,
.20 (dd, 6H, ArH), 4.15 (t, 2H, OCH CH ), 1.81 (q, 2H, OCH CH ), 1.47
q, 2H), 1.40e1.05 (m, 24H), 0.76 (t, 3H, CH CH
), ꢀ2.99 (s, 2H, NH);
6
): d (ppm) 9.99 (s, 3H, OH), 8.87 (m,
Laser Flash Photolysis Spectrometer, using the third harmonic
355 nm) of a Brilliant Nd-YAG Q-switched laser. The 150 W xenon
8
7
(
H, b
(
2
2
2
2
lamp was used as the light source. Spectra were performed in the
range from 350 to 800 nm with 1 nm interval. The quartz cell with
optical length of 10 mm was used for all measurements. For flash
photolysis and fluorescence measurements toluene or methanol
solutions of compounds were used. All chemicals and solvents were
purchased from Acros Organics.
2
3
þ
ESI MS (m/z): 904.8 [M þ H] .
2
.3. Tetrakis-5,10,15,20-(4-hydroxyphenyl)porphyrine (5)
(C
44
30
H N
4
O
4
¼ 678.734)
This compound was obtained similar to 1, using 4-hydroxy-
benzaldehyde instead of 3-hydroxybenzaldehyde. Yield: 12%.
2
.1. Tetrakis-5,10,15,20-(3-hydroxyphenyl)porphyrine (1)
1
6
H NMR (400 MHz, DMSO-d ): d (ppm) 8.93 (s, 8H, bH), 8.87 (s,
44 30 4 4
(C H N O
¼ 678.734)
4
H, OH), 8.07 (d, 8H, J ¼ 8.0 Hz, ArH), 7.30 (d, 8H, J ¼ 8.0 Hz,
þ
ArH), ꢀ2.68 (s, 2H, NH); ESI MS (m/z): 679.3 [M þ H] .
A solution of 3-hydroxybenzaldehyde (8.8 g, 72 mmol) in pro-
pionic acid (300 mL) was brought to reflux. Pyrrole (5 mL, 72 mmol)
was added quickly. The resulting mixture was refluxing during
additional 1.5 h. After that 200 mL of propionic acid was evapo-
rated. Cooled to room temperature residue was neutralized with
saturated solution of NaHCO . Precipitated crude porphyrin was
3
washed with chloroform and finally chromatographed on silica gel
2
.4. Tetrakis-5,10,15,20-(4-hydroxy-3-methoxyphenyl)porphyrine
(6) (C48
38 4 8
H N O
¼ 798.27)
This compound was obtained similar to 1, using 4-hydroxy-3-
methoxybenzaldehyde (vanillin) instead of 3-hydroxybenzalde-
hyde. Product was chromatographed on silica gel with chlor-
oform:ethyl acetate (5:1, v/v). Yield: 22%.
1
6
H NMR (400 MHz, DMSO-d ): d (ppm) 9.53 (s, 4H, OH), 8.91 (s,
Table 4
Triplet state lifetimes
quantum yield of singlet oxygen
s
T
values (
m
s) in the presence and absence of oxygen and
for compounds 1, 2 and 4e19.
8H,
b
H), 7.77 (s, 4H, ArH), 7.58 (d, 4H, J ¼ 8.0 Hz, ArH), 7.21 (d, 4H,
F
D
J ¼ 8.0 Hz, ArH), 3.86 (s, 12H, OCH
3
), ꢀ2.88 (s, 2H, NH); ESI MS
þ
(m/z): 798.6 [M þ H] .
Porphyrin
s
T
[
m
s] [oxygen]
s
T
[
ms] [oxygen-free]
F
D
1
2
4
5
6
7
8
9
0.275
0.219
0.257
0.231
0.258
0.324
0.232
0.279
0.237
0.266
0.265
0.271
0.276
0.300
0.273
0.252
0.286
0.217
2.00
1.27
1.48
2.00
1.90
2.01
1.77
1.35
1.13
1.80
1.43
1.33
1.48
1.20
1.81
1.70
1.20
1.27
0.60
0.57
0.60
0.61
0.62
0.63
0.64
0.63
0.65
0.64
0.68
0.62
0.69
0.62
e
2
.5. Tetrakis-(4-hydroxy-3,5-dimethoxyphenylene)porphyrine (7)
46 4
(C52H N O
12 ¼ 918.94)
This compound was obtained similar to 6, using 4-hydroxy-3,5-
dimethoxybenzaldehyde instead of 4-hydroxy-3-methoxy-
benzaldehyde. Yield: 22%.
1
10
11
12
13
14
15
16
17
18
19
H NMR (400 MHz, CDCl
3
):
d
(ppm) 8.95 (s, 8H,
b
H), 7.48 (s, 8H,
ArH), 5.90 (s, 4H, OH), 4.01 (s, 24H, OCH
3
), ꢀ2.74 (s, 2H, NH); ESI MS
þ
(m/z): 919.7 [M þ H] .
2.6. 5-(4-Hexadecyloxyphenyl)-10,15,20-tris(4-hydroxyphenyl)
porphyrine (8) (C60
¼ 903.16)
62 4 4
H N O
e
0.61
0.67
A 0.262 g (0.386 mmol) of 5 was stirred in 5 mL dime-
thylformamide with 0.024 g (0.579 mmol) 60% NaH for 30 min at

M. Rojkiewicz et al. / Dyes and Pigments 99 (2013) 627e635
631
room temperature. 0.118 g (0.386 mmol) of 1-bromohexadecane
was added. The reaction mixture was stirred for 24 h at 80e90 C.
The solvent was evaporated in vacuum then water (100 mL) was
added and the resulting mixture was extracted three times
2.11. [5-(3-Methoxy-4-oxyphenyl)-10,15,20-tris(4-hydroxy-3-
methoxyphenyl)porphyrine] palmitate (13) (C64
¼ 1036.50)
ꢂ
68 4 9
H N O
This compound was obtained similar to 10, using porphyrine 6
(
3 ꢁ 50 mL) with dichloromethane-ethyl acetate (3:2) mixture.
Combined organic fraction was washed with water (3 ꢁ 100 mL),
dried with anhydrous Na SO . Solvents were evaporated and the
as a parent substance. Yield: 12%.
1
H NMR (400 MHz, CDCl
(m, 9H, ArH), 7.34 (d, 3H, ArH), 6.00 (s, 3H, OH), 4.06 (s, 9H, OCH
4.01 (s, 3H, OCH
3
):
d
(ppm) 8.97 (s, 8H,
b
H), 7.89e7.81
),
3
), 1.69 (t, 2H), 1.30e0.97 (m, 26H), 0.77 (t,
2
4
3
residue was chromatographed on silica gel with chloroform-ethyl
acetate (5:1, v/v). Yield: 0.056 g (16%).
þ
3H), ꢀ2.71 (s, 2H, NH). ESI MS (m/z): 1037.2 [M þ H] .
1
6
H NMR (400 MHz, DMSO-d ): d (ppm) 9.99 (s, 3H, OH), 8.88 (m,
8
4
2
H,
.11 (t, 2H, OCH
H, OCH CH CH
b
H), 7.99 (d, 8H, J ¼ 8.0 Hz, ArH), 7.21 (d, 8H, J ¼ 8.0 Hz, ArH),
2.12. 5-(4-Hexadecyloxy-3,5-dimethoxyphenyl)-10,15,20-tris(4-
2
CH
2
), 1.83e1.71 (m, 2H, OCH
2
CH
2
), 1.50e1.39 (m,
), ꢀ2.85
hydroxy-3,5-dimethoxyphenyl) porphyrine (14) (C68
1143.37)
H
78
N
4
O
12
¼
2
2
2
), 1.29e1.10 (m, 24H, CH
2
), 0.78 (t, 3H, CH
3
þ
(
s, 2H, NH); ESI MS (m/z): 905.0 [M þ H] .
This compound was obtained similar to 8, using porphyrine 7 as
2
.7. 5-(3-Hexadecyloxyphenyl)-10,15,20-tris(3-hydroxyphenyl)
a parent substance. Yield: 22%.
1
porphyrine (9) (C60
62
H N
4
O
4
¼ 903.16)
H NMR (400 MHz, CDCl
ArH), 7.52 (s, 2H, ArH), 5.98(s, 3H, OH), 4.37 (t, 2H), 4.07 (s,18H, OCH
4.01, (s, 6H, OCH
3
):
d
(ppm) 9.00 (s, 8H,
b
H), 7.54 (s, 6H,
),
3
), 2.08e1.98 (m, 2H), 1.70 (m, 2H), 1.40e1.28 (m,
3
This compound was obtained similar to 8, using porphyrine 1 as
þ
a parent substance. Yield: 14%.
24H), 0.92 (t, 3H), ꢀ2.69 (s, 2H, NH). ESI MS (m/z): 1145.0 [M þ H] .
1
H NMR (400 MHz, DMSO-d
H), 7.76 (m, 2H, ArH), 7.69 (t, 1H, ArH), 7.65e7.55(m, 9H, ArH),
.39 (d,1H, ArH), 7.24 (d, 3H, ArH), 4.16 (t, 2H, OCH CH ),1.79 (q, 2H,
OCH CH ), 1.44 (q, 2H), 1.35e1.00 (m, 24H), 0.76 (t, 3H,
CH CH
), ꢀ2.97 (s, 2H, NH); ESI MS (m/z): 905 [M þ H] .
6
): d (ppm) 9.87 (s, 3H, OH), 8.88 (m,
8
7
H,
b
2.13. [5-(3,5-Dimethoxy-4-oxyphenyl)-10,15,20-tris(4-hydroxy-3,5-
dimethoxyphenyl)porphyrine] palmitate (15) (C68
2
2
76
H N
4
O
13 ¼1156.54)
2
2
þ
2
3
This compound was obtained similar to 10, using porphyrine 7
as a parent substance. Yield: 19%.
1
2.8. [5-(4-Oxyphenyl)-10,15,20-tris(4-hydroxyphenyl)porphyrine]
H NMR (400 MHz, CDCl
3
):
d
(ppm) 8.99 (s, 8H,
b
H), 7.56 (s, 6H,
), 4.03 (s,
palmitate (10) (C60
H
60
N
4
O
5
¼ 917.14)
ArH), 7.50 (s, 2H, ArH), 5.95 (s, 3H, OH), 4.11 (s, 18H, OCH
H, OCH
3
6
3
),1.63 (t, 2H),1.33e1.01 (m, 26H), 0.79 (t, 3H), ꢀ2.68 (s, 2H,
þ
0
.212 g (0.313 mmol) of 5 was stirred in 5 mL dimethylforma-
NH). ESI MS (m/z): 1157.6 [M þ H] .
mide with 0.082 g (0.3 mmol) of palmitoyl chloride. The reaction
mixture was stirred for 48 h at 80 C. Water (100 mL) and trie-
ꢂ
2.14. 5-(4-Acetylaminophenyl)-10,15,20-tris(4-methoxyphenyl)
thylamine (2 mL) were added and the resulting mixture was
porphyrine (16) (C49
H
39
N
5
O
4
¼ 761.86)
extracted four times (4 ꢁ 50 mL) with chloroform-ethyl acetate
(
(
3:2) mixture. Combined organic fraction was washed with water
4-Acetamidbenzaldehyde (3.26 g, 0.02 mol), 4-methoxy-
benzaldehyde (8.16 g, 0.06 mol) were dissolved in 100 mL of pro-
pionic acid and heated to reflux. Pyrrole (5.6 mL, 0.08 mol) was
added and the resulting mixture was heated under reflux for 1.5 h.
50 mL of propionic acid was removed by distillation. 200 mL of
water was added to the rest of cooled mixture. Propionic acid was
neutralized by solid sodium carbonate. Precipitated organic com-
pounds were dissolved in dichloromethane (400 mL), washed with
5 ꢁ 50 mL), dried with anhydrous Na
2 4
SO . Solvents were evapo-
rated and the residue was chromatographed on silica gel with
chloroform-ethyl acetate (5:1, v/v). Yield: 0.061 g (22%).
1
6
H NMR (400 MHz, DMSO-d ): d (ppm) 9.95 (s, 3H, OH), 8.88 (m,
6
H,
b
H), 8.70 (d, 2H,
b
H), 8.23 (d, 2H, J ¼ 8.8 Hz, ArH), 8.00 (d, 6H,
J ¼ 8.4 Hz, ArH), 7.56 (d, 2H, J ¼ 8.8 Hz, ArH), 7.20 (d, 6H, J ¼ 8.4 Hz,
ArH), 2.75 (t, 2H),1.79 (q, 2H),1.71 (q, 2H),1.60 (q, 2H),1.30e1.18 (m,
2
0H), 0.80 (t, 3H, CH
3
), ꢀ2.88 (s, 2H, NH). ESI MS (m/z): 919.0
water (3 ꢁ 150 mL) and dried with anhydrous Na
2 4
SO . Dichloro-
þ
[M þ H] .
methane was evaporated and the residue was chromatographed on
silica gel with chloroformeethyl acetate (3:1, v/v) mixture as
2
.9. [5-(3-Oxyphenyl)-10,15,20-tris(3-hydroxyphenyl)porphyrine]
eluent. Yield: 0.457 g (w3%).
1
palmitate (11) (C60
60
H N
4
O
5
¼ 917.14)
3
H NMR (400 MHz, CDCl ): d (ppm) 8.87 (m, 8H, bH), 8.47 (d, 2H,
J ¼ 8.0 Hz, ArH), 8.13 (d, 6H, J ¼ 8.8 Hz, ArH), 7.86 (d, 2H, J ¼ 8.0 Hz,
ArH), 7.29 (d, 6H, J ¼ 8.8 Hz, ArH), 4.10 (s, 9H, OCH ), 2.10 (s, 3H,
CH
), ꢀ2.75 (s, 2H, NH).
ESI MS (m/z): 762.7 [M þ H] .
This compound was obtained similar to 10, using porphyrine 1
3
as a parent substance. Yield: 18%.
3
1
þ
6
H NMR (400 MHz, DMSO-d ): d (ppm) 9.91 (s, 3H, OH), 8.89
(
s, 8H,
b
H), 8.12 (d,1H, ArH), 7.98 (t,1H, ArH), 7.85 (t,1H, ArH), 7.75e
7
0
.55 (m, 9H, Ar), 7.24 (d, 4H, ArH), 1.69 (t, 2H), 1.34e0.97 (m, 26H),
.77 (t, 3H), ꢀ2.98 (s, 2H, NH). ESI MS (m/z): 918.9 (100) [M þ H] .
2.15. 5-(4-Aminophenyl)-10,15,20-tris(4-methoxyphenyl)porphyrine
(17) (C47
¼ 719.83)
þ
37 5 3
H N O
2
.10. 5-(4-Hexadecyloxy-3-methoxyphenyl)-10,15,20-tris(4-hydroxy-
0.21 g (0.276 mmol) of 16 was dissolved in the mixture of 20 mL
of trifluoroacetic acid and 21 mL of concentrated hydrochloric acid
and heated at 80 C with stirring during 20 h. 200 mL of water was
3-methoxyphenyl)porphyrine (12) (C64
H N O
70 4 8
¼ 1023.26)
ꢂ
This compound was obtained similar to 8, using porphyrine 6 as
a parent substance. Yield: 11%.
added to the rest of cooled mixture. Precipitated green organic
compounds were dissolved in chloroform-ethyl acetate mixture
(300 mL; 3:1, v/v), washed with water (100 mL), saturated sodium
carbonate solution (2 ꢁ 100 mL), water (100 mL) and dried with
1
H NMR (400 MHz, CDCl
ArH), 7.80e7.74 (m, 8H, ArH), 7.34 (d, 3H, ArH), 6.02 (s, 3H, OH), 4.34
t, 2H), 4.04 (s, 9H, OCH ), 4.01 (s, 3H, OCH ), 2.12e2.04 (m, 2H),
.70e1.62 (m, 2H), 1.40e1.24 (m, 24H), 0.92 (t, 3H), ꢀ2.70 (s, 2H,
3
): d (ppm) 8.97 (s, 8H, bH), 7.82 (s, 1H,
(
1
3
3
anhydrous Na
2
SO
H NMR (400 MHz, CDCl
8.12 (d, 6H, J ¼ 8.4 Hz, ArH), 7.99 (d, 2H, J ¼ 8.0 Hz, ArH), 7.29 (d, 6H,
4
. Solvent was evaporated. Yield: 0.145 g (73%).
1
3
): d 8.92 (d, 2H, bH), 8.86 (m, 6H, bH),
þ
NH). ESI MS (m/z): 1024.2 [M þ H] .

632
M. Rojkiewicz et al. / Dyes and Pigments 99 (2013) 627e635
J ¼ 8.4 Hz, ArH), 7.06 (d, 2H, J ¼ 8.0 Hz, ArH), 4.10 (s, 9H,
3. Results and discussion
þ
OCH
3
), ꢀ2.73 (s, 2H, NH); ESI MS (m/z): 721.2 (100) [M þ H] .
3.1. Porphyrin synthesis
2.16. N-[5-(para-phenylene)-10,15,20-tris(4-methoxyphenyl)
porphyrine] palmitylamide (18) (C63
H
67
N
5
O
4
¼ 958.23)
Compounds 1, 4e7, 16 and 19 were synthesized by condensation
of appropriate aldehydes with pyrrole in propionic acid in typical
Adler-Longo procedure. Compound 17 was obtained from 16 by
acid (trifluoroacetic acid) hydrolysis. Compound 2 was obtained
from 1 using procedure described in [15].
Palmitic acid 0.128 g (0.5 mmol) and 0.5 mL of 1 M DCC solution
0.5 mmol) dissolved in 10 mL dichloromethane were refrigerated
(
for 4 days. After that 0.030 g (0.042 mmol) of 17 dissolved in 10 mL
of dichloromethane was added and the resulting mixture was
stirred for 24 h at room temperature. 50 mL of dichloromethane
was added to the mixture and resulting solution was washed with
Ether derivatives of porphyrins 8, 9, 12 and 14 were obtained
from porphyrins 5, 1, 6 and 7, respectively, in a typical Williamson
ether synthesis. The reaction was carried out in DMF using NaH to
obtain suitable phenoxide salts of porphyrins, and cetyl bromide as
an alkylating agent. Compared with post-cyclisation reaction, more
convenient method for synthesis of compound 4 and 19 is mixed
Adler-Longo condensation (Scheme 1). It eliminates possibility of
non separable isomers formation. E.g. Derivatisation of 5-(4-
hydroxyphenyl)-10,15,20-tris(3-hydroxyphenyl)-porphyrin obtained
first via 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde and pyr-
role condensation would lead to 5-(4-hexadecyloxyphenyl)-10,15,20-
tris(3-hydroxyphenyl)-porphyrin and 5-(3-hexadecyloxyphenyl)-
water (3 ꢁ 50 mL) and dried with anhydrous Na
2 4
SO . Dichloro-
methane was evaporated and the residue was chromatographed on
silica gel with dichloromethaneemethanol (100:1, v/v) mixture as
eluent. Yield: 0.0293 g (73%).
1
3
H NMR (400 MHz, CDCl ): d 8.87 (m, 8H, bH), 8.13 (d, 2H,
J ¼ 8.4 Hz, ArH), 8.12 (d, 6H, J ¼ 8.0 Hz, ArH), 7.88 (d, 2H, J ¼ 8.4 Hz,
ArH), 7.28 (d, 6H, J ¼ 8.0 Hz, ArH), 4.09 (s, 9H, OCH ), 2.50 (t, 2H),
3
1
.86 (q, 2H), 1.47 (q, 2H), 1.40e1.20 (m, 22H), 0.89 (t, 3H), ꢀ2.74 (s,
þ
2
H); ESI MS (m/z): 959.8 [M þ H] .
1
0,15,20-tris(3-hydroxyphenyl)porphyrin and mixture of such com-
2
.17. N-[5-(para-phenylene)-10,15,20-tris(4-hydroxyphenyl)
pounds seems to impossible to separate. Thus, mixed condensation
of 4-hexadecyloxybenzaldehyde, 3-hydroxybenzaldehyde and pyr-
role was performed to obtain compound 4. Other compounds e.g. 8
or 9 could be either obtains by this method or by post-cyclization
derivatisation. Palmitic acid esters 10, 11, 13 and 15 were obtained
from porphyrins 5, 1, 6 and 7, respectively, by acylation with palmitic
acid chloride (Scheme 2). In our experiments we tried to obtain
these esters from suitable porphyrin and acid using DCC and DMAP,
but it turned out that using acid chlorides leads to better yields of
final compounds and in shorter time periods. Amide 18 was ob-
tained from 17 and palmitic acid in the presence of DCC and DMAP
in dichloromethane. Generally, one can conclude that introduction
of long alkyl chain into porphyrin molecule considerably ameliorates
its solubility in organic solvents which is useful during later product
purification and spectroscopic studies of these compounds.
porphyrine] palmitylamide (19) (C60
61
H N
5
O
4
¼ 915.47)
N-(4-formylphenyl)amide of palmitic acid (2.39 g, 6.66 mmol),
-hydroxybenzaldehyde (2.44 g, 20 mmol) were dissolved in
4
1
00 mL of propionic acid and heated to reflux. Pyrrole (1.9 mL,
7 mmol) was added and the resulting mixture were heated under
reflux for 1.5 h. 50 mL of propionic acid was removed by distillation.
00 mL of water was added to the rest of cooled mixture. Propionic
2
2
acid was neutralized by solid sodium carbonate. Precipitated
porphyrin mixture was separated and dried on air. Pure 19 was
separated by column chromatography on silica gel with chloro-
formeethyl acetate (5:1, v/v) mixture as eluent. Yield: 0.152 g
(
w2.5%).
1H NMR (400 MHz, DMSO-d
H, OH), 8.89 (s, 8H,
6
): d (ppm) 10.31 (s, 1H, NH), 9.97 (s,
3
b
H), 8.14 (d, 2H, J ¼ 8.0 Hz, ArH), 8.08 (d, 2H,
3.2. Mass spectra
J ¼ 8.0 Hz, ArH), 8.02 (d, 6H, J ¼ 8.0 Hz, ArH), 7.23 (d, 6H, J ¼ 8.0 Hz,
ArH), 1.71 (t, 2H), 1.28-1.12 (m, 26H), 0.79 (t, 3H), -2.85 (s, 2H, NH).
ESI MS (m/z): 916.2 [M þ H]þ (Scheme 1).
ESI MS mass spectra performed by direct sample introduction
into ionizing chamber demonstrated high purity of the synthesized
þ
compounds. In all cases single [M þ H] peaks (of the highest in-
þ
tensity) were present. Besides these peaks, [2M þ H] ion peaks
were sometimes observed, corresponding to porphyrin aggregates,
þ
þ
as well as [M þ Na] and [2M þ Na] ion peaks, but of considerably
lesser intensity. Addition of sodium salts (any) to porphyrin solu-
þ
tions immediately increased intensity of [M þ Na] ion which
became one with the highest intensity. Similar effect was observed
with other alkaline ions (following addition of their salts).
3.3. Lipophilicity
Lipophilicity of the majority of compounds described herein was
the subject matter of our previous report [16]. It is an important
parameter from the perspective of applying these compounds to
prepare liposomes (i.e. to incorporate the long alkyl chain into the
liposomal bilayer).
According to expectations, attachment of alkyl chain to
porphyrin molecule considerably increased its hydrophobic prop-
erties and positively affected its solubility in various organic sol-
vents. The manner in which long alkyl chain was attached to
phenylporphyrin is not insignificant. Ether bond most strongly
increased hydrophobic properties of the obtained compounds;
however, from the biological perspective, such bond between the
Scheme 1. Porphyrin synthesis via Adler-Longo method.

M. Rojkiewicz et al. / Dyes and Pigments 99 (2013) 627e635
633
Scheme 2. Reaction of attaching the alkyl chain to the porphyrin via ether and ester bond.
two moieties is not the best solution, especially in the context of
later catabolism of the molecule. Ester or amide bonds are much
better in this respect but they tend to increase the hydrophilic
character of the molecule (compared to one with ether bond). The
consideration that the ester or amide bond is better then the ether
bond, based on the metabolic stability of the compound. It is gen-
eral rule that compounds with reducted lipophilicity are more
stable [17]. We already proved that compounds with alkyl chain
attached via ether bond are more lipophylic then these where the
alkyl chain is attached via ester or amide bond. Therefore esters or
amides could be easier removed from the organism after photo-
dynamic action. We do not have data at this point concerning
emission the sample, deaerated with argon for 30 min, was excited
at 420 nm. Porphyrin fluorescence quantum yields ( ) were
determined in dilute solutions (absorption range 0.02e0.05) in the
F
F
Soret band region using tetrakisphenylporphyrin (
standard [19].
F
F
¼ 0.11) as a
The fluorescence quantum yield was found using equation:
N
Z
If ð
l l
Þd
ꢀ
A
$
A
w
n2
1 ꢀ 10
0
4
¼ 4
$
w N
Z
ꢀ
2
1 ꢀ 10
n
w
w
f
I ð
l l
Þd
“biological response” and usefulness of compounds differing by
0
bond type between hydrophilic and hydrophobic fragments of
porphyrin derivatives. Such knowledge requires separate biological
studies of these compounds.
Z
Z
N
N
w
where
If ð
l
Þd
l
and
I ð
l l
are areas under the emission
Þd
f
0
0
curves, A and A
w
are absorbances of the sample and standard, n and
3.4. Absorption spectroscopy
w
n are refractive indexes of solvents used to dissolution the sample
and standard respectively.
Absorption spectra were measured between 300 and 800 nm in
Fluorescence spectra of all the obtained porphyrins show similar
shapes with maxima at 650 and 720 nm (Fig. 4). Fluorescence
quantum yields (F ) of all the porphyrins studied are relatively
F
small; this shows that the studied compounds might be promising
PDT agents. The yields for all the compounds studied are lower than
that of chlorin 2 which has been used as photosensitizer. Stokes
shift which characterizes the magnitude of shift between Q(0e0)
chloroform solutions using a 1 cm cuvette and a 1 nm slit width.
ꢀ
6
ꢀ4
Solutions were made at concentrations 10 M and 10 M for Soret
band and Q bands regions, respectively.
Table 2 shows data concerning spectral properties of all the
synthesized porphyrin derivatives. They are very similar to those of
known tetrakisphenylporphyrin with a Soret band at 420 nm, and
four less intense Q bands around 520, 550, 590 and 650 nm [18].
Particular compounds show minute differences between maxima
and intensities of absorption bands.
Comparison of the porphyrins’ spectra leads to the conclusion
that they are not affected by the type and nature of the long alkyl
chain in the molecule.
x
band of the fluorescence spectrum and Q (0e0) band of the ab-
sorption spectrum are minute in the case of the compounds studied
and this likely reflects minor structural alterations occurring in
porphyrin molecules upon excitation [20].
3.6. Triplet state lifetimes and singlet oxygen quantum yields
Table 2 also shows spectrum of chlorin 2 which basically does
not differ from the remaining studied compounds. The greatest
Table 4 shows data concerning the most important photo-
chemical parameters from the standpoint of PDT usefulness. They
change in the spectrum concerns intensity of the last Q
x
(0e0) band.
are triplet state lifetimes (
and presence of oxygen and singlet oxygen quantum yields (F
s
T
) of the photosensitizer in the absence
).
3.5. Fluorescence spectra
D
The triplet lifetimes for the investigated compounds were deter-
mined using laser flash photolysis spectrometry. Absorbance of the
solutions was in the 0.2e0.3 range at 355 nm. The maximum of
Fluorescence experiments were performed at room temperature
using Eclipse Cary (Varian) spectrofluorimeter. For fluorescence

634
M. Rojkiewicz et al. / Dyes and Pigments 99 (2013) 627e635
There are numerous methods available to determine quantum
field of singlet oxygen; these were discussed in [14].
In our experiments the singlet oxygen quantum yields were
determined using laser flash photolysis spectroscopy. The proce-
dure employs values of oxygen luminescence measured by
different laser energies for sample and standard (Fig. 6). The sample
and standard absorbance were adjusted to 0.2. The characteristic
singlet oxygen phosphorescence was observed at 1270 nm after
laser pulse. The oxygen luminescence intensities were extrapolated
to time-zero and the singlet oxygen quantum yields were deter-
mined from the ration of the slopes obtained for investigated
compound and standard. Whole procedure is described in litera-
ture [22]. Phenalenone and tetrakisphenylporphyrin were used as
reference and their singlet oxygen quantum yields are 0.95 and 0.7,
respectively [14].
As can be seen from Table 4 quantum yields of singlet oxygen are
comparable for all the porphyrins studied as well as with such yield
for Foscan. As can be noticed, presence of additional substituents in
phenyl fragments does not influence the process of energy transfer
from photosensitizer to oxygen molecules. Quantum yield of singlet
oxygen (0.59) reported in the literature for Foscan [23] is comparable
to that determined in our study (0.57) and to that of Photofrin 0.2
Fig. 4. Absorption and emission spectra of compound 8.
[
24]. It can be thus deduced that the studied porphyrins meet
tripletetriplet absorption was determined from transient absorp-
tion measurement (for the investigated compounds the triplete
triplet transition maximum was in the 440e470 nm range). The
triplet lifetimes were determined for aerated and deaerated sam-
ples. After sample excitation the decay curves were observed
necessary requirements for potential photosensitizers useful for PDT.
3
.7. Photostability
(
Fig. 5). All decays were fitted to monoexponential which is in
This is an additional important parameter of any potential
agreement with literature data [21].
photosensitizer. It should be stable in the dark. Upon light exposure
it should go into an excited state, transfer its energy to neighboring
molecules (for example oxygen) and return to ground state. It can
so happen that as a result of such processes photosensitizer
molecule will be degraded and shall lose its photosensitizing
properties. Such process can be influenced by numerous external
factors such as the solvent, substituents present or the compound’s
aggregation. In our study we determined stability of synthesized
compound by using UVeVis spectroscopy. We measured Soret
band and Q bands absorbance values prior to and after light irra-
diation. Dose and dose rate of irradiation were chosen in such a way
as to correspond to values that may occur in a biological setting. It
turns out that all of the synthesized compounds are stable under
such conditions. Only in the case of compound 2 loss of absorbance
was observed after irradiation but after 60 min the absorbance was
still at 90% level of the initial value. Photosensitizer solutions were
In order for the compound to be a good photosensitizer it should
have high quantum yield of triplet state lifetime. A compound that
remains in the triplet state for a relatively long time can transfer its
energy to other molecules present in the vicinity; in case of PDT
these are oxygen molecules which, as a result of this process
become the actual therapeutic agent.
Table 4 lists triplet state lifetimes for particular compounds; the
lifetimes are averaged from ten measurements. Extended triplet
state lifetimes are noted for lack of oxygen presence conditions
which suggests effective quenching of triplet states by oxygen when
present in the sample at the time of measurement. Also in this case
it can be seen that triplet state lifetimes for the majority of obtained
compounds are distinctively longer than that for Foscan (2).
Fig. 5. Triplet state decay curves: aerated and deaerated.
Fig. 6. Dependence of oxygen luminescence and laser energies.

M. Rojkiewicz et al. / Dyes and Pigments 99 (2013) 627e635
635
ꢂ
kept in the dark (4 C) for 30 days and no decay in absorbance
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Photophysical properties of 5,10,15,20-tetrakis(m-hydroxyphenyl)porphyrin
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conditions the examined compounds were stable and probably did
not undergo aggregation.
(m-THPP), 5,10,15,20-tetrakis(m-hydroxyphenyl)chlorine (m-THPC) and
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. Conclusion
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manganeseemesoporphyrin with oleic acid vesicles. Biochemistry 1995;34:
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use in PDT or PDD. Their photochemical properties are akin to those
of tetrakis(3-hydroxyphenyl)-porphyrin, the source compound of
Foscan, widely used in PDT. Our further studies upon these com-
pounds will likely involve synthesis of chlorin and bacteriochlorin
derivatives. So far we were able to obtain two such derivatives but
as an isomer mixtures. In the case of single substitution of the
starting symmetrical porphyrins one obtains two different com-
pounds which are very often difficult to separate. Further studies
involving choice of suitable liposomal formulations for biological
transfer of the obtained photosensitizers are underway.
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in CTAB micelles. Journal of Colloid and Interface Science 2008;322:281e6.
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Acknowledgments
This research was partially supported by the Polish State Com-
mittee for Scientific Research (Grant No R 0504303). The work of
two authors (Patrycja Kozub and Marta Kempa) was partially
supported by the scholarships within the framework of the TWING
project co-financed by the European Social Fund.
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Part 1. Tetra-(Hydroxyphenyl)Porphyrins with long alkyl chain in the mole-
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