Carbohydrate-porphyrin conjugates with two-photon absorption properties as potential photosensitizing agents for photodynamic therapy

Article abstract of DOI:10.1002/ejoc.201001209

We report the synthesis of a series of conjugated zinc porphyrin oligomers designed as photodynamic therapy agents. These compounds exhibit exceptionally high two-photon absorption cross-sections, redshifted linear absorption spectra, and high singlet oxy

Full text of DOI:10.1002/ejoc.201001209

FULL PAPER
DOI: 10.1002/ejoc.201001209
Carbohydrate–Porphyrin Conjugates with Two-Photon Absorption Properties
as Potential Photosensitizing Agents for Photodynamic Therapy
Sylvain Achelle,[a,b] Pierre Couleaud,[c] Patrice Baldeck,[d] Marie-Paule Teulade-Fichou,[a,b]
and Philippe Maillard*[a,b]
Keywords: Porphyrinoids / Photodynamic therapy / Two-photon absorption / Carbohydrates / Conjugation
We report the synthesis of a series of conjugated zinc por-
phyrin oligomers designed as photodynamic therapy agents.
These compounds exhibit exceptionally high two-photon ab-
sorption cross-sections, redshifted linear absorption spectra,
and high singlet oxygen quantum yields, making them ideal
for one-photon- and two-photon-excited photodynamic ther-
apy. These products are substituted by three α-mannose units
on each chromophore with the aim to target tumor cells with
over-expressing lectin-type membrane receptors.
either by a redshifted absorbing PS, by exciting the PS using
sequential discrete absorption (up-conversion), or by simul-
taneous two-photon absorption (TPA).[4] In this nonlinear
optical process, two photons of lower excitation energy
whose combined energy is sufficient to induce the transition
are simultaneously absorbed. The real advantage is that the
excitation in the near-infrared (NIR) region avoids tissue
absorbing or scattering and induces a deeper light penetra-
tion in the tissue. Consequently, it is a better treatment for
deep or large-sized tumors. Porphyrin compounds have a
strong one-photon absorption between 400 and 500 nm
(Soret band) corresponding to the combined energy of two
photons in the wavelength range from 800 to 1000 nm. This
is just within the biological optical window. Because por-
phyrin monomers exhibit relatively small TPA values using
femtosecond pulse lasers (less than 50 GM where 1 GM =
10–50 cm4 smolecule–1),[5] dimers and oligomers of conju-
gated porphyrins have been shown to exhibit very strong
TPA with δmax values up to 500 times those of monomeric
analogues.[6] To obtain conjugated porphyrin oligomers,
monomers should be linked with bridges that do not twist
out of plane with the porphyrin macrocycle. Because of
steric hindrance, alkynyl bridges are one of the most effec-
tive ways of making connections to the meso position of a
porphyrin. Indeed, butadiyne,[7] diethynylbenzene,[8] dieth-
ynylthiophene,[9] diethynylanthracene,[10] diethynyltetra-
Introduction
Photodynamic therapy (PDT) is a promising light-acti-
vated treatment that is used clinically to destroy locally dis-
eased tissues.[1] When exposed to light, the photosensitizer
(PS) transfers its excitation energy to ground-state triplet
oxygen to generate highly reactive singlet oxygen and other
cytotoxic reactive oxygen species, inducing oxidative dam-
age to the cell that causes localized cell death and ultimately
tissue apoptosis or necrosis. A major advantage of PDT in
comparison with other treatments such as chemotherapy is
that, in the absence of light, the PS is benign.
The most common photosensitizers used in PDT are
porphyrin compounds thanks to their long triplet excited-
state lifetime.[2] Amongst them, Photofrin currently used in
the clinic has one-photon absorption peaks in the visible
wavelength range. However due to the significant absorp-
tion in this region by biological tissues, this PS cannot be
used to treat deep cancers. Designing a PS excitable in the
near-infrared or infrared region between 700–1100 nm may
reduce this limitation, as the absorption and diffusion of
tissues are much lower in this range currently named the
optical window of biological tissues.[3] This can be achieved
[a] UMR 176 CNRS/Institut Curie, Institut Curie, Bât 110, Univ.
Paris-Sud,
91405 Orsay, France
[b] Institut Curie, Section de Recherches, Centre Universitaire, thiafulvalene,[11] diethynylsquaraine,[12] and triethynylphen-
ylamine[13] π-conjugated cores have been described in the
Univ. Paris-Sud,
91405 Orsay, France
literature. Recently, in vivo experiments have shown that
PDT performed with PS exhibiting high TPA was able to
treat tumors more than 0.8 cm in diameter with a total irra-
diation time of less than 30 min. Excellent regression or to-
tal disappearance of the tumor was observed during the
week following the treatment.[14] TPA PDT should allow
greater precision than is achieved by conventional one-pho-
[c] Laboratoire Réactions et Génie des Procédés, UPR 3349,
Nancy Université,
1 rue Grandville, B. P. 20451, 54001 Nancy, cedex, France
[d] Laboratoire de Spectrométrie Physique, UMR 5588, Université
Joseph Fourier/CNRS,
140 rue de la physique, B.P. 87, 38402 Saint Martin d’Hères,
cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001209.
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FULL PAPER
ton excitation, as a consequence of the quadratic depen-
dence of two-photon excitation on the local light inten-
sity.[15]
Results and Discussion
Porphyrin 5 (Scheme 1) bearing a protected ethynyl
Another limitation of PDT is the low selectivity and group is the key parent molecule for the synthesis of conju-
specificity of the PS for tumor cells. High doses of the drug gated zinc porphyrin oligomers 1–4 (Figure 1). Porphyrin 5
and light are thus required to compensate for this, leading was obtained in five steps starting from trisubstituted por-
to the damage of healthy tissues. Active targeting of mem- phyrin 6 (Scheme 1).[22] The first step involved deprotection
brane receptors represents an obvious improvement.[16] with the removal of the two isopropyloxy groups with BBr3
However, only a few examples of cell-targeted TPA PSs are (85%). The second step was a Williamson reaction with
described in the literature.[14,17] It has been reported that 2-bromoethoxy-O-2Ј,3Ј,4Ј,6Ј-tetraacetyl-α-d-mannose[23]
lectin-type receptors are over-expressed in certain malig- leading to glycoconjugated porphyrin 8 with a moderate
nant cells[18] and that carbohydrates such as α-mannose and yield (58%). Then, monobromination with N-bromosuc-
β-galactose have a specific interaction with these recep- cinimide (NBS) followed by metalation with zinc acetate
tors.[19] For over a decade we have focused our efforts on the quantitatively afforded zinc porphyrin 10. Sonogashira
preparation, as well as, the in vitro and in vivo evaluation of cross-coupling with trimethylsilylacetylene (TMSA), led to
the phototoxicity of glycoconjugated tetrapyrrolic macro- porphyrin 5 in good yield (92%).
cycles. Several of our studies have contributed to establish
Oligomer synthesis started with the deprotection of the
trimethylsilyl group of monomer 5 with tetrabutylammo-
the proof of the concept.[20,21]
The aim of the present article is to describe the synthesis nium fluoride (TBAF)[24] leading to compound 11, which
of new α-mannose-conjugated zinc porphyrin oligomers was not isolated due to its instability, and was immediately
having remarkable TPA as well as singlet oxygen generating engaged in the following reaction (Scheme 2). Butadiyne
properties. Various neutral π-conjugated cores, ethynyl, but- core dimer 1 was obtained by Glaser–Hay oxidative cou-
adiyne, diethynylbenzene, and electron-donor triphenyl- pling in good yield (72%). Dimers 2 and 3 as well as trimer
amine, have been incorporated between porphyrin moieties. 4 were obtained by Heck cross-coupling reactions with the
Using a convergent pathway, this has led to the synthesis of corresponding halogenated derivatives in moderate to good
four linear (dimeric) and octupolar (trimeric) structures yields (31, 42, and 80%, respectively). Deprotection of com-
(i.e., 1–4) from a single parent molecule (i.e., 5).
pounds 1 and 4 (Scheme 3), selected among the four oligo-
Scheme 1. Reagents and conditions: (i) BBr3, CH2Cl2, 15 h, room temp., 85%; (ii) 2-bromoethoxy-O-2Ј,3Ј,4Ј,6Ј-tetraacetyl-α-d-mannose,
Cs2CO3, dimethylformamide (DMF), 60 °C, 15 h, 58%; (iii) NBS, pyridine, CHCl3, 15 min, 0 °C, 97%; (iv) Zn(OAc)2, CHCl3/MeOH,
5 min, Δ, 99%; (v) TMSA, CuI, Pd(PPh3)2Cl2, tetrahydrofuran (THF)/triethylamine (Et3N), 15 h, 78°K Ǟ room temp., 92%.
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Carbohydrate–Porphyrin Conjugates for Photodynamic Therapy
Figure 1. Structures of conjugated zinc porphyrin oligomers.
mers because of their ease of synthesis, was carried out
using Zemplén conditions[25] and led to compounds 12 and
1
13 in 73 and 85% yield, respectively. H NMR, 13C NMR,
and, UV/Vis spectroscopy, MALDI-TOF analyses, and
microanalyses were used to characterize compounds 1–4.
Assignments of the resonance to individual protons were
based on integration and selective homonuclear correlation
(COSY). Heteronuclear multiple coherence (HMQC,
HMBC) spectra were obtained for all compounds and the
carbon resonances were assigned. Due to insolubility, we
were unable to record any interpretable NMR spectra for
compounds 12 and 13.
All photophysical analyses were carried out with pro-
tected compounds due to the low solubility of the depro-
tected derivatives. It was assumed that their optical proper-
ties were similar in the absence of aggregation. Figure 2
shows the one-photon UV/Vis absorption spectra of oligo-
mers 1–4 and corresponding monomer 5 in CH2Cl2. As ex-
pected based upon literature precedence,[6,26] for all oligo-
meric compounds the typical Soret band (around 400–
440 nm) is remarkably broadened in comparison to that of
the monomer with absorption maxima at similar wave-
lengths Ϫ or slightly redshifted. Also as expected for oligo-
Scheme 2. Reagents and conditions: (i) TBAF, THF/CH2Cl2, room
temp., 30 min, not isolated. (ii) CuCl, tetramethylethylenediamine
(TMEDA), CH2Cl2, room temp., 20 min, 72% in two steps. (iii) p-
diiodobenzene, AsPh3, Pd2(dba)3, THF/Et3N, Δ, 15 h, 31%.
(iv) tris(4-iodophenyl)amine, AsPh3, Pd2(dba)3, THF/Et3N, Δ, 15 h,
80%. (v) 10, AsPh3, Pd2(dba)3, THF/Et3N, Δ, 15 h, 42%.
meric structures, the Q-Bands (590–690 nm range) of the nificantly higher (2- to 5-fold) than that of the monomer.
oligomer compounds were stronger, as the molar absorp- In addition, the lowest-energy vibronic shoulder was red-
tion coefficient of the conjugated dimers (Table 1) was sig- shifted, especially in the case of dimer 1 compared to mono-
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Figure 2. Normalized absorption of monomer 5 and oligomers 1–
4 in CH2Cl2 (6ϫ10–6 to 2ϫ10–5 m).
Table 1. Photophysical parameters of porphyrins: monomer 5 and
oligomers 1–4 in CH2Cl2.[a]
λabs
[nm]
ε
λem
ΦF ΦΔ TPA λmax δmax
[10–3 M–1cm–1] [nm]
[nm]
(GM)
5
1
432
566
611
470
15
13
630
679
0.14 nd
0.07 0.75
790
50
419
450
481
565
630
677
215
244
157
22
35
48
619
712
790
8000
2
3
446
570
640
294
19
44
655
707
0.10 0.61
0.08 0.43
820
790
260
Scheme 3. Reagents and conditions: (i) NaOMe/MeOH, THF,
room temp., 1 h.
424
450
481
558
631
677
242
168
111
20
23
31
4200
mer 5. As described above, the ground-state absorptions of
oligomers differ remarkably from that of the reference
monomer, indicating a higher conjugation of the former.
The absorption of the conjugated dimers (Table 1) com-
pares favorably with the well-known PDT sensitizers, for
example, ε ≈ 4ϫ104 cm–1 m–1 for Foscan at 654 nm, for
chlorin e6 at 664 nm, and for verteporfin at 690 nm.[27]
The large NIR extinction coefficients of new oligomers
1–4 indicate that they have potential as one-photon PDT
agents. UV/Vis spectra of deprotected compounds 12 and
13 were recorded in a mixture of polyethyleneglycol
(PEG)400/EtOH/H2O (3:2:5), the mixture generally used
for in vivo injection of PS.[21b,28] The spectra obtained,
4
440
573
632
535
36
88
647
698
0.05 0.47
790
1300
[a] λabs = absorption peak wavelength; ε = molar extinction coeffi-
cient; λem = emission peaks (λexc = 450 nm); ΦF = emission quan-
tum yield vs. Rhodamine 101 in ethanol (1.00);[1] ΦΔ = singlet oxy-
gen quantum yield vs. tetraphenylporphyrin (0.60);[26] TPA λmax
=
wavelength for which the highest recorded TPA cross-section is ob-
tained; δmax = TPA cross-section.
characteristic of monomer species, were similar to the corre- This is a good indication for a favored intersystem crossing
sponding protected derivatives with a small solvatochromic (ISC) de-excitation pathway. Monomer 5 and trimer 4 exhi-
effect and molar extinction coefficients in the same range bit two emission bands that are shifted to the red in the
(see Supporting Information).
case of 4. In the case of compound 1, two emission bands
Emission spectra of monomer 5 and oligomers 1–4 in are observed at 619 and 712 nm. On the basis of reports of
CH2Cl2 are presented in Figure 3 and photophysical pa- similar dimers, these two emission peaks can be assigned to
rameters are summarized in Table 1. Interestingly, the fluo- the two excited-state conformations of 1, defined by dif-
rescence quantum yield (ΦF) of the four oligomers is signifi- ferent torsional angles around the central butadiyne
cantly lower (1.5–2-fold) than that of monomer 5 (0.14). bridge.[29]
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Carbohydrate–Porphyrin Conjugates for Photodynamic Therapy
Conclusions
In summary we have described the synthesis of four
carbohydrate–porphyrin oligomers. The high TPA efficienc-
ies of these compounds at wavelengths within the optical
window of biological tissues, combined with their high sing-
let oxygen quantum yields, highlights the potential of these
products as promising PS for two-photon excited PDT to
treat tumor cells with overexpressing lectin-type receptors.
Evaluation of the in vitro phototoxicity of free glycoconju-
gated PS is currently in progress.
Experimental Section
Figure 3. Normalized emission spectra of monomer 5 and oligo-
mers 1–4 in CH2Cl2 (6ϫ10–6 to 2ϫ10–5 m; λexc = 450 nm).
General Methods: All solvents were reagent grade. The starting ma-
terials were acquired from Sigma–Aldrich and used without purifi-
cation. Tris(4-iodophenylamine) was acquired from TCI Europe
and used without purification. Dry MeOH was kept over 3 Å mo-
lecular sieves, and dichloromethane (DCM) was distilled from cal-
cium hydride and kept over 4 Å molecular sieves. DMF was dis-
tilled under slow argon flow and kept over 4 Å molecular sieves.
Dry, amine-free DMF was obtained by bubbling with argon for
30 min. Column chromatography was performed with the indicated
solvents using E. Merck silica gel 60 (particle size 0.035–0.070 mm).
Macherey–Nagel precoated plates (SIL G-200, 2 mm) were used
for preparative thin-layer chromatography. Yields refer to chro-
matographically and spectroscopically pure compounds. 1H and
13C NMR spectra were recorded at 300 and 75.3 MHz, respectively,
with a Bruker AC-300 spectrometer at ambient temperature by
using an internal deuterium lock. Chemical shift values are given
in ppm relative to tetramethylsilane (TMS). Acidic impurities in
CDCl3 were removed by treatment with anhydrous K2CO3. Quanti-
tative UV/Vis spectra were recorded with a UVIKON xm SECO-
MAM spectrometer. Fluorescence spectra were recorded by using
a Spex FluoroMax-3 Jobin–Yvon Horiba apparatus. Microanalyses
were obtained from ICSN-CNRS Elemental Analysis Centre at
Gif-sur-Yvette, France. MALDI-TOF mass spectra were performed
with a MALDI-TOF Voyager Spec equipped with a N2 Laser emit-
The singlet oxygen quantum yields of all porphyrin
oligomers in dichloromethane have been determined after
one-photon excitation and are given in Table 1. High O2
1
quantum yields (ΦΔ from 0.43 up to 0.75) were obtained.
These values, measured in organic solvent with protected
glycosylated compounds 1–4, are highly encouraging for fu-
ture use in PDT, even if values in water for deprotected
compounds will probably be lower.
TPA cross-sections of monomer 5 and oligomers 1–4
were established by detecting the up-converted fluorescence
following excitation between 790 and 950 nm (Table 1). The
dependence of the fluorescence intensity on the power was
almost quadratic rather than linear, indicating that the val-
ues obtained are mainly due to TPA. As expected, high TPA
cross-sections were obtained for porphyrin oligomers, in
particular for dimers 1 and 3 and trimer 4 (8000, 4200 and
1300 GM, respectively). These values are considerably
higher than that of monomer 5 (50 GM), validating the ting at 337 nm. The TPA cross-sections in the range 750–950 nm
oligomeric design.[6] In addition, this indicates that the pres-
were obtained by up-conversion fluorescence by using a mode
locked Ti/sapphire femtosecond laser (Tsunami Spectra-Physics)
ence of the protected carbohydrate units does not signifi-
with a pulse duration of 100 fs and at a repetition rate of 82 MHz.
cantly affect the capacity of the structure for TPA. The
The measurements were obtained at room temperature in DCM
comparison of the four oligomer compounds shows that
and a concentration of approximately 5ϫ10–6 to 10–5 m. The exci-
ethynyl and butadiyne linkers are the most efficient in terms
tation beam (5 mm diameter) was focused with a lens (focal length
of TPA. This is consistent with the literature data that em-
10 cm) at the middle of the fluorescence cell (10 mm). The fluores-
phasizes the importance of electronic conjugation between
cence, collected at 90° to the excitation beam, was focused into an
the two porphyrin units.[26] Indeed, compound 2 displays a
optical fiber (diameter 600 μm) connected to an Ocean Optics
dramatic decrease in TPA cross-sections as compared to di-
mers 1 and 3, probably due to the nonplanarity of the two 50 mW to ensure an intensity-squared dependence of the fluores-
S2000 spectrometer. The incident beam intensity was adjusted to
cence over the whole range. The detector integration time was fixed
to 1 s. The spectra were compared with the published Fluorescein
and Rhodamine B two-photon absorption spectra.[30] One-photon
singlet oxygen (1O2) generation was detected by its phosphores-
cence at 1270 nm through a PTI S/N 1565 monochromator, and
the emission was monitored by a liquid nitrogen-cooled Ge-detec-
tor model (EO-817L, North Coast Scientific Co). Excitation oc-
curred with a Xe-arc; the light was separated in a SPEX 1680,
0.22 μm double monochromator. The 1O2 quantum yields (ΦΔ)
were calculated by a comparative method using tetraphenylpor-
phyrin in DCM (ΦΔ = 0.60) as a standard.[26]
porphyrin moieties providing lower conjugation within the
structure. Finally trimeric scaffold 4, although showing a
strong enhancement in TPA cross-sections compared to the
monomer, appears less efficient than dimers 1 and 3. This
could be attributed to the propeller shape of the tri-
phenylamine core, which is less favorable to electronic con-
jugation between the porphyrin units. The TPA cross-sec-
tions of this series of conjugated porphyrin oligomers com-
pare favorably with the values of other potential photosen-
sitizers designed for two-photon excited PDT.[7d]
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5,10,15-Tri(4-hydroxyphenyl)porphyrin (7): A solution of 5,15-bis(4-
(C-3Ј), 68.6 (C-5Ј), 66.9 (CH2α), 66.7 (CH2β), 66.1 (C-4Ј), 62.4 (C-
isopropyloxyphenyl)-10-(4-hydroxyphenyl)porphyrin
(800 mg,
6Ј), 20.8 (CH3, acetyl), 20.7 (CH3, acetyl), 20.62 (CH3, acetyl),
1.19 mmol) in DCM (100 mL) was cooled to –20 °C before ad-
dition of boron tribromide (2.26 mL, 23.8 mmol). After 15 min, the
cold bath was removed and stirring was continued for 15 h at room
temperature. The green mixture was poured into a water/ice mix-
ture and neutralized with ammonia. DCM was removed by evapo-
ration, and the porphyrin was extracted with ethyl acetate
(4ϫ100 mL). The combined organic extracts were washed with di-
luted ammonia and water and then dried with Na2SO4. After fil-
tration, much of the ethyl acetate was removed by evaporation, n-
heptane was added, and a precipitate formed. Compound 7
(595 mg, 1.01 mmol, 85%) was collected by filtration as a purple
solid. C38H26N4O3 (586.65): calcd. C 77.80, H 4.47, N 9.55; found
C 77.69, H 5.14, N 8.74. UV/Vis (acetone): λmax (ε, Lmmol–1 cm–1)
= 412 (420), 509 (15.3), 545 (7.8), 586 (4.5), 642 (3.3) nm. 1H NMR
([D6]DMSO): δ = 10.42 (s, 1 H, 20-H), 9.94 (s, 3 H, OH), 9.52 (d,
J = 4.8 Hz, 2 H, 2-H and 18-H), 8.98 (d, J = 4.8 Hz, 2 H, 3-H and
17-H), 8.89 (d, J = 4.8 Hz, 2 H, 7/8-H and 12/13-H), 8.86 (d, J =
4.8 Hz, 2 H, 7/8-H and 12/13-H), 8.00 (d, J = 8.4 Hz, 4 H, o-
phenol-H), 7.96 (d, J = 8.4 Hz, 2 H, o-phenol-H), 7.20 (d, J =
8.4 Hz, 4 H, m-phenol-H), 7.16 (d, J = 8.4 Hz, 4 H, m-phenol-H),
–3.15 (s, 2 H, NH) ppm. 13C NMR ([D6]acetone): δ = 159.43 (C-
p-phenol), 159.37 (C-p-phenol), 148.7–148.0 (C-1, C-4, C-6, C-9,
C-11, C-14, C-16, and C-19), 137.6 (C-o-phenol), 137.4 (C-o-phen-
ol), 135.5 (C-1-phenol), 134.6 (C-1-phenol), 131.3–129.6 (C-2, C-3,
C-7, C-8, C-12, C-13, C-17, and C-18), 122.6, (C-10), 121.5 (C-
5 and C-15), 115.8 (C-m-phenol), 115.6 (C-m-phenol), 106.5 (C-
20) ppm.
20.59 (CH3, acetyl) ppm.
20-Bromo-5,10,15-tri{p-O-[2-O-(2Ј,3Ј,4Ј,6Ј-tetraacetyl-α-D-
mannosyloxy)ethoxy]phenyl}porphyrin (9): NBS (16.40 mg,
0.092 mmol) was added to a solution of 8 (150 mg, 0.088 mmol) in
a mixture of chloroform (35 mL) and pyridine (0.25 mL) at 0 °C.
The mixture was stirred at this temperature for 15 min. The reac-
tion was quenched with acetone, and the solvents were evaporated
under vacuum. The crude product was washed with water to give
9 (152 mg, 0.085 mmol, 97%) as a purple solid. UV/Vis (DCM):
λmax (ε, Lmmol–1 cm–1): 422 (384), 519 (15.9), 557 (10.6), 597 (4.95),
1
655 (4.74) nm. H NMR (CDCl3): δ = 9.66 (d, J = 4.6 Hz, 2 H, 2-
H, and 18-H), 8.93 (d, J = 4.6 Hz, 2 H, 2-H and 18-H), 8.82 (s, 4
H, 7-H, 13/8-H, and 12-H), 8.09 (d, J = 8.0 Hz, 6 H, o-phenoxy-
H), 7.26 (d, J = 8.0 Hz, 6 H, m-phenoxy-H), 5.50 (m, 3 H, 3Ј-H),
5.43 (m, 3 H, 2Ј-H), 5.39 (m, 3 H, 4Ј-H), 5.09 (s, 3 H, 1Ј-H), 4.42
(m, 9 H, 6Ј-H and CH2α), 4.32–4.20 (m, 9 H, 6Ј-H and CH2β),
4.05 (m, 3 H, 5Ј-H), 2.23 (s, 9 H, AcO), 2.18 (s, 9 H, AcO), 2.08
(s, 9 H, AcO), 2.05 (s, 9 H, AcO), –2.72 (s, 2 H, NH) ppm. 13C
NMR (CDCl3): δ = 171.2 (C=O, acetyl), 170.6 (C=O, acetyl), 170.4
(C=O, acetyl), 170.3 (C=O, acetyl), 158.9 (C-p-phenoxy), 148.2–
143.9 (C-2, C-3, C-7, C-8, C-12, C-13, C-17, and C-18), 136.1 (C-
1-phenoxy), 136.0 (C-1-phenoxy), 135.2 (C-1-phenoxy), 135.0 (C-
1-phenoxy), 132.3–132.1 (C-1, C-4, C-6, C-9, and C-11), 121.1 (C-
10), 120.8 (C-5 and C-15), 113.3 (C-m-phenoxy), 103.0 (C-20), 98.3
(C-1Ј), 70.1 (C-2Ј), 69.6 (C-3Ј), 69.2 (C-5Ј), 67.4 (CH2α), 67.2
(CH2β), 66.6 (C-4Ј), 63.0 (C-6Ј), 21.4 (CH3, acetyl), 21.3 (CH3,
acetyl), 21.21 (CH3, acetyl), 21.20 (CH3, acetyl) ppm.
20-Bromo-5,10,15-tri{p-O-[2-O-(2Ј,3Ј,4Ј,6Ј-tetraacetyl-α-D-
5,10,15-Tri{p-O-[2-O-(2Ј,3Ј,4Ј,6Ј-tetraacetyl-α-
ethoxy]phenyl}porphyrin (8): A mixture of 7 (232 mg, 0.395 mmol),
2-bromoethoxy-O-2Ј,3Ј,4Ј,6Ј-tetraacetyl-α-d-mannose (2.34 g,
D-mannosyloxy)-
mannosyloxy)ethoxy]phenyl}porphyrinatozinc(II) (10): Zinc acetate
(78 mg, 0.425 mmol) was diluted in methanol (45 mL) and added
to a solution of 9 (152 mg, 0.085 mmol) in chloroform (90 mL).
The mixture was heated to reflux for 5 min. After cooling, the sol-
vents were evaporated under vacuum, and a mixture of water and
DCM (100 mL, 1:1) was added. The organic layer was separated,
washed with water (2ϫ50 mL), and dried with Na2SO4. Filtering
followed by evaporation of the solvents under vacuum gave the
crude product. Crystallization (AcOEt/n-heptane) yielded 10
(156 mg, 0.084 mmol, 99%) as a purple solid. C86H89BrN4O33Zn
(1851.95): calcd. C 55.77, H 4.85, N 3.03; found C 55.46, H 5.20,
N 2.85. UV/Vis (DCM): λmax (ε, Lmmol–1 cm–1): 425 (415), 558
5.14 mmol), and cesium carbonate (4.12 g, 12.7 mmol) in dry DMF
(60 mL) was stirred under argon at 60 °C overnight. The mixture
was concentrated under vacuum, a mixture of water and ethyl acet-
ate (2:1, 150 mL) was added, and the organic layer was separated.
The aqueous layer was extracted with ethyl acetate (3ϫ50 mL).
The combined organic extracts were washed with water
(2ϫ50 mL), dried with Na2SO4, and filtered, and the solvent was
evaporated under vacuum. The product was partially purified by
crystallization (3ϫ, DCM/n-heptane) and preparative TLC (silica;
DCM/acetone, 9:1). Another crystallization (DCM/n-heptane) pro-
1
(16.1), 600 (7.9) nm. H NMR (CDCl3): δ = 9.73 (d, J = 4.5 Hz, 2
duced
8 (392 mg, 229 mmol, 58%) as a deep red solid.
H, 2-H and 18-H), 9.01 (d, J = 4.6 Hz, 2 H, 2-H and 18-H), 8.92
(s, 4 H, 7-H, 13-H, 8-H, and 12-H), 8.09 (d, J = 8.1 Hz, 6 H, o-
phenoxy-H), 7.26 (d, J = 8.1 Hz, 6 H, m-phenoxy-H), 5.46–5.43
(m, 3 H, 3Ј-H), 5.37–5.33 (m, 3 H, 2Ј-H), 5.32–5.31 (m, 3 H, 4Ј-
H), 5.02 (s, 3 H, 1Ј-H), 4.42–4.31 (m, 9 H, 6Ј-H and CH2α), 4.28–
4.15 (m, 9 H, 6Ј-H and CH2β), 4.07–4.03 (m, 3 H, 5Ј-H), 2.14 (s,
9 H, AcO), 2.12 (s, 9 H, AcO), 2.03 (s, 9 H, AcO), 1.97 (s, 9 H,
AcO) ppm. 13C NMR (CDCl3): δ = 170.7 (C=O, acetyl), 170.1
(C=O, acetyl), 169.9 (C=O, acetyl), 169.9 (C=O, acetyl), 158.2 (C-
p-phenoxy), 150.9 (C-4, C-16/6, C-14/9, and C-11), 150.8 (C-4, C-
16/6, C-14/9, and C-11), 150.7 (C-4, C-16/6, C-14/9, and C-11),
149.6 (C-1 and C-19), 135.6 (C-o-phenoxy), 135.5 (C-o-phenoxy),
135.4 (C-1-phenoxy), 133.1–132.1 (C-2, C-3, C-7, C-8, C-12, C-13,
C-17 and C-18), 121.3 (C-10), 121.1 (C-5 and C-15), 112.6 (C-m-
phenoxy), 104.0 (C-Br), 97.8 (C-1Ј), 69.6 (C-2Ј), 69.1 (C-3Ј), 68.7
(C-5Ј), 66.9 (CH2β), 66.7 (CH2α), 66.1 (C-4Ј), 62.5 (C-6Ј), 20.9
(CH3, acetyl), 20.8 (CH3, acetyl), 20.73 (CH3, acetyl), 20.69 (CH3,
acetyl) ppm.
C86H92N4O33·6H2O (1709.66 + 6 H2O): calcd. C 56.82, H 5.77,
N 3.08; found C 57.19, H 5.54, N 2.72. UV/Vis (DCM): λmax (ε,
Lmmol–1 cm–1) = 415 (355), 509 (16.7), 545 (7.3), 586 (5.2), 642
1
(3.2) nm. H NMR (CDCl3): δ = 10.19 (s, 1 H, 20-H), 9.33 (d, J =
4.6 Hz, 2 H, 2-H and 18-H), 9.04 (d, J = 4.6 Hz, 2 H, 2-H and 18-
H), 8.91 (d, J = 4.6 Hz, 2 H, 7-H, 13/8-H, and 12-H), 8.89 (d, J =
4.6 Hz, 2 H, 7-H, 13/8-H, and 12-H), 8.15 (d, J = 8.0 Hz, 2 H, o-
phenoxy-H), 8.13 (d, J = 8.0 Hz, 4 H, o-phenoxy-H), 7.31 (d, J =
8.7 Hz, 4 H, m-phenoxy-H), 7.28 (d, J = 8.7 Hz, 2 H, m-phenoxy-
H), 5.49 (m, 3 H, 3Ј-H), 5.43 (m, 3 H, 2Ј-H), 5.38 (m, 3 H, 4Ј-H),
5.09 (s, 3 H, 1Ј-H), 4.46 (m, 9 H, 6Ј-H and CH2α), 4.27–4.22 (m,
9 H, 6Ј-H and CH2β), 4.11 (m, 3 H, 5Ј-H), 2.23 (s, 9 H, AcO), 2.17
(s, 9 H, AcO), 2.06 (s, 9 H, AcO), 2.04 (s, 9 H, AcO), –2.97 (s, 2
H, NH) ppm. 13C NMR (CDCl3): δ = 170.6 (C=O, acetyl), 170.0
(C=O, acetyl), 169.8 (C=O, acetyl), 169.7 (C=O, acetyl), 158.3 (C-
p-phenoxy), 147.5–146.3 (C-1, C-4, C-6, and C-9), 135.6 (C-o-phen-
oxy), 135.43 (C-o-phenoxy), 135.36 (C-1-phenoxy), 134.5 (C-1-
phenoxy), 131.3–131.0 (C-2, C-3, C-7, C-8, C-12, C-13, C-17, and
C-18), 120.1 (C-10), 119.0 (C-5 and C-15), 112.8 (C-m-phenoxy), (5,10,15-Tri{p-O-[2-O-(2Ј,3Ј,4Ј,6Ј-tetraacetyl-α-
D-mannosyloxy)-
112.5 (C-m-phenoxy), 105.0 (C-20), 97.7 (C-1Ј), 69.5 (C-2Ј), 69.0 ethoxy]phenyl}-20-trimethylsilylethenylporphyrinato)zinc(II) (5): A
1276
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1271–1279

Carbohydrate–Porphyrin Conjugates for Photodynamic Therapy
flask containing 10 (147 mg, 0.079 mmol), copper(I) iodide
(1.5 mg, 7.94 μmol), and dichlorobis(triphenylphosphanyl)palladi-
um(II) (5.57 mg, 7.94 μmol) was purged with argon, followed by
the addition of anhydrous THF (5 mL) and dry Et3N (1 mL). The
solution was frozen with liquid nitrogen, TMSA (0.158 mL,
1.11 mmol) was added, and the mixture was degassed. After stir-
ring for 12 h at room temperature, the mixture was quenched with
water, and the organic solvents were evaporated. Upon extracting
with DCM, the organic layer was dried with anhydrous Na2SO4,
filtered, and the solvents evaporated to dryness under reduced pres-
sure. The residue was purified using a silica gel column (DCM and
then DCM/acetone, 10:1) to give 5 (137 mg, 0.073 mmol, 92%) as
4.31–4.20 (m, 12 H, 6Ј-H and CH2β), 4.12–4.07 (m, 6 H, 5Ј-H),
2.19 (s, 18 H, AcO), 2.16 (s, 18 H, AcO), 2.06 (s, 18 H, AcO), 2.03
(s, 18 H, AcO) ppm. 13C NMR (CDCl3): δ = 170.7 (C=O, acetyl),
170.1 (C=O, acetyl), 169.9 (C=O, acetyl), 169.8 (C=O, acetyl),
158.3 (C-p-phenoxy), 153.3 (C-1 and C-19), 151.0 (C-4, C-16/6, C-
14/9, and C-11), 150.1 (C-4, C-16/6, C-14/9, and C-11), 149.9 (C-
4, C-16/6, C-14/9, and C-11), 135.5 (C-o-phenoxy), 135.3 (C-o-
phenoxy), 134.3 (C-1-phenoxy), 134.2 (C-1-phenoxy), 133.3–130.3
(C-2, C-3, C-7, C-8, C-12, C-13, C-17, and C-18), 123.1 (C-10),
122.0 (C-5 and C-15), 112.7 (C-m-phenoxy), 112.6 (C-m-phenoxy),
104.5 (C-20), 101.0 (C-triple bond), 97.8 (C-1Ј), 87.5 (C-triple
bond), 69.6 (C-2Ј), 69.1 (C-3Ј), 68.7 (C-5Ј), 66.9 (CH2α), 66.7
a purple solid. C91H98N4O33SiZn·3H2O (1869.25 + 3 H2O): calcd. (CH2β), 66.1 (C-4Ј), 62.5 (C-6Ј), 20.9 (CH3, acetyl), 20.8 (CH3,
C 56.83, H 5.45, N 2.91; found C 57.01, H 5.70, N 3.25. UV/Vis
(DCM): λmax (ε, L mmol–1 cm–1): 432 (470), 566 (15.0), 611
(12.4) nm. 1H NMR (CDCl3): δ = 9.73 (d, J = 4.5 Hz, 2 H, 2-H
and 18-H), 9.00 (d, J = 4.6 Hz, 2 H, 2-H and 18-H), 8.90 (s, 4 H,
7-H, 13-H, 8-H, and 12-H), 8.12 (d, J = 8.0 Hz, 2 H, o-phenoxy-
H), 8.09 (d, J = 8.0 Hz, 4 H, o-phenoxy-H), 7.29 (d, J = 8.7 Hz, 4
H, m-phenoxy-H), 7.27 (d, J = 8.7 Hz, 2 H, m-phenoxy-H), 5.49–
5.45 (m, 3 H, 3Ј-H), 5.38–5.34 (m, 3 H, 2Ј-H), 5.34–5.31 (m, 3 H,
4Ј-H), 5.05 (s, 3 H, 1Ј-H), 4.46–4.35 (m, 9 H, 6Ј-H and CH2α),
4.29–4.17 (m, 9 H, 6Ј-H and CH2β), 4.09–4.05 (m, 3 H, 5Ј-H), 2.16
(s, 9 H, AcO), 2.14 (s, 9 H, AcO), 2.05 (s, 9 H, AcO), 1.99 (s, 9 H,
AcO), 0.62 (s, 9 H, SiMe3) ppm. 13C NMR (CDCl3): δ = 171.1
(C=O, acetyl), 170.5 (C=O, acetyl), 170.3 (C=O, acetyl), 170.2
(C=O, acetyl), 158.6 (C-p-phenoxy), 153.0 (C-1 and C-19), 151.2
(C-4, C-16/6, C-14/9, and C-11), 150.5 (C-4, C-16/6, C-14/9, and
C-11), 150.4 (C-4, C-16/6, C-14/9, and C-11), 135.9 (C-o-phenoxy),
135.8 (C-o-phenoxy), 134.4 (C-1-phenoxy), 134.3 (C-1-phenoxy),
132.4–131.4 (C-2, C-3, C-7, C-8, C-12, C-13, C-17, and C-18),
122.9 (C-10), 121.7 (C-5 and C-15), 113.0 (C-m-phenoxy), 112.9
(C-m-phenoxy), 105.6 (C-20), 101.0 (C-triple bond), 99.3 (C-
SiMe3), 99.3 (C-1Ј), 70.0 (C-2Ј), 69.6 (C-3Ј), 69.2 (C-5Ј), 67.4
(CH2β), 67.2 (CH2α), 66.6 (C-4Ј), 63.0 (C-6Ј), 21.4 (CH3, acetyl),
21.3 (CH3, acetyl), 21.19 (CH3, acetyl), 21.16 (CH3, acetyl), 0.87
(SiMe3) ppm.
acetyl), 20.73 (CH3, acetyl), 20.67 (CH3, acetyl) ppm. MS:
(MALDI-TOF): m/z = 3587.72 [M + H] (requires 3587.94).
General Procedure for the Synthesis of Porphyrinatozinc(II) Dimer
2 and 3 and Porphyrinatozinc(II) Trimer 4: Tetrabutylammonium
fluoride (1 m in THF, 2.6 equiv.) was added to 5 (1 equiv.) dissolved
in DCM (12 mL). The reaction was stirred at room temperature
for 15 min followed by addition of anhydrous calcium chloride
(2 g). The mixture was stirred for 10 min, filtered into a flask, and
the solvent was evaporated. The product was combined with the
iodo or bromo derivative (0.85 equiv. of halogen atom), tris(di-
benzylideneacetone)dipalladium(0) (0.3 equiv.), and triphenylarsine
(1.5 equiv.) in anhydrous THF (20 mm of 5) and Et3N (20 mm of
5) under argon. The reaction mixture was heated at reflux for 14 h
under argon. The solvent was evaporated to dryness under vacuum.
The crude product was purified by chromatography and crystalli-
zation.
Porphyrinatozinc(II) Dimer 2: Dimer 2 was obtained according to
the general procedure, starting from 5 (110 mg, 0.059 mmol) and
p-diiodobenzene (8.15 mg, 0.025 mmol). The crude product was
purified by preparative TLC on silica gel (DCM/acetone, 5:1) and
crystallized (AcOEt/n-heptane) to give 2 (32 mg, 9.08 μmol, 31%)
as a dark green solid. UV/Vis (DCM): λmax (ε, Lmmol–1 cm–1): 446
1
(294), 570 (19.4), 640 (44.0) nm. H NMR (CDCl3): δ = 9.89 (d, J
= 4.5 Hz, 4 H, 2-H and 18-H), 9.08 (d, J = 4.6 Hz, 4 H, 3-H and
17-H), 8.91 (s, 8 H, 7-H, 13-H, 8-H, and 12-H), 8.24 (s, 4 H, Ph-
H), 8.16 (d, J = 8.4 Hz, 8 H, o-phenoxy-H), 8.12 (d, J = 8.4 Hz, 4
H, o-phenoxy-H), 7.33 (d, J = 8.4 Hz, 8 H, m-phenoxy-H), 7.29 (d,
J = 8.4 Hz, 4 H, m-phenoxy-H), 5.51–5.43 (m, 6 H, 3Ј-H), 5.42–
5.35 (m, 12 H, 2Ј-H and 4Ј-H), 5.10 (s, 6 H, 1Ј-H), 4.48–4.37 (m,
18 H, 6Ј-H and CH2α), 4.31–4.22 (m, 18 H, 6Ј-H and CH2β), 4.13–
4.10 (m, 6 H, 5Ј-H), 2.22 (s, 18 H, AcO), 2.18 (s, 18 H, AcO), 2.08
(s, 18 H, AcO), 2.04 (s, 18 H, AcO) ppm. 13C NMR (CDCl3): δ =
170.7 (C=O, acetyl), 170.1 (C=O, acetyl), 169.9 (C=O, acetyl),
169.8 (C=O, acetyl), 158.2 (C-p-phenoxy), 152.2 (C-1, C-19/4, C-
16/6, C-14/9, and C-11), 151.34 (C-1, C-19/4, C-16/6, C-14/9, and
C-11), 151.31 (C-1, C-19/4, C-16/6, C-14/9, and C-11), 150.9 (C-1,
C-19/4, C-16/6, C-14/9, and C-11), 135.5 (C-o-phenoxy), 135.4 (C-
1-phenoxy), 131.9–130.7 (C-2, C-3, C-7, C-8, C-12, C-13, C-17, and
C-18), 131.8 (C-2-Ph), 129.3 (C-20), 120.9 (C-10), 119.5 (C-5 and
C-15), 112.7 (C-m-phenoxy), 112.5 (C-1-Ph), 105.7 (C-triple bond),
104.8 (C-triple bond), 97.8 (C-1Ј), 69.6 (C-2Ј), 69.1 (C-3Ј), 68.7 (C-
5Ј), 67.0 (CH2α), 66.7 (CH2β), 66.2 (C-4Ј), 62.5 (C-6Ј), 20.9 (CH3,
acetyl), 20.83 (CH3, acetyl), 20.77 (CH3, acetyl), 20.7 (CH3, ace-
tyl) ppm. MS: (MALDI-TOF): m/z = 3662.96 [M + H] (requires
3662.97).
Porphyrinatozinc(II) Dimer (1): Tetrabutylammonium fluoride (1 m
in THF, 0.172 mL, 0.172 mmol) was added to
5 (124 mg,
0.066 mmol) dissolved in DCM (15 mL). The reaction was stirred
at room temperature for 15 min followed by addition of anhydrous
calcium chloride (2 g). The mixture was stirred for 10 min, filtered,
and the solvent evaporated. The crude product was dried under
vacuum and dissolved in DCM (50 mL). The mixture was stirred
vigorously for 15 min to aerate the solution, whereupon copper(I)
chloride (197 mg, 1.99 mmol) was added. After an additional
2 min, TMEDA (0.300 mL, 1.990 mmol) was added, and the reac-
tion was followed by TLC. After 20 min, TLC showed no further
change, and the reaction was quenched with H2O (250 mL). The
organic layer was washed with water until the aqueous washings
were no longer blue. The crude product was purified by filtration
through a silica pad (THF) and crystallized (AcOEt/n-heptane) to
give
1 (86 mg, 0.024 mmol, 72%) as a dark green solid.
C176H178N8O66Zn2 (3592.13): calcd. C 58.85, H 4.99, N 3.12; found
C 58.93, H 5.15, N 3.07. UV/Vis (DCM): λmax (ε, Lmmol–1 cm–1):
419 (215), 450 (244), 481 (157), 565 (22.5), 630 (35.2), 677
(47.7) nm. 1H NMR (CDCl3): δ = 9.99 (d, J = 4.5 Hz, 4 H, 2-H
and 18-H), 9.10 (d, J = 4.6 Hz, 4 H, 2-H and 18-H), 8.90 (s, 8 H,
7-H, 13-H, 8-H, and 12-H), 8.16 (d, J = 8.0 Hz, 4 H, o-phenoxy-
H), 8.12 (d, J = 8.0 Hz, 8 H, o-phenoxy-H), 7.32 (d, J = 8.7 Hz, 8 Porphyrinatozinc(II) Trimer (4): Trimer 4 was obtained according
H, m-phenoxy-H), 7.29 (d, J = 8.7 Hz, 4 H, m-phenoxy-H), 5.52– to the general procedure, starting from 5 (310 mg, 0.166 mmol) and
5.47 (m, 6 H, 3Ј-H), 5.40–5.38 (m, 6 H, 2Ј-H), 5.38–5.34 (m, 6 H, tris(4-iodophenylamine) (28.9 mg, 0.046 mmol). The crude product
4Ј-H), 5.08 (s, 6 H, 1Ј-H), 4.47–4.37 (m, 12 H, 6Ј-H and CH2α), was purified by preparative TLC on silica gel (THF/n-heptane, 1:1)
Eur. J. Org. Chem. 2011, 1271–1279
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1277

S. Achelle, P. Couleaud, P. Baldeck, M.-P. Teulade-Fichou, P. Maillard
FULL PAPER
and crystallized (AcOEt/n-heptane) to give 4 (190 mg, 37 μmol,
80%) as a dark green solid. C282H279N13O99Zn3 (5630.49): calcd.
C 60.15, H 4.99, N 3.23; found C 59.93, H 5.15, N 3.07. UV/Vis
was obtained as a dark green solid (13 mg, 5.03 μmol, 73%).
C128H130N8O42Zn2·18H2O (2583.69 + 18 H2O): calcd. C 53.54, H
5.69, N 3.90; found C 53.53, H 6.11, N 4.18. UV/Vis (PEG400/
(DCM): λmax (ε, Lmmol–1 cm–1): 440 (535), 573 (36.3), 632 EtOH/H2O, 3:2:5): λmax (ε, Lmmol–1 cm–1): 429 (286), 453 (189),
1
(87.7) nm. H NMR (C5D5N): δ = 10.34 (d, J = 4.3 Hz, 6 H, 2-H
and 18-H), 9.37 (d, J = 4.4 Hz, 6 H, 2-H and 18-H), 9.21 (s, 12 H,
7-H, 13/8-H, and 12-H), 8.34–8.31 (m, J = 8.0 Hz, 24 H, o-phen-
oxy-H, o-NPh2-H), 7.64 (d, J = 8.4 Hz, 6 H, o-NPh2-H), 7.48 (d,
J = 7.8 Hz, 18 H, m-phenoxy-H), 5.94–5.91 (m, 27 H, 3Ј-H, 2Ј-H,
and 4Ј-H), 5.41 (s, 9 H, 1Ј-H), 4.87–4.71 (m, 27 H, 6Ј-H and CH2α),
4.65 (m, 18 H, CH2β), 4.52–4.48 (m, 9 H, 6Ј-H), 4.30–4.27 (m, 9
H, 5Ј-H), 2.15 (s, 9 H, AcO), 2.08 (s, 9 H, AcO), 2.05 (s, 9 H,
AcO), 2.03 (s, 9 H, AcO) ppm. 13C NMR (CDCl3): δ = 170.7 (C=O,
acetyl), 170.1 (C=O, acetyl), 169.9 (C=O, acetyl), 169.8 (C=O, acet-
yl), 158.2 (C-p-phenoxy), 152.2–150.0 (C-1, C-4, C-6, C-9, C-11,
C-14, C-16, and C-19), 140.7 (C-p-NPh2), 135.44 (C-o-phenoxy),
135.4 (C-o-phenoxy), 132.9 (C-1-phenoxy), 132.8 (C-1-phenoxy),
132.2–130.7 (C-2, C-3, C-7, C-8, C-12, C-13, C-17, and C-18),
126.1 (C-m-NPh2), 122.2 (C-10), 122.0 (C-5 and C-15), 121.54 (C-
1-NPh2), 121.46 (C-o-NPh2), 112.7 (C-m-phenoxy), 106.0 (C-20),
102.9 (C-triple bond), 100.4 (C-triple bond), 97.7 (C-1Ј), 69.5 (C-
2Ј), 69.0 (C-3Ј), 68.6 (C-5Ј), 66.9 (CH2α), 66.7 (CH2β), 66.0 (C-4Ј),
62.5 (C-6Ј), 20.84 (CH3, acetyl), 20.76 (CH3, acetyl), 20.71 (CH3,
acetyl), 21.64 (CH3, acetyl) ppm. MS: (MALDI-TOF): m/z =
5623.56 [M + H] (requires 5623.51).
481 (157), 568 (15.8), 648 (26.2), 706 (38.5) nm. MS: (MALDI-
TOF): m/z 2579.76 [M + H] (requires 2579.69).
Deprotected Porphyrinatozinc(II) Trimer (13): Starting from 4
(32 mg, 5.68 μmol) and following the general procedure, trimer 13
was obtained as a dark green solid (20 mg, 4.86 μmol, 85%).
C210H207N13O63Zn3·15H2O (4117.17): calcd. C 57.49, H 5.44, N
4.15; found C 57.25, H 5.63, N 3.95. UV/Vis (PEG400/EtOH/H2O,
3:2:5): λmax (ε, Lmmol–1 cm–1): 443 (485), 580 (28.2), 648 (84.5) nm.
MS: (MALDI-TOF): m/z = 4110.95 [M + H] (requires 4111.13).
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR and 13C NMR of 1–4 and 7–10 and UV visible
spectra of 12 and 13.
Acknowledgments
We thank Mr. Jean Bernard for TPA measurements and Vincent
Guérineau for MALDI-TOF analyses. This work was supported
by the Institut Nationale du Cancer (INCa 2009–1-RT-08-
IC-1) and the non-profit French organization Rétinostop (http://
www.retinostop.org), S. A. also thanks the foundation Pierre-Gilles
de Gennes for a postdoctoral fellowship.
Porphyrinatozinc(II) Dimer (3): Dimer 3 was obtained according to
the general procedure, starting from 5 (50 mg, 0.027 mmol) and 10
(56 mg, 0.030 mmol). The crude product was purified by prepara-
tive TLC on silica gel (AcOEt/n-hexane, 3:1) and crystallized
(DCM/n-heptane) to give 3 (38 mg, 11 μmol, 42%) as a dark green
solid. UV/Vis (DCM): λmax (ε, Lmmol–1 cm–1): 424 (242), 450 (168),
481 (11.1), 558 (19.9), 631 (23.3), 677 (31.1) nm. 1H NMR (CDCl3):
δ = 9.99 (d, J = 4.5 Hz, 4 H, 2-H and 18-H), 9.10 (d, J = 4.6 Hz,
4 H, 2-H and 18-H), 8.90 (s, 8 H, 7-H, 13-H, 8-H, and 12-H), 8.17–
8.10 (m, 12 H, o-phenoxy-H), 7.32–7.26 (m, 12 H, m-phenoxy-H),
5.52–5.48 (m, 6 H, 3Ј-H), 5.41–5.35 (m, 12 H, 2Ј-H and 4Ј-H), 5.09
(s, 6 H, 1Ј-H), 4.47–4.40 (m, 18 H, 6Ј-H and CH2α), 4.32–4.21 (m,
18 H, 6Ј-H and CH2β), 4.11–4.08 (m, 6 H, 5Ј-H), 2.21 (s, 18 H,
AcO), 2.17 (s, 18 H, AcO), 2.07 (s, 9 H, AcO), 2.03 (s, 18 H,
AcO) ppm. 13C NMR (CDCl3): δ = 170.7 (C=O, acetyl), 170.0
(C=O, acetyl), 169.9 (C=O, acetyl), 169.8 (C=O, acetyl), 158.1 (C-
p-phenoxy), 150.9 (C-1, C-19/4, C-16/6, C-14/9, and C-11), 150.5
(C-1, C-19/4, C-16/6, C-14/9, and C-11), 150.1 (C-1, C-19/4, C-16/
6, C-14/9, and C-11), 149.8 (C-1, C-19/4, C-16/6, C-14/9, and C-
11), 135.5 (C-o-phenoxy), 135.4 (C-o-phenoxy), 135.2 (C-1-phen-
oxy), 133.1–131.6 (C-2, C-3, C-7, C-8, C-12, C-13, C-17, and C-18),
121.7 (C-10), 121.6 (C-5 and C-15), 112.6 (C-m-phenoxy), 112.5 (C-
m-phenoxy), 107.2 (C-20), 100.9 (C-triple bond), 97.7 (C-1Ј), 69.5
(C-2Ј), 69.0 (C-3Ј), 68.6 (C-5Ј), 66.9 (CH2α), 66.7 (CH2β), 66.1 (C-
4Ј), 62.5 (C-6Ј), 20.9 (CH3, acetyl), 20.8 (CH3, acetyl), 20.71 (CH3,
acetyl), 20.66 (CH3, acetyl) ppm. MS (MALDI-TOF): m/z =
3562.93 [M + H] (requires 3562.94).
[1] a) T. J. Dougherty, C. J. Gomer, B. W. Henderson, G. Jori, D.
Kessel, M. Korbelik, J. Moan, Q. Peng, J. Nat. Canc. Inst.
1998, 90, 889–905; b) R. Bonnet, Chemical Aspects of Photody-
namic Therapy, Gordon and Breach Science Publishers, Am-
sterdam, 2000; c) I. J. MacDonald, T. J. Dougherty, J. Por-
phyrins Phthalocyanines 2001, 5, 105–129; d) D. E. J. G. J. Dol-
mans, D. Fukumura, R. K. Jain, Nature Rev. 2003, 3, 380–386;
e) C. A. Robertson, D. Hawkins Evans, H. Abrahamse, J. Pho-
tochem. Photobiol. B: Biology 2009, 96, 1–8.
[2] R. Bonnett, Chem. Soc. Rev. 1995, 24, 19–33.
[3] R. W. Waynant, M. N. Ediger (Eds.), Electrooptics Handbook,
McGraw-Hill, New York, 1993, ch. 24.
[4] a) M. Pawlicki, H. A. Collins, R. G. Denning, H. L. Anderson,
Angew. Chem. 2009, 121, 3292; Angew. Chem. Int. Ed. 2009,
48, 3244–3266; b) K. Ogawa, Y. Kobuke, Anti-Cancer Agents
Med. Chem. 2008, 8, 269–279.
[5] a) M. Drobizhev, A. Karotki, M. Kruk, A. Rebane, Chem.
Phys. Lett. 2002, 355, 175–182; b) A. Karotki, M. Khurana,
J. R. Lepock, B. C. Wilson, Photochem. Photobiol. 2006, 82,
443–452.
[6] a) M. Drobizhev, Y. Stepanenko, Y. Dzenis, A. Karotki, A.
Rebane, P. N. Taylor, H. L. Anderson, J. Am. Chem. Soc. 2004,
126, 15352–15353; b) A. Karotki, M. Drobizhev, Y. Dzenis,
P. N. Taylor, H. L. Anderson, A. Rebane, Phys. Chem. Chem.
Phys. 2004, 6, 7–10; c) M. Drobizhev, V. Stepaznenko, Y.
Dzenis, A. Karotki, A. Rebane, P. N. Taylor, H. L. Anderson,
J. Phys. Chem. B 2005, 109, 7223–7236; d) H. M. Kim, B. R.
Cho, Chem. Commun. 2009, 153–164; e) G. S. He, L.-S. Tan,
Q. Zheng, P. N. Prasad, Chem. Rev. 2008, 108, 1245–1330; f)
K. S. Kim, J. M. Lim, A. Osuka, D. Kim, J. Photochem. Pho-
tobiol. C: Photochem. Rev. 2008, 9, 13–28.
[7] a) D. P. Arnold, A. W. Johnson, M. Mahendran, J. Chem. Soc.
Perkin Trans. 1 1978, 366–370; b) D. P. Arnold, D. A. James, J.
Org. Chem. 1997, 62, 3460–3469; c) H. L. Anderson, Chem.
Commun. 1999, 2323–2330; d) M. Balaz, H. A. Collins, E.
Dahlstedt, H. L. Anderson, Org. Biomol. Chem. 2009, 7, 874–
888; e) M. K. Kuimova, H. A. Collins, M. Balaz, E. Dahlstedt,
J. A. Levitt, N. Sergent, K. Suhling, M. Drobizhev, N. S. Mak-
General Procedure for the Synthesis of Porphyrinatozinc(II) Dimers
12 and 13: To a solution of acetylated carbohydrate compounds in
anhydrous THF (20 mL) was added 10 drops of a freshly prepared
solution of sodium methoxide in methanol. The solution was
stirred at room temperature for 1 h. Then, IWT ion-exchange resin
(500 mg) was added, and the mixture was carefully stirred for an
additional 30 min. The resin was filtered, washed with a mixture of
pyridine and water (1:1), and the solvents were evaporated under
vacuum.
Deprotected Porphyrinatozinc(II) Dimer (12): Starting with
1
(25 mg, 6.96 μmol) and following the general procedure, dimer 12
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1271–1279

Carbohydrate–Porphyrin Conjugates for Photodynamic Therapy
arov, A. Rebane, H. L. Anderson, D. Phillips, Org. Biomol.
Chem. 2009, 7, 889–896.
a) D. P. Arnold, L. J. Nitschinsk, Tetrahedron Lett. 1993, 34,
693–696; b) D. P. Arnold, D. A. James, J. Org. Chem. 1997, 62,
3460–3469.
D. P. Arnold, D. A. James, C. H. L. Kennard, G. Smith, J.
Chem. Soc., Chem. Commun. 1994, 2131–2132.
P. N. Taylor, A. P. Wylie, J. Huuskonen, H. L. Anderson, An-
gew. Chem. 1998, 110, 1033; Angew. Chem. Int. Ed. 1998, 37,
986–989.
K. Ogawa, Y. Nagatsuka, J. Porphyrins Phthalocyanines 2009,
13, 114–121.
S. A. Odom, S. Webster, L. A. Padilha, D. Peceli, H. Hu, G.
Nootz, S.-J. Chung, S. Ohira, J. D. Matichak, O. V. Przhonska,
A. D. Kachkovski, S. Barlow, J.-L. Brédas, H. L. Anderson,
D. J. Hagan, E. W. Van Stryland, S. R. Marder, J. Am. Chem.
Soc. 2009, 131, 7510–7511.
L. Tang, R. M. Hoffman, S. Yamashita, J. Controlled Release
2009, 134, 2–10.
[19] a) S. Ballut, A. Makky, B. Loock, J.-Ph. Michel, Ph. Maillard,
V. Rosilio, Chem. Commun. 2009, 224–226; b) Y. K. Park, B.
Bold, B. C. Cui, W. Lee, Y. K. Shim, Bull. Korean Chem. Soc.
2008, 29, 130–134.
[8]
[9]
[20] a) Ph. Maillard, J.-L. Guerquin-Kern, M. Momenteau, S. Gas-
pard, J. Am. Chem. Soc. 1989, 111, 9125–9127; b) M. Momen-
teau, Ph. Maillard, M.-A. de Bélinay, D. Carrez, A. Croisy, J.
Biomed. Opt. 1999, 4, 298–318; c) I. Laville, T. Figueiredo, B.
Loock, S. Pigaglio, Ph. Maillard, D. S. Grierson, D. Carrez, A.
Croisy, J. Blais, Bioorg. Med. Chem. 2003, 11, 1643–1652; d) I.
Laville, S. Pigaglio, J.-C. Blais, F. Doz, B. Loock, Ph. Maillard,
D. S. Grieson, J. Blais, J. Med. Chem. 2006, 49, 2558–2567; e)
Ph. Maillard, B. Loock, D. S. Grierson, I. Laville, J. Blais, F.
Doz, L. Desjardins, D. Carrez, J.-L. Guerquin-Kern, A. Croisy,
Photodiagn. Photodynamic Ther. 2007, 4, 261–268.
[21] a) M. Lupu, C. D. Thomas, Ph. Maillard, B. Loock, B. Chau-
vin, I. Aerts, A. Croisy, E. Beloir, A. Volk, J. Mispelter, Photod-
iagn. Photodynamic Ther. 2009, 6, 214–220; b) B. Di Stasio, C.
Frochot, D. Dumas, P. Even, J. Zwier, A. Müller, D. Didelon,
F. Guillemin, M. L. Viriot, M. Barberi-Heyob, Eur. J. Med.
Chem. 2005, 40, 1111–1122.
[10]
[11]
[12]
[13] J.-W. Seo, S. Y. Jang, D. Kim, H.-J. Kim, Tetrahedron 2008, 64,
2735–2739.
[14] J. R. Starkey, A. K. Rebane, M. A. Drobizhev, F. Meng, A.
Gong, A. Elliott, K. McInnerney, C. W. Spangler, Clin. Cancer
Res. 2008, 14, 6564–6573.
[15] H. A. Collins, M. Khurana, E. H. Moriyama, A. Mariampillai,
E. Dahlstedt, M. Balaz, M. K. Kuimova, M. Drobizhev,
V. X. D. Yang, D. Phillips, A. Rebane, B. C. Wilson, H. L. An-
derson, Nature Photonics 2008, 2, 420–424.
[16] a) M. Hamblin, J. L. Miller, B. Ortel, Photochem. Photobiol.
2000, 72, 533–540; b) W. M. Sharman, J. E. van Lier, C. M.
Allen, Adv. Drug Delivery Rev. 2004, 56, 53–76; c) J. T. C.
Wojtyk, R. Goyan, E. Gudgin-Dickson, R. Pottier, Med. Laser
Appl. 2006, 21, 225–238; d) X. Zheng, R. K. Pandey, Anti Can-
[22] M. Varamo, B. Loock, Ph. Maillard, D. S. Grierson, Org. Lett.
2007, 9, 4689–4692.
[23] J. Dahmen, T. Frejd, G. Groenberg, T. Lave, G. Magnusson,
G. Noori, Carbohydr. Res. 1983, 116, 303–307.
[24] a) D. P. Arnold, R. D. Hartnell, Tetrahedron 2001, 57, 1335–
1345; b) C. Maeda, S. Yamaguchi, C. Ikeda, H. Shinokubo, A.
Osuka, Org. Lett. 2008, 10, 549–552; c) M. Fathalla, J. Jayaw-
ickramarajah, Eur. J. Org. Chem. 2009, 6095–6099.
[25] G. Zemplén, Ber. Dtsch. Chem. Ges. 1927, 1555–1564.
cer Agents Med. Chem. 2008, 8, 241–268; e) M. B. Bakar, M. [26] M. Drobizhev, Y. Stepanenko, Y. Dzenis, A. Karotki, A. Re-
Oelgemöller, M. O. Senge, Tetrahedron 2009, 65, 7064–7078; f)
R. Schneider, L. Tirand, C. Frochot, R. Vanderesse, N.
Thomas, J. Gravier, F. Guillemin, M. Barberi-Heyob, Curr.
Med. Chem. 2006, 6, 469–488; g) J.-P. Taquet, C. Frochot, V.
Manneville, M. Barberi-Heyob, Curr. Med. Chem. 2007, 14,
103–112.
bane, P. N. Taylor, H. L. Anderson, J. Phys. Chem. B 2005, 109,
7223–7236.
[27] G. Jori, J. Photochem. Photobiol. B: Biology 1996, 36, 87–93.
[28] M.-C. Desroches, A. Bautista-Sanchez, C. Lamotte, B.
Labèque, D. Auchère, R. Farinotti, Ph. Maillard, D. S. Grier-
son, P. Prognon, A. Kasselouri, J. Photochem. Photobiol. B:
Biology 2006, 85, 56–64.
[29] a) M. U. Winters, J. Kärnbratt, M. Eng, C. J. Wilson, H. L.
Anderson, B. Albinsson, J. Phys. Chem. C 2007, 111, 7192–
7199; b) M. K. Kuimova, M. Balaz, H. L. Anderson, P. R. Og-
ilby, J. Am. Chem. Soc. 2009, 131, 7948–7918.
[30] N. S. Makarov, M. Drobizhev, A. Rebane, Proc. SPIE 2008,
6891, 689105.
[17] V. Lebret, L. Raehm, J.-O. Durand, M. Smaïhi, M. H. V. Werts,
M. Blanchard-Desce, D. Méthy-Gonnod, C. Dubernet, J. Sol-
Gel Sci. Technol. 2008, 48, 32–39.
[18] a) M. Monsigny, A. C. Roche, C. Kieda, P. Midoux, A. Ob-
renovitch, Biochimie 1988, 70, 1633–1649; b) R. Lotan, A. Raz,
Ann. N. Y. Acad. Sci. 1988, 551, 385–396; c) S. Griegel, M. F.
Rajewsky, T. Ciesiolka, H. J. Gabius, Anticancer Res. 1989, 9,
723–730; d) S. Sakuma, T. Yano, Y. Masaoka, M. Kataoka, K.
Hiwatari, H. Tachikawa, Y. Shoji, R. Kimura, H. Ma, Z. Yang,
Received: August 26, 2010
Published Online: January 18, 2011
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