Effects of the number and position of the substituents on the in vitro photodynamic activities of glucosylated zinc(ii) phthalocyanines

Article abstract of DOI:10.1039/b822128f

A series of mono-β-, di-α- and di-β-substituted phthalonitriles which contain one or two tetraethylene-glycol-linked 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose unit(s) were prepared by typical substitution reactions. These precursors underwent self-cyc

Full text of DOI:10.1039/b822128f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Effects of the number and position of the substituents on the in vitro
photodynamic activities of glucosylated zinc(II) phthalocyanines†
Jian-Yong Liu,a Pui-Chi Lo,a Wing-Ping Fongb and Dennis K. P. Ng*a
Received 10th December 2008, Accepted 15th January 2009
First published as an Advance Article on the web 18th February 2009
DOI: 10.1039/b822128f
A series of mono-b-, di-a- and di-b-substituted phthalonitriles which contain one or two
tetraethylene-glycol-linked 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose unit(s) were prepared by
typical substitution reactions. These precursors underwent self-cyclisation or mixed-cyclisation with an
excess of unsubstituted phthalonitrile in the presence of Zn(OAc)2·2H2O and DBU to give the
corresponding zinc(II) phthalocyanines with 1, 2 or 4 glucosylated substituent(s). For the di-a- and
tetra-b-glucosylated analogues, removal of the isopropylidene groups was also performed by the
treatment with trifluoroacetic acid and water to give the corresponding water-soluble deprotected
glucosylated derivatives. All of these glucoconjugated phthalocyanines were fully characterised with
various spectroscopic methods and studied for their photophysical properties and in vitro
photodynamic activities against HT29 human colon adenocarcinoma and HepG2 human
hepatocarcinoma cells. The tetra-b-glucosylated phthalocyanines ZnPc(b-PGlu)4 (4) and ZnPc(b-Glu)4
(5) were found to be essentially non-cytotoxic. By contrast, the mono- and di-glucosylated analogues
ZnPc(b-PGlu) (7), ZnPc(a-PGlu)2 (11), ZnPc(a-Glu)2 (12) and ZnPc(b-PGlu)2 (20) exhibited
substantial photocytotoxicity. The isopropylidene-protected di-a-substituted derivative 11 was
particularly potent, having IC50 values as low as 0.03 mM. The different photodynamic activities of
these compounds can be attributed to their different extent of cellular uptake and aggregation tendency
in the biological media, which greatly affect their singlet oxygen generation efficiency.
On the basis that cancer cells have increased levels of glucose
Introduction
uptake and glycolysis to provide sufficient metabolic energy to
sustain their proliferation,4 glucoconjugation may promote the
uptake of photosensitisers through the glucose transporter pro-
teins, which are over-expressed in a variety of human carcinomas.5
The hydrophilic glucose moieties connected to the hydrophobic
core of the photosensitisers can also tune the amphiphilicity of
the resulting conjugates, which is an important parameter for
cellular uptake.6 This strategy has been employed for various pho-
tosensitisers such as porphyrins,7 chlorins,8 pyropheophorbides9
and hypocrellins.10 Recently, we have extended the studies to
phthalocyanines. A series of glycosylated silicon(IV)11 and zinc(II)12
phthalocyanines have been synthesised and evaluated for their
in vitro photodynamic activities. These compounds, particularly
the silicon(IV) analogues, are highly potent, having IC50 values as
low as 6 nM. In this paper, we report the synthesis, character-
isation, photophysical properties and in vitro photocytotoxicity
of a new series of zinc(II) phthalocyanines substituted with
1, 2 or 4 tetraethylene-glycol-linked glucose unit(s) at the a-
or b-position(s). By studying this series of structurally related
compounds, we aim to reveal the effects of the number and position
of this substituent on the photodynamic activities of this novel
series of glycoconjugated photosensitisers.
Owing to the strong absorption in the red visible region, high
efficiency at generating singlet oxygen and extraordinary sta-
bility, phthalocyanines have emerged as a promising class of
photosensitisers for photodynamic therapy (PDT).1 In addition
to certain classical phthalocyanine-based photosensitisers, such
as liposomal zinc(II) phthalocyanine, sulfonated zinc(II) and
aluminum(III) phthalocyanines and the silicon(IV) phthalocyanine
Pc4 developed by Kenney and co-workers, a substantial number
of other phthalocyanine derivatives have been studied over the
past few years with a view to improving the therapeutic outcomes
and gaining insight about the structure–activity relationships.2
Recently, considerable effort has been devoted to enhance their
selectivity towards malignant tissues. To this end, various tumour-
specific vectors such as antibodies, synthetic peptides, epidermal
growth factor and adenoviruses have been conjugated to these
photosensitisers.3 Unfortunately, only a limited target specificity
has been achieved so far.
aDepartment of Chemistry and Centre of Novel Functional Molecules, The
Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China. E-mail:
dkpn@cuhk.edu.hk; Fax: +852 2603 5057; Tel: +852 2609 6375
bDepartment of Biochemistry and Centre of Novel Functional Molecules,
The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
Results and discussion
† Electronic supplementary information (ESI) available: HPLC chro-
matograms of 5 and 12; electronic absorption and fluorescence spectra
of all the glucosylated phthalocyanines in the RPMI medium 1640;
Synthesis and characterisation
1
1H and 13C{ H} NMR spectra of all the new compounds. See DOI:
Scheme 1 shows the synthetic route for the tetra-b-glucosylated
phthalocyanines 4 and 5. Treatment of the sugar-substituted
10.1039/b822128f
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Scheme 1 Synthesis of tetra-b-glucosylated phthalocyanines 4 and 5.
tetraethylene glycol 111b with 4-nitrophthalonitrile (2) in the pres-
ence of K2CO3 in DMF led to nucleophilic aromatic substitution
giving the substituted phthalonitrile 3. This compound then
underwent self-cyclisation in the presence Zn(OAc)2·2H2O and
DBU to afford ZnPc(b-PGlu)4 (4) as a mixture of structural
isomers. Upon treatment with trifluoroacetic acid (TFA) and water
(9 : 1 v/v), the isopropylidene groups of 4 were removed, giving the
deprotected glucosylated analogue ZnPc(b-Glu)4 (5).
To enhance the amphiphilicity of the molecules, which is gener-
ally believed to be an advantageous character of photosensitisers,6
we also prepared the mono- and di-glucosylated derivatives. As
shown in Scheme 2, mixed cyclisation of the glucose-appended
phthalonitrile 3 with an excess of unsubstituted phthalonitrile (6)
(9 equiv.) in the presence of Zn(OAc)2·2H2O and DBU afforded
the mono-b-glucosylated phthalocyanine ZnPc(b-PGlu) (7). This
compound could be isolated readily from the reaction mixture (in
15% yield) by silica gel column chromatography followed by size
exclusion chromatography.
remains relatively rare,13 but has recently been shown to possess
desirable characteristics for PDT application.2g,14 For this com-
pound, deprotection was also performed, again with TFA and
water (9 : 1 v/v), to give the deprotected derivative ZnPc(a-Glu)2
(12) in excellent yield.
The di-b-glucosylated analogue ZnPc(b-PGlu)2 (20) was pre-
pared according to Scheme 4. Firstly, 4,5-dibromocatechol (13)
was treated with tetraethylene glycol monotosylate 14 to afford
the disubstituted product 15, which was then converted to
the ditosylate 16. This compound then underwent nucleophilic
substitution with 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose
(17) to give 18. Reaction of this compound with CuCN led to the
formation of phthalonitrile 19, which was then converted to 20 by
typical mixed cyclisation with phthalonitrile (6).
All of the new compounds were fully characterised with various
spectroscopic methods. For the tetra-b-glucosylated phthalo-
cyanine ZnPc(b-PGlu)4 (4), although it exists as a mixture of
1
structural isomers, the H NMR spectrum recorded in CDCl3
Scheme 3 shows the pathway used to prepare the di-a-
substituted derivatives. Treatment of tosylate 8, prepared from
1 in 86%, with 2,3-dicyanohydroquinone (9) and K2CO3 resulted
in disubstitution, giving phthalonitrile 10. This compound then
underwent a typical mixed cyclisation reaction with phthalonitrile
(6) to afford the di-a-glucosylated phthalocyanine ZnPc(a-PGlu)2
(11) in 12% yield. This kind of 1,4-disubstituted phthalocyanine
in the presence of a trace amount of pyridine-d5 is simpler
than expected. Three well-separated multiplets in the region d
7.7–9.3 were observed for the three sets of phthalocyanine ring
protons. The signals for the sugar and tetraethylene glycol protons
could also be partially assigned with the aid of 2D COSY
spectroscopy. The spectra for the other substituted analogues also
1
showed distinct H NMR patterns for the phthalocyanine ring
Scheme 2 Synthesis of mono-b-glucosylated phthalocyanine 7.
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Scheme 3 Synthesis of di-a-glucosylated phthalocyanines 11 and 12.
Scheme 4 Synthesis of di-b-glucosylated phthalocyanine 20.
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protons, and the signals could be assigned unambiguously (see the
Experimental Section).
For the two deprotected analogues ZnPc(b-Glu)4 (5) and
ZnPc(a-Glu)2 (12), the spectra still showed downfield signals,
which could be assigned to the phthalocyanine ring protons.
However, the signals for the sugar and tetraethylene glycol protons
were significantly broadened and overlapped. Assignment of these
signals was found to be difficult. It is likely that the deprotected
sugar moieties promote the aggregation of the macrocycles
through hydrogen bonding formation. This possible phenomenon,
together with the anomerisation of the sugar moieties, hinders the
assignment of signals. Nevertheless, the purity of these compounds
was confirmed by HPLC (see the chromatograms in Fig. S1†).
The ESI mass spectra of all these phthalocyanines were also
recorded. The protonated [M + H]+ and/or sodiated [M + Na]+
molecular ion signal(s) could be detected in all the cases. The iso-
topic distribution was in good agreement with the corresponding
simulated pattern. The identity of these species was also confirmed
by accurate mass measurements.
Fig. 1 Electronic absorption spectra of ZnPc(a-PGlu)2 (11) at different
concentrations in DMF.
respectively) are significantly higher than that of the unsubstituted
zinc(II) phthalocyanine (ZnPc) (UD = 0.56), which was used as the
reference.17 The relatively higher singlet oxygen quantum yield
for 11 and 12 is unexceptional, which in fact has been generally
observed for other di-a-substituted zinc(II) phthalocyanines.2g,14
The results suggest that as the HOMO–LUMO gap becomes
smaller, the singlet excited state has a higher tendency to undergo
intersystem crossing to generate singlet oxygen.
Electronic absorption and photophysical properties
The electronic absorption and basic photophysical data of all these
phthalocyanines were measured in DMF and are summarised in
Table 1. All of these compounds gave typical UV-Vis spectra for
non-aggregated phthalocyanines showing an intense and sharp
Q band in the red visible region. It is likely that DMF, being a
coordinating solvent, binds axially to these zinc(II) macrocycles,
reducing their aggregation tendency. Fig. 1 shows the spectrum
of ZnPc(a-PGlu)2 (11) as an example. The Q band for this di-
a-substituted phthalocyanine was significantly red-shifted (by
19 nm) compared with that for the di-b-substituted counterpart
20 (Table 1). a-Glucosylation also led to weakening and red shift
of the fluorescence emission. These results are in accord with the
observations and theoretical calculations reported previously for
a series of metal-free and zinc(II) phthalocyanines.15 The effects
of sugar moieties are insignificant both on the absorption and
fluorescence emission properties.
The singlet oxygen quantum yields (UD) of these glucosy-
lated phthalocyanines were also determined in DMF using 1,3-
diphenylisobenzofuran as the scavenger. The concentration of the
quencher was monitored spectroscopically at 411 nm along with
time, from which the values of UD could be determined by the
method described previously.16 These data are also compiled in
Table 1. It can be seen that all of these phthalocyanines are efficient
singlet oxygen generators, particularly the di-a-substituted zinc(II)
analogues 11 and 12, for which the values of UD (0.86 and 0.78
In vitro photodynamic activities
The photodynamic activities of all these glucosylated zinc(II)
phthalocyanines in Cremophor EL emulsions were investigated
against two different cell lines, namely HT29 human colon
adenocarcinoma and HepG2 human hepatocarcinoma cells. In
the absence of light, all of these compounds were essentially non-
toxic to the cells. Upon illumination, these compounds exhibited
different degrees of photocytotoxicities. The tetra-b-glucosylated
phthalocyanines ZnPc(b-PGlu)4 (4) and ZnPc(b-Glu)4 (5) were
least cytotoxic. The cell viability dropped by less than 20% upon
incubation with up to 8 mM of these dyes. Fig. 2 shows the
dose response curves for the other glucosylated phthalocyanines
against the two cell lines. The corresponding IC50 values, defined
as the dye concentrations required to kill 50% of the cells, are
compiled in Table 2. It can be seen that the photocytotoxicity
follows the order ZnPc(a-PGlu)2 (11) > ZnPc(b-PGlu)2 (20) >
ZnPc(b-PGlu) (7) > ZnPc(a-Glu)2 (12). The di-a-substituted
derivative 11 obviously has a much higher potency, while the
deprotected counterpart 12 shows the lowest photocytotoxicity.
Table 1 Electronic absorption and photophysical data for all the glucosylated phthalocyanines in DMF
b
c
Compound
l
max/nm (loge)
l
em/nma
UF
UD
ZnPc(b-PGlu)4 (4)
ZnPc(b-Glu)4 (5)
ZnPc(b-PGlu) (7)
ZnPc(a-PGlu)2 (11)
ZnPc(a-Glu)2 (12)
ZnPc(b-PGlu)2 (20)
355 (4.97), 611 (4.60), 679 (5.31)
353 (4.85), 612 (4.49), 679 (5.16)
346 (4.66), 606 (4.44), 672 (5.21)
334 (4.62), 621 (4.46), 689 (5.23)
335 (4.47), 621 (4.36), 688 (5.13)
340 (4.73), 605 (4.54), 670 (5.35)
684
686
676
698
697
676
0.33
0.23
0.32
0.15
0.18
0.31
0.49
0.58
0.43
0.86
0.78
0.51
a Excited at 610 nm. b Relative to ZnPc in DMF (UF = 0.28).18 c Relative to ZnPc in DMF (UD = 0.56).
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Table 2 Comparison of the IC50 values of phthalocyanines 7, 11, 12 and
20 against HT29 and HepG2 cells
the phthalocyanine core. Compared with the non-glucosylated
analogue ZnPc[a-O(CH2CH2O)4Me]2 (IC50 = 0.05–0.09 mM),14a
the photocytotoxicity of the most potent compound ZnPc(a-
PGlu)2 (11) is also marginally higher, but the small difference
suggests that the sugar moieties do not play a functional role in
the uptake process.
IC50/mM
Compound
For HT29
For HepG2
ZnPc(b-PGlu) (7)
ZnPc(a-PGlu)2 (11)
ZnPc(a-Glu)2 (12)
ZnPc(b-PGlu)2 (20)
1.38
0.03
2.97
0.26
1.52
0.04
2.48
0.28
To account for the different photodynamic activities of these
compounds, their aggregation behaviour in the culture media was
examined by absorption and fluorescence spectroscopic methods.
Fig. 3 shows the UV-Vis spectra of all the glucosylated phthalo-
cyanines in Dulbecco’s modified Eagle’s medium (DMEM) used
for HT29 cells. It can be seen that a Q band can be observed readily
for the mono- and di-substituted analogues 7, 11, 12 and 20. The
Q band of 11 is relatively sharp and intense. These observations
indicate that these compounds, particularly 11, are not extensively
aggregated in the culture medium. By contrast, for the tetra-b-
substituted analogues 4 and 5, the Q bands are much broadened
and shifted to the blue, showing that these two compounds
are highly aggregated in the medium. These conclusions were
also supported by their different fluorescence spectra. As shown
in Fig. 4, a fluorescence emission can be observed for the
mono- and di-substituted derivatives 7, 11, 12 and 20, while the
Fig. 3 Electronic absorption spectra of all the glucosylated phthalo-
cyanines, formulated with Cremophor EL, in the DMEM medium. The
concentrations of the phthalocyanines were fixed at 8 mM.
Fig. 2 Effects of 7 (circles), 11 (squares), 12 (stars) and 20 (triangles)
on (a) HT29 and (b) HepG2 cells in the absence (closed symbols) and
presence (open symbols) of light (l > 610 nm, 40 mW cm-2, 48 J cm-2).
Data are expressed as mean values standard error of the mean of three
independent experiments, each performed in quadruplicate.
The potency of these compounds is significantly higher than
that of the classical photosensitiser porfimer sodium, for which
the IC50 values were found to be ca. 4.5 mg mL-1 for both the
cell lines under the same conditions (versus ca. 50 ng mL-1 for
the most potent 11). The mono-b-substituted derivative ZnPc(b-
PGlu) (7) is slightly more photocytotoxic compared with the non-
tetraethylene-glycol-linked analogue (IC50 = 1.8–2.0 mM),12 which
may be due to the advantageous properties of the linker such
as the high hydrophilicity and ability to reduce aggregation of
Fig. 4 Fluorescence spectra of all the glucosylated phthalocyanines, for-
mulated with Cremophor EL, in the DMEM medium. The concentrations
of the phthalocyanines were fixed at 8 mM.
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tetra-b-substituted analogues 4 and 5 are not fluorescent in the
medium. The weaker and red-shifted emission of 11 and 12 is
related to their di-a-substitution pattern.15 Very similar results
were obtained in the RPMI medium 1640 used for HepG2 cells.
It is clear that the aggregation behaviour of these compounds in
the culture media depends on the number, position and nature of
the sugar substituent. While substituents at the a positions are
effective to prevent stacking of the molecules, a larger number
of substituents at the b-positions exaggerates the aggregation.
As molecular aggregation provides an efficient non-radiative
relaxation pathway for the singlet excited state of the dyes, the
fluorescence intensity as well as efficiency at generating singlet
oxygen will be reduced as the aggregation tendency increases.19
Thus, these results can explain that even though 4 and 5 have a
reasonably high singlet oxygen quantum yield in DMF (Table 1),
they are virtually non-photocytotoxic. The very high potency of
11 is related to its low aggregation tendency in the media.
To further explain the photocytotoxicity results, fluorescence
microscopic studies were also carried out to shed light on the
cellular uptake of these compounds. HT29 cells were incubated
respectively with all of these glucosylated phthalocyanines (8 mM)
for 2 h. Upon excitation at 630 nm, the fluorescence images of
the cells were then taken (Fig. 5). It was found that for the
tetra-b-substituted analogues 4 and 5, no fluorescence could be
observed. This indicated that the cellular uptake is negligible for
these compounds and/or they are highly aggregated within the
cells, both of which disfavour the photodynamic action. Hence,
these compounds are not photocytotoxic. By contrast, the mono-
and di-substituted derivatives 7, 10, 11 and 20 showed intracellular
fluorescence throughout the cytoplasm. The apparent intensity,
which reflects the extent of cellular uptake and aggregation of
the dyes, follows the order: 11 > 20 > 7 > 12, which is in good
agreement with the trend in photocytotoxicity. For the deprotected
derivative 12, since it does not seem to have a high aggregation
tendency in the media, the weak intracellular fluorescence intensity
may be due to its low cellular uptake, which can explain its
relatively low photocytotoxicity.
Conclusions
In summary, we have prepared and characterised a new series of
tetraethylene-glycol-linked glucosylated zinc(II) phthalocyanines.
Their in vitro photodynamic activities have also been evaluated
and compared. It has been found that both the number and
position of the substituents have a great influence on their in vitro
photocytotoxicity, which follows the order: di-a-substituted > di-
b-substituted > mono-a-substituted > tetra-b-substituted deriva-
tives. Removal of the isopropylidene protecting groups leads
to an adverse effect on the photocytotoxicity. The different
photodynamic activities of these compounds can be explained by
their different extent of cellular uptake and aggregation tendency.
The di-a-substituted analogue 11 is particularly potent having
IC50 values as low as 0.03 mM, and is thus a very promising
photosensitiser for further investigation. Although it seems that
the sugar moieties of this compound cannot promote the cellular
uptake in vitro, whether they have a functional role in vivo will also
be worth examining.
Experimental
All the reactions were performed under a nitrogen atmosphere.
Experimental details regarding the purification of solvents, in-
strumentation and in vitro studies are described elsewhere.11b Chro-
matographic purifications were performed on silica gel (Macherey-
Nagel, 70–230 mesh) columns with the indicated eluents. Size
exclusion chromatography was carried out on Bio-Rad Bio-
Beads S-X1 beads (200–400 mesh). The glucosylated tetraethylene
glycol 1,11b 4,5-dibromocatechol (13),20 tosylate 1421 and protected
glucose 1722 were prepared as described.
Glucosylated phthalonitrile 3
To a solution of 1 (1.11 g, 2.54 mmol) and 3-nitrophthalonitrile
(2) (0.66 g, 3.81 mmol) in DMF (8 mL) was added anhydrous
K2CO3 (1.57 g, 11.36 mmol). The mixture was stirred at 80 ◦C
for 48 h, then the volatiles were removed in vacuo. The residue
was mixed with water (80 mL) and the mixture was extracted
with CHCl3 (80 mL ¥ 3). The combined organic fractions were
dried over anhydrous MgSO4, then evaporated to dryness under
reduced pressure. The crude product was purified by silica gel
column chromatography using ethyl acetate–hexane (1 : 1 v/v) as
the eluent. The product was obtained as a colourless liquid (0.56 g,
1
39%). H NMR (300 MHz, CDCl3): d 7.71 (d, J = 8.7 Hz, 1 H,
ArH), 7.32 (d, J = 2.7 Hz, 1 H, ArH), 7.23 (dd, J = 2.7, 8.7 Hz,
1 H, ArH), 5.87 (d, J = 3.6 Hz, 1 H, H1), 4.57 (d, J = 3.6 Hz,
1 H, H2), 4.28–4.34 (m, 1 H, H5), 4.23 (virtual t, J = 4.5 Hz, 2
H, ArOCH2), 4.06–4.14 (m, 2 H, H6), 3.96–4.02 (m, 1 H, H4),
3.92 (d, J = 3.0 Hz, 1 H, H3), 3.89 (virtual t, J = 4.5 Hz, 2 H,
CH2), 3.61–3.77 (m, 12 H, CH2), 1.49 (s, 3 H, CH3), 1.42 (s, 3
H, CH3), 1.35 (s, 3 H, CH3), 1.31 (s, 3 H, CH3). 13C{ H} NMR
1
(75.4 MHz, CDCl3): d 162.0, 135.1, 119.8, 119.5, 117.4, 115.6,
115.2, 111.7, 108.9, 107.4, 105.2, 82.7, 82.6, 81.1, 72.5, 70.9, 70.6
(three overlapping CH2 signals), 70.4, 70.1, 69.2, 68.6, 67.1, 26.8,
26.7, 26.2, 25.4. MS (ESI): an isotopic cluster peaking at m/z 585
{100%, [M + Na]+}. HRMS (ESI): m/z calcd for C28H38N2NaO10
[M + Na]+ 585.2419, found 585.2417.
Fig. 5 Fluorescence microscopic images of HT29 cells after being
incubated with (a) 7, (b) 11, (c) 12 and (d) 20 (all at 8 mM) for 2 h.
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1.36 (s, 3 H, CH3), 1.30 (s, 3 H, CH3). 13C{ H} NMR (100.6 MHz,
CDCl3 with a trace amount of pyridine-d5): d 160.3, 153.4, 153.3,
153.2, 153.0, 152.7, 152.6, 152.5, 140.1, 138.3, 138.2, 138.1, 137.9,
131.5, 128.8, 128.7, 128.6, 123.3, 122.4, 122.2, 118.2, 111.6, 108.8,
105.2, 82.6, 82.5, 81.0, 72.5, 71.0, 70.7 (two overlapping signals),
70.6, 70.4, 70.1, 69.9, 68.0, 67.1, 26.7 (two overlapping signals),
26.2, 25.4 (some of the Pc signals are overlapped). MS (ESI): an
isotopic cluster peaking at m/z 1011 {100%, [M + H]+}. HRMS
(ESI): m/z calcd for C52H51N8O10Zn [M + H]+: 1011.3014, found
1011.3023.
1
ZnPc(b-PGlu)4 (4)
mixture of phthalonitrile
A
3 (0.56 g, 1.0 mmol) and
Zn(OAc)2·2H2O (55 mg, 0.25 mmol) in n-pentanol (10 mL) was
heated to 100 ◦C, then a small amount of ◦DBU (0.8 mL) was
added. The mixture was stirred at 140–150 C for 24 h. After a
brief cooling, the volatiles were removed under reduced pressure.
The residue was purified by silica gel column chromatography
using THF–hexane (3 : 2 v/v) as the eluent, followed by size
exclusion chromatography using THF as the eluent. The crude
product was further purified by recrystallisation from a mixture
1
of THF and hexane (0.14 g, 24%). H NMR (300 MHz, CDCl3
with a trace amount of pyridine-d5): d 9.21–9.28 (m, 4 H, Pc-Ha),
8.82 (virtual s, 4 H, Pc-Ha), 7.69–7.75 (m, 4 H, Pc-Hb), 5.89–5.90
(m, 4 H, H1), 4.70 (br s, 8 H, PcOCH2), 4.59–4.61 (m, 4 H, H2),
4.32–4.39 (m, 4 H, H5), 3.98–4.21 (m, 20 H, CH2, H4 and H6),
3.92–3.96 (m, 12 H, CH2 and H3), 3.83 (virtual t, J = 4.5 Hz, 8 H,
CH2), 3.69–3.78 (m, 24 H, CH2), 3.66 (t, J = 4.2 Hz, 8 H, CH2),
1.47 (s, 12 H, CH3), 1.42 (s, 12 H, CH3), 1.36 (s, 12 H, CH3), 1.29
(s, 12 H, CH3). MS (ESI): an isotopic cluster peaking at m/z 2316
{100%, [M + H]+}. HRMS (ESI): m/z calcd for C112H153N8O40Zn
[M + H]+: 2314.9504, found 2314.9502.
Glucosylated tosylate 8
To a solution of p-toluenesulfonyl chloride (345 mg, 1.81 mmol) in
pyridine (2 mL) was added the glucose-substituted tetraethylene
glycol 1 (280 mg, 0.64 mmol). The mixture was stirred at
room temperature for 24 h, then water (5 mL) was added to
quench the reaction. The mixture was then extracted with CH2Cl2
(20 mL ¥ 3). The combined organic fractions were dried over
anhydrous MgSO4 and rotary-evaporated to dryness. The residue
was chromatographed using ethyl acetate as the eluent to give the
product as a colourless liquid (325 mg, 86%). 1H NMR (300 MHz,
CDCl3): d 7.80 (d, J = 8.1 Hz, 2 H, ArH), 7.34 (d, J = 8.1 Hz,
2 H, ArH), 5.86 (d, J = 3.6 Hz, 1 H, H1), 4.57 (d, J = 3.6 Hz, 1
H, H2), 4.26–4.32 (m, 1 H, H5), 4.05–4.18 (m, 4 H, CH2 and H6),
3.96–4.02 (m, 1 H, H4), 3.92 (d, J = 2.7 Hz, 1 H, H3), 3.71–3.77
(m, 2 H, CH2), 3.69 (t, J = 4.8 Hz, 2 H, CH2), 3.58–3.63 (m, 10
H, CH2), 2.45 (s, 3 H, CH3), 1.49 (s, 3 H, CH3), 1.42 (s, 3 H, CH3),
ZnPc(b-Glu)4 (5)
A mixture of phthalocyanine 4 (70 mg, 0.03 mmol) in TFA/water
(9 : 1 v/v) (2 mL) was stirred at room temperature for 30 min. The
volatiles were then removed under reduced pressure. The residue
was dissolved in water (2 mL), then CH3OH (ca. 10 mL) was added
to induce precipitation. The product was collected by filtration as
a blue solid which was then dried in vacuo (46 mg, 77%). 1H NMR
(300 MHz, CDCl3 with a trace amount of pyridine-d5): d 9.25
(br s, 4 H, Pc-Ha), 8.84 (br s, 4 H, Pc-Ha), 7.71 (br s, 4 H, Pc-
Hb), 3.6–5.9 (several multiplets). MS (ESI): an isotopic cluster
peaking at m/z 1995 {100%, [M + H]+}. HRMS (ESI): m/z calcd
for C88H121N8O40Zn [M + H]+: 1993.6966, found 1993.6934.
1.34 (s, 3 H, CH3), 1.31 (s, 3 H, CH3). 13C{ H} NMR (75.4 MHz,
1
CDCl3): d 144.8, 133.0, 129.8, 127.9, 111.7, 108.8, 105.2, 82.7,
82.6, 81.1, 72.5, 70.7, 70.6 (two overlapping signals), 70.5, 70.4,
70.1, 69.2, 68.7, 67.1, 26.8, 26.7, 26.2, 25.4, 21.6. MS (ESI): an
isotopic cluster peaking at m/z 613 {100%, [M + Na]+}. HRMS
(ESI): m/z calcd for C27H42NaO12S [M + Na]+ 613.2289, found
613.2282.
ZnPc(b-PGlu) (7)
Bis(glucosylated) phthalonitrile 10
A mixture of phthalonitrile 3 (0.56 g, 1.0 mmol), unsubstituted
phthalonitrile (6) (1.15 g, 9.0 mmol) and Zn(OAc)2·2H2O (0.55 g,
2.5 mmol) in n-pentanol (15 mL) was heated to 100 ◦C, then a
small amount of DBU (1 mL) was added. The mixture was stirred
To a mixture of tosylate 8 (2.70 g, 4.57 mmol) and 2,3-
dicyanohydroquinone (9) (0.37 g, 2.31 mmol) in DMF (10 mL)
was added anhydrous K2CO3 (1.26 g, 9.12 mmol). The mixture
was stirred at 110 ◦C for 24 h, then the solvent was removed at ca.
60 ◦C in vacuo. The residue was mixed with water (100 mL) and the
mixture was extracted with CH2Cl2 (100 mL ¥ 3). The combined
organic fractions were dried over anhydrous MgSO4 and rotary-
evaporated to dryness. The crude product was purified by silica
gel column chromatography using ethyl acetate–CHCl3 (1 : 5 v/v)
as the eluent. The product was isolated as a colourless oil (2.10 g,
92%). 1H NMR (300 MHz, CDCl3): d 7.23 (s, 2 H, ArH), 5.87 (d,
J = 3.6 Hz, 2 H, H1), 4.58 (d, J = 3.6 Hz, 2 H, H2), 4.28–4.33 (m,
2 H, H5), 4.23 (virtual t, J = 4.8 Hz, 4 H, ArOCH2), 4.06–4.14
(m, 4 H, H6), 3.96–4.02 (m, 2 H, H4), 3.88–3.93 (m, 6 H, CH2 and
H3), 3.72–3.78 (m, 8 H, CH2), 3.61–3.69 (m, 16 H, CH2), 1.49 (s, 6
H, CH3), 1.42 (s, 6 H, CH3), 1.35 (s, 6 H, CH3), 1.31 (s, 6 H, CH3).
◦
at 140–150 C for 24 h. After a brief cooling, the volatiles were
removed under reduced pressure. The residue was dissolved in
CHCl3 (150 mL), then filtered to remove part of the unsubstituted
zinc(II) phthalocyanine formed. The filtrate was collected and
evaporated to dryness in vacuo. The residue was purified by silica
gel column chromatography using CHCl3–CH3OH (30 : 1 v/v) as
the eluent, followed by size exclusion chromatography using THF
as the eluent. The product was further purified by recrystallisation
from a mixture of THF and hexane (0.15 g, 15%). 1H NMR
(300 MHz, CDCl3 with a trace amount of pyridine-d5): d 9.31–
9.39 (m, 6 H, Pc-Ha), 9.14 (d, J = 8.4 Hz, 1 H, Pc-Ha), 8.71 (s, 1
H, Pc-Ha), 8.06–8.15 (m, 6 H, Pc-Hb), 7.62–7.69 (m, 1 H, Pc-Hb),
5.89 (d, J = 3.6 Hz, 1 H, H1), 4.68 (virtual t, J = 4.5 Hz, 2 H,
PcOCH2), 4.60 (d, J = 3.6 Hz, 1 H, H2), 4.31–4.38 (m, 1 H, H5),
4.08–4.20 (m, 4 H, CH2 and H6), 3.92–4.03 (m, 4 H, CH2, H3 and
H4), 3.82–3.86 (m, 2 H, CH2), 3.72–3.79 (m, 6 H, CH2), 3.67 (t,
J = 4.5 Hz, 2 H, CH2), 1.48 (s, 3 H, CH3), 1.43 (s, 3 H, CH3),
1
13C{ H} NMR (75.4 MHz, CDCl3): d 155.3, 119.1, 112.9, 111.7,
108.8, 105.2, 82.6, 82.5, 81.0, 72.5, 71.1, 70.6, 70.4, 70.1, 70.0, 69.3,
67.1, 26.8, 26.7, 26.2, 25.4 (some of the signals are overlapped).
MS (ESI): an isotopic cluster peaking at m/z 1020 {100%, [M +
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Na]+}. HRMS (ESI): m/z calcd for C48H72N2NaO20 [M + Na]+
Ditosylate 16
1019.4572, found 1019.4573.
A mixture of the diol 15 (4.80 g, 7.7 mmol), tosyl chloride (5.72 g,
30.0 mmol) and triethylamine (2.6 mL, 18.6 mmol) in CH2Cl2
(60 mL) was stirred at room temperature for 24 h. The mixture
was poured into 2 N hydrochloric acid (60 mL), then extracted
with CH2Cl2 (180 mL). The organic layer was washed with water
(100 mL ¥ 3) and dried over anhydrous MgSO4. After evaporation,
the residue was chromatographed on a silica gel column using ethyl
acetate–hexane (1 : 1 v/v) followed by ethyl acetate as the eluents.
ZnPc(a-PGlu)2 (11)
According to the procedure described for 7, phthalonitrile 10
(0.50 g, 0.50 mmol) was treated with unsubstituted phthalonitrile
(6) (0.58 g, 4.51 mmol) and Zn(OAc)2·2H2O (0.28 g, 1.25 mmol)
to give 11 as a blue-green solid (87 mg, 12%). 1H NMR (300 MHz,
CDCl3 with a trace amount of pyridine-d5): d 9.37–9.43 (m, 4 H,
Pc-Ha), 9.30 (d, J = 6.0 Hz, 2 H, Pc-Ha), 8.08–8.17 (m, 6 H, Pc-
Hb), 7.45 (s, 2 H, Pc-Hb), 5.87 (d, J = 3.6 Hz, 2 H, H1), 4.93 (t,
J = 5.1 Hz, 4 H, PcOCH2), 4.56 (d, J = 3.6 Hz, 2 H, H2), 4.53 (t,
J = 5.1 Hz, 4 H, CH2), 4.28–4.35 (m, 2 H, H5), 4.06–4.17 (m, 8
H, CH2 and H6), 3.97–4.01 (m, 2 H, H4), 3.86–3.91 (m, 6 H, CH2
and H3), 3.58–3.75 (m, 16 H, CH2), 1.47 (s, 6 H, CH3), 1.41 (s, 6
1
The product was isolated as a colourless oil (4.88 g, 68%). H
NMR (300 MHz, CDCl3): d 7.79 (d, J = 8.4 Hz, 4 H, ArH),
7.34 (d, J = 8.4 Hz, 4 H, ArH), 7.13 (s, 2 H, ArH), 4.10–4.17
(m, 8 H, CH2), 3.83 (virtual t, J = 5.1 Hz, 4 H, CH2), 3.58–3.71
1
(m, 20 H, CH2), 2.44 (s, 6 H, CH3). 13C{ H} NMR (75.4 MHz,
CDCl3): d 148.8, 144.7, 132.9, 129.8, 127.9, 119.0, 115.2, 70.8,
70.7, 70.6, 70.5, 69.5, 69.2 (two overlapping signals), 68.6, 21.6.
MS (ESI): several isotopic clusters peaking at m/z 793 {64%, [M +
Na - 2 Br]+}, 873 {42%, [M + Na - Br]+} and 951 {100%, [M +
Na]+}. HRMS (ESI): m/z calcd for C36H48Br2NaO14S2 [M + Na]+:
951.0724, found 951.0723.
H, CH3), 1.34 (s, 6 H, CH3), 1.28 (s, 6 H, CH3). 13C{ H} NMR
1
(75.4 MHz, CDCl3 with a trace amount of pyridine-d5): d 153.9,
153.8, 153.6, 152.6, 150.4, 138.9, 138.5, 129.0, 127.4, 122.6, 122.5,
115.0, 111.6, 108.8, 105.2, 82.6, 82.5, 81.0, 72.5, 71.1, 70.8, 70.7,
70.6, 70.5, 70.4, 70.0, 69.2, 67.1, 26.7 (two overlapping signals),
26.2, 25.4 (some of the Pc signals are overlapped). MS (ESI): an
isotopic cluster peaking at m/z 1468 {100%, [M + Na]+}. HRMS
(ESI): m/z calcd for C72H84N8NaO20Zn [M + Na]+: 1467.4986,
found 1467.4976.
Bis(glucosylated) dibromobenzene 18
Ditosylate 16 (5.85 g, 6.3 mmol) was added into a mixture
of 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (17) (3.28 g,
12.6 mmol) and NaH (60% in mineral oil, 0.50 g, 12.5 mmol)
in THF (60 mL). The mixture was stirred at room temperature
overnight, then evaporated in vacuo. The residue was mixed with
water (120 mL) and the mixture was extracted with CH2Cl2
(120 mL ¥ 3). The combined organic fractions were dried over
anhydrous MgSO4. After evaporation, the residue was chro-
matographed on a silica gel column using ethyl acetate as the
eluent (6.05 g, 87%). 1H NMR (300 MHz, CDCl3): d 7.15 (s, 2 H,
ArH), 5.87 (d, J = 3.6 Hz, 2 H, H1), 4.57 (d, J = 3.6 Hz, 2 H,
H2), 4.27–4.33 (m, 2 H, H5), 4.05–4.15 (m, 8 H, CH2 and H6),
3.97–4.02 (m, 2 H, H4), 3.92 (d, J = 3.0 Hz, 2 H, H3), 3.83 (t, J =
5.1 Hz, 4 H, CH2), 3.60–3.76 (m, 24 H, CH2), 1.49 (s, 6 H, CH3),
ZnPc(a-Glu)2 (12)
Phthalocyanine 11 (60 mg, 0.04 mmol) was dissolved in
TFA/water (9 : 1 v/v) (2 mL). The mixture was stirred at room
temperature for 30 min, then the volatiles were removed in vacuo.
The residue was dissolved in water (2 mL), then CH3OH (ca.
10 mL) was added to induce precipitation. The product was
collected by filtration as a blue solid which was then dried in
1
vacuo (47 mg, 89%). H NMR (300 MHz, CDCl3 with a trace
amount of pyridine-d5): d 9.24 (br s, 4 H, Pc-Ha), 9.15 (br s, 2
H, Pc-Ha), 7.90–8.00 (m, 6 H, Pc-Hb), 7.36 (s, 2 H, Pc-Hb), 3.1–
5.4 (several multiplets). MS (ESI): an isotopic cluster peaking
at m/z 1307 {100%, [M + Na]+}. HRMS (ESI): m/z calcd for
C60H68N8NaO20Zn [M + Na]+: 1307.3734, found 1307.3734.
1
1.42 (s, 6 H, CH3), 1.34 (s, 6 H, CH3), 1.31 (s, 6 H, CH3). 13C{ H}
NMR (75.4 MHz, CDCl3): d 148.8, 119.1, 115.3, 111.7, 108.9,
105.2, 82.7, 82.6, 81.1, 72.5, 70.9, 70.7 (three overlapping signals),
70.4, 70.1, 69.6, 69.2, 67.1, 26.8, 26.7, 26.2, 25.4. MS (ESI): an
isotopic cluster peaking at m/z 1127 {100%, [M + Na]+}. HRMS
(ESI): m/z calcd for C46H72Br2NaO20 [M + Na]+: 1127.2855, found
1127.2857.
Diol 15
A mixture of 4,5-dibromocatechol (13) (3.1 g, 11.6 mmol), tosylate
14 (16.0 g, 45.9 mmol) and K2CO3 (21.1 g, 0.15 mol) in DMF
(80 mL) was stirred at 100 ◦C for ca. 60 h. The mixture was
allowed to cool down to room temperature, then it was poured
into water (160 mL). The organic layer was extracted with CH2Cl2
(120 mL ¥ 3), washed with water (90 mL ¥ 4), and dried over
anhydrous MgSO4. The crude product was purified by silica gel
column chromatography using CH2Cl2–CH3OH (8 : 1 v/v) as the
Bis(glucosylated) phthalonitrile 19
A mixture of 18 (1.62 g, 1.47 mmol) and CuCN (0.39 g, 4.35 mmol)
in DMF (15 mL) was refluxed for 12 h. The mixture was allowed to
cool down to room temperature, then poured into 30% aqueous
ammonia (25 mL). The blue solution was bubbled with air for
2 h, then filtered. The filtrate was extracted with CH2Cl2 (200 mL)
and the organic portion was washed with water (90 mL ¥ 3).
After evaporation, the residue was chromatographed on a silica
gel column using ethyl acetate as the eluent to give the product
as a colourless oil (0.18 g, 12%). 1H NMR (300 MHz, CDCl3): d
7.34 (s, 2 H, ArH), 5.87 (d, J = 3.6 Hz, 2 H, H1), 4.57 (d, J =
3.6 Hz, 2 H, H2), 4.20–4.33 (m, 6 H, CH2 and H5), 4.05–4.14
(m, 4 H, H6), 3.97–4.02 (m, 2 H, H4), 3.87–3.92 (m, 6 H, CH2
1
eluent to give the product as a colourless liquid (6.4 g, 90%). H
NMR (300 MHz, CDCl3): d 7.13 (s, 2 H, ArH), 4.13 (t, J = 4.8 Hz,
4 H, CH2), 3.85 (t, J = 4.8 Hz, 4 H, CH2), 3.65–3.75 (m, 20 H,
CH2), 3.57–3.61 (m, 4 H, CH2), 3.07 (t, J = 5.4 Hz, 2 H, OH).
1
13C{ H} NMR (75.4 MHz, CDCl3): d 148.5, 118.5, 115.1, 72.5,
70.6, 70.4, 70.3, 70.0, 69.3, 69.0, 61.4. MS (ESI): several isotopic
clusters peaking at m/z 485 {100%, [M + Na - 2 Br]+}, 565 {29%,
[M + Na - Br]+} and 643 {56%, [M + Na]+}. HRMS (ESI): m/z
calcd for C22H36Br2NaO10 [M + Na]+: 643.0547, found 643.0545.
1590 | Org. Biomol. Chem., 2009, 7, 1583–1591
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and H3), 3.60–3.77 (m, 24 H, CH2), 1.49 (s, 6 H, CH3), 1.42 (s, 6
(e) M. Sibrian-Vazquez, J. Ortiz, I. V. Nesterova, F. Ferna´ndez-La´zaro,
A. Sastre-Santos, S. A. Soper and M. G. H. Vicente, Bioconjugate
Chem., 2007, 18, 410; (f) H. Li, T. J. Jensen, F. R. Fronczek and M. G. H.
Vicente, J. Med. Chem., 2008, 51, 502; (g) J.-Y. Liu, X.-J. Jiang, W.-P.
Fong and D. K. P. Ng, Metal-Based Drugs, 2008, Article ID 284691;
(h) S. C. H. Leung, P.-C. Lo, D. K. P. Ng, W.-K. Liu, K.-P. Fung and
W.-P. Fong, Br. J. Pharm., 2008, 154, 4.
3 J.-P. Taquet, C. Frochot, V. Manneville and M. Barberi-Heyob, Curr.
Med. Chem., 2007, 14, 1673.
4 O. Warburg, Science, 1956, 123, 309.
1
H, CH3), 1.35 (s, 6 H, CH3), 1.31 (s, 6 H, CH3). 13C{ H} NMR
(75.4 MHz, CDCl3): d 152.3, 117.1, 115.7, 113.5, 111.7, 108.9,
105.2, 82.7, 82.6, 81.1, 72.5, 70.6, 70.4, 70.1, 69.4, 69.3, 67.1, 26.8,
26.7, 26.2, 25.4 (some of the signals are overlapped). MS (ESI): an
isotopic cluster peaking at m/z 1019 {100%, [M + Na]+}. HRMS
(ESI): m/z calcd for C48H72N2NaO20 [M + Na]+: 1019.4571, found
1019.4579.
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ZnPc(b-PGlu)2 (20)
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According to the procedure described for 7, phthalonitrile 19
(218 mg, 0.22 mmol) was treated with unsubstituted phthalonitrile
(6) (281 mg, 2.19 mmol) and Zn(OAc)2·2H2O (132 mg, 0.60 mmol)
to give 20 as a blue solid (45 mg, 14%). 1H NMR (300 MHz, CDCl3
with a trace amount of pyridine-d5): d 9.23–9.35 (m, 6 H, Pc-Ha),
8.58 (s, 2 H, Pc-Ha), 8.06–8.14 (m, 6 H, Pc-Hb), 5.88 (d, J =
3.6 Hz, 2 H, H1), 4.72 (t, J = 4.8 Hz, 4 H, PcOCH2), 4.59 (d,
J = 3.6 Hz, 2 H, H2), 4.30–4.37 (m, 2 H, H5), 4.24 (virtual t, J =
4.8 Hz, 4 H, CH2), 4.08–4.15 (m, 4 H, H6), 3.98–4.02 (m, 6 H,
CH2 and H4), 3.94 (d, J = 3.0 Hz, 2 H, H3), 3.85–3.88 (m, 4 H,
CH2), 3.72–3.82 (m, 12 H, CH2), 3.65–3.68 (m, 4 H, CH2), 1.48
(s, 6 H, CH3), 1.42 (s, 6 H, CH3), 1.35 (s, 6 H, CH3), 1.30 (s, 6
1
H, CH3). 13C{ H} NMR (75.4 MHz, CDCl3 with a trace amount
of pyridine-d5): d 153.1, 153.0, 152.8, 150.7, 138.3, 138.1, 132.1,
128.7, 122.4, 111.6, 108.8, 105.6, 105.2, 82.6 (two overlapping
signals), 81.0, 72.5, 71.0, 70.8, 70.7, 70.6, 70.4, 70.0, 69.8, 68.9,
67.0, 26.7 (two overlapping signals), 26.1, 25.4 (some of the Pc
signals are overlapped). MS (ESI): an isotopic cluster peaking
at m/z 1468 {100%, [M + Na]+}. HRMS (ESI): m/z calcd for
C72H84N8NaO20Zn [M + Na]+: 1467.4986, found 1467.4981.
Acknowledgements
We thank Prof. Wing-Hung Ko of the Physiology Department for
technical support in the fluorescence imaging study. This work
was supported by a grant from the Research Grants Council of
the Hong Kong Special Administrative Region, China (Project
No. 402505) and a strategic investments scheme administered by
The Chinese University of Hong Kong.
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