Synthesis of carbohydrate-conjugated azaphthalocyanine complexes for PDT

Article abstract of DOI:10.1016/j.tetlet.2015.05.065

Abstract A series of azaphthalocyanine (AzaPc) complexes conjugated with one or two carbohydrate groups for photodynamic therapy (PDT) were synthesized by the alkyne-azide click chemistry reaction with previously-developed AzaPc complexes incorporating th

Full text of DOI:10.1016/j.tetlet.2015.05.065

Accepted Manuscript
Synthesis of carbohydrate-conjugated azaphthalocyanine complexes for PDT
Jong Min Park, Cheol Jun Song, Wang Yao, Chang Young Jung, In Ho Hyun,
Dong Hoon Seong, Jae Yun Jaung
PII:
S0040-4039(15)00874-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.05.065
TETL 46337
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 April 2015
12 May 2015
18 May 2015
Please cite this article as: Park, J.M., Song, C.J., Yao, W., Jung, C.Y., Hyun, I.H., Seong, D.H., Jaung, J.Y., Synthesis
of carbohydrate-conjugated azaphthalocyanine complexes for PDT, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.05.065
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Synthesis of carbohydrate-conjugated
azaphthalocyanine complexes for PDT
Leave this area blank for abstract info.
Jong Min Park, Cheol Jun Song, Wang Yao, Chang Young Jung, In Ho Hyun, Dong Hoon Seong and Jae Yun
Jaung∗
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Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of carbohydrate-conjugated azaphthalocyanine complexes for PDT
Jong Min Park, Cheol Jun Song, Wang Yao, Chang Young Jung, In Ho Hyun, Dong Hoon Seong and Jae
Yun Jaung∗
Department of Organic and Nano Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of azaphthalocyanine (AzaPc) complexes conjugated with one or two carbohydrate
groups for photodynamic therapy (PDT) were synthesized by the alkyne – azide click chemistry
reaction with previously-developed AzaPc complexes incorporating the bornane group.
Received in revised form
Accepted
2
015 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Azaphthalocyanine
Sugar conjugation
Photodynamic therapy
Photosensitizer
Click chemistry
Phthalocyanines (Pcs) are remarkable compounds possessing
photophysical, semiconducting, and photoconducting properties
due to their 18π-electron aromatic macrocyclic structures .
bioconjugation to porphyrins and related molecules, which
represent the majority of PDT agents. Sugars are an attractive
type of biomolecule to conjugate with photosensitizers, because
they are not only biologically active, but also improve water
1
Among the phthalocyanines, azaphthalocyanines (AzaPcs), in
which nitrogens replace some of the carbons with the four fused
benzo- substituents of the phthalocyanine, have unique physical
1
5
solubility .
2
,
3
.
In this paper, we synthesized asymmetric A B-type AzaPc
3
properties including color, oxidation potential, and stability
complexes incorporating bornanes and two distinct carbohydrate
units, β-D-glucose and β-D-galactose, to investigate important
properties with applications in PDT sensitizers. Carbohydrate
groups were introduced at the periphery of the AzaPcs to enhance
their hydrophilicity. As bornane groups have bulky three-
dimensional structures, their introduction into the overall
structure was expected to aid in prevention of the axial or
peripheral approach between photosensitizers (PSs) without
Moreover, 2,3-dicyanopyrazines, the precursors of AzaPcs, are
comparatively easy to prepare, and their numerous derivatives
have been designed and prepared for potential use as biologically
4
active materials . The classical synthesis of 2,3-dicyanopyrazines
involves the condensation of diaminomalonitrile with 1,2-
dicarbonyl compounds. The reaction is facile and it’s the most
widely used synthetic method for 1,2-dicyanopyrazine
5
derivatives .
3
altering optical properties, because of the fully sp structure of
1
6
The potential applications of phthalocyanines (Pcs) have been
explored for decades in various fields including photodynamic
therapy (PDT) , the dyeing industry , semiconducting device ,
bornane .
6
7
8
The reaction pathways for the preparation of the complexes
are shown in Scheme 1. The synthesis procedures of compounds
9
10
11
liquid crystals , chemosensors and solar cells .
17
18
and 6 have been explained by previous researchers.
1
Dicyanopyrazines 2, substituted with the triisopropylsilyl (TIPS)
acetylene group, were obtained through the Heck reaction
The solubility of Pc in various solvents is critical for
application in PDT; however, many phthalocyanines are not
soluble in common organic solutions, though their solubility can
be improved by peripheral or axial substituents such as long
2 3
between diketones 1 and TIPS-acetylene with Pd(OAc) and PPh
as the catalyst, followed by a condensation reaction with
diaminomaleonitrile (DAMN) in the presence of p-
toluenesulfonic acid as a catalyst. The metal free AzaPc
complexes 4 were obtained in two steps. First, 3.5 equivalents of
1
2
13
14
alkyl , alkoxy , and other bulky groups .
Recent research has focused on the use of biomolecules with
specific selectivity for tumor-associated antigens, receptors, or
specific structural features of tumor morphology. The use of
biomolecules with an affinity for tumor tissue as targeting agents
for PDT sensitizers has grown together with methods for
3
and 1 equivalent of 2 were reacted in the presence of Mg
turnings in n-butanol to give the AzaPc Mg complexes, and then
the crude AzaPc Mg complexes were treated with excess p-
—
——
∗
Corresponding author. Tel.: +82-2-2220-0492; fax: +82-2-2220-4092; e-mail: jjy1004@hanyang.ac.kr

2
Tetrahedron
1
3
NMR, C NMR, elemental analysis, and MALDI-TOF mass
toluenesulfonic acid to remove the complexed Mg. After
purification via chromatography on silica gel with the appropriate
solvent, the pure A B-type, metal-free AzaPc was treated with
Zn(OAc) in DMF/toluene solvent (1/1) at reflux to obtain AzaPc
Zn complexes 5. To obtain the carbohydrate-conjugated AzaPc
complexes 7, the TIPS groups were removed using excess
tetrabutylammonium fluoride, and then the unprotected AzaPc
was reacted with compound 6 through click chemistry using a
1
spectra. The H NMR peaks from the AzaPc macrocycles were
3
broad due to the nonsymmetrical structure of the AzaPc
complexes and the shielding and deshielding effects in the
1
complicated heterocyclic structure. In the H NMR spectrum of
2
8a, the protons of the bornane groups appeared near δ 0.85 ppm ~
2.60 ppm, and the local protons of the carbohydrate and ethylene
glycol groups were observed as multiples near δ 3.08 ppm ~ 5.32
ppm. The protons of the aromatic and triazole groups were
observed as broad peaks around δ 7.67 ppm ~ 8.08 ppm and δ
catalytic
amount
of
CuI
and
N,N,N’,N’,N”-
pentamethyldiethylenetriamine (PMDTA) in THF at reflux. The
final products 8 were obtained through deacetylation of the
AzaPc complexes 7 using sodium methoxide in methanol.
1
3
8.86 ppm, respectively. In the C NMR spectrum, carbon peaks
of bornane, carbohydrate, and ethylene glycol groups were
observed as a strong peak below δ 100 ppm; however, the peaks
1
The structures of the target compounds were confirmed via H
Scheme 1. Synthesis of AzaPc complexes 8. (i) PPh
EtOH, reflux, 3h, (iii) Mg turnings, I , reflux, 4h, (iv) p-TsOH, THF, r.t., 1h, (v) Zn(OAc)
h, (vi) TBAF, THF, r.t., 3h, (vii) 6, CuI, PMDTA, THF, reflux, 5h, (viii) CH ONa, MeOH, r.t. 4h.
3
, Pd(OAc)
2
, (i-Pr)
3
SiC≡CH, TEA, reflux, 4h, (ii) DAMN, p-TsOH,
2
2
, DMF/Toluene(1:1), reflux,
4
3

3
was investigated in DMSO and DMSO / water mixture as
solvent. As mentioned above, the absorption spectra of 8b-Glc
indicated that they existed as monomeric state in DMSO. On the
other hand, as the water ratio was increased, the new band was
found near 602 nm, caused by aggregation, and below 25% of
water ratio, obvious isosbestic point was exhibited, indicating
that monomer and aggregate (probably dimer) are in equilibrium.
8
b-Gal showed similar spectral behavior in the same condition.
Figure 1. UV-Vis absorption spectra of 8 in DMSO normalized at B-
band
of the aromatic and central carbons were exhibited weakly above
δ 100 ppm. In the MALDI-TOF mass spectra of 8a-Glc, the
peaks were observed at 1391.96 and 1180.01. The peak at
1
391.96 corresponded with the original molecular weight of 8a-
Glc. The peak at 1180.01 corresponded with triazole ring
fragmented form of 8a-Glc. Due to the fragmentation of triazole
ring, the conjugated parts including ethylene glycol and
1
9
carbohydrate fell off from AzaPc complexes . Other compounds
1
8a-Gal, 8b-Glc and 8b-Gal) showed similar behaviors with H
Figure 3. UV-Vis absorption spectra of 8b-Glc in DMSO and DMSO /
water mixture. The specific concentrations are 10 µM.
(
NMR, C NMR, and MALDI-TOF mass spectra as well.
1
3
3
In summary, we have synthesized A B-type AzaPc complexes
The UV-Vis absorption spectra of AzaPc complex 8 in DMSO
is shown in Figure 1. All compounds are monomeric in DMSO,
which axially bind to Pc Zn(II) macromolecules, reducing their
conjugated with one or two carbohydrate groups, and have
1
13
confirmed their structure using H NMR, C NMR, Elemental
analysis, and MALDI-TOF mass spectra. The synthesized
compounds did not show aggregation in DMSO. 8b was slightly
soluble and aggregated in water. Future testing of the AzaPc
complexes against different cancer cell lines is being perused to
determine their potential targeting selectivity.
2
0
aggregation behavior . Thus, a sharp and strong Q-band and a
broad and weak B-band in aprotic polar solvents were observed
near 637 nm and 336 nm, respectively. Moreover, 8b-Glc obeyed
Lambert-Beer’s law in concentration ranging from 1 µM to 15
µM. As the concentration of 8b-Glc was increased, the Q-band
absorption intensity increased as well, and the new bands,
induced by aggregation, were not found in DMSO (Figure 2).
The other AzaPc complexes 8 also showed a similar behavior in
DMSO. The solubility of AzaPc 8 in water showed variation,
based on the number of carbohydrate groups. 8a were insoluble
in water because the inter-force between the carbohydrate group
and water is most likely insufficient for 8a to dissolve. In
comparison to 8a, 8b were dissolved in water. To research for
aggregation behavior, the UV-Vis absorption spectra of 8b-Glc
Acknowledgments
This work was supported by the Technology Innovation
Program (No. 10047759, Development of tetra-pyrrole type for
Color, light-emitting, detecting Devices) funded by the Ministry
of Trade, Industry & Energy (MI, Korea)
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at
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