First example of an octa-glycoconjugated magnesium(II)porphyrazine

Article abstract of DOI:10.1016/j.tetlet.2015.12.076

Treatment of disodium maleonitriledithiolate with 1,2:3,4-di-O-isopropylidene-6-O-trifluoromethanesulfonyl-α-d-galactopyranose gives 2,3-bis(6-deoxy-1,2:3,4-di-O-isopropylidene-6-thio-α-d-galactopyranos-6-yl)maleonitrile in 87% yield. Heating of the latter with magnesium bis(butan-1-olate) in butan-1-ol affords [2,3,7,8,12,13,17,18-octakis(6-deoxy-1,2:3,4-di-O-isopropylidene-6-thio-α-d-galactopyranos-6-yl)porphyrazinato]magnesium(II) in 53% yield. The glycoconjugated porphyrazine has an absorbance maximum at 673 nm and is a candidate as photosensitizer for photodynamic therapy.

Full text of DOI:10.1016/j.tetlet.2015.12.076

Tetrahedron Letters 57 (2016) 495–497
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First example of an octa-glycoconjugated magnesium
(II)porphyrazine
⇑
Thomas Klein, Thomas Ziegler
Institute of Organic Chemistry, University of Tuebingen, Auf der Morgenstelle 18, 72076 Tuebingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of disodium maleonitriledithiolate with 1,2:3,4-di-O-isopropylidene-6-O-trifluoromethane-
Received 21 October 2015
Revised 17 December 2015
Accepted 18 December 2015
Available online 19 December 2015
sulfonyl-
ranos-6-yl)maleonitrile in 87% yield. Heating of the latter with magnesium bis(butan-1-olate) in
butan-1-ol affords [2,3,7,8,12,13,17,18-octakis(6-deoxy-1,2:3,4-di-O-isopropylidene-6-thio- -galac-
topyranos-6-yl)porphyrazinato]magnesium(II) in 53% yield. The glycoconjugated porphyrazine has an
absorbance maximum at 673 nm and is a candidate as photosensitizer for photodynamic therapy.
Ó 2015 Elsevier Ltd. All rights reserved.
a-D-galactopyranose gives 2,3-bis(6-deoxy-1,2:3,4-di-O-isopropylidene-6-thio-a-D-galactopy-
a-D
Keywords:
Glycoconjugate
Porphyrazine
Glycosidation
Photosensitizer
Photodynamic therapy
Introduction
of these glycosylated Pc showed UV–Vis absorbance at wave-
lengths >700 nm and a diminished tendency to form aggregates
Photodynamic therapy (PDT), introduced into modern medicine
as a new treatment for cancer by Raab1 and von Tappeiner2,3 in
1904, has developed into an inalienable pillar of today’s strategies
for fighting cancer beside surgery, chemotherapy, and radiation
treatment.4 In general, PDT is applied by injecting a suitable photo-
sensitizer into the malignant tissue and irradiating the area with
light whereupon the photosensitizer becomes excited and converts
triplet oxygen usually abundantly present in tissues into singlet
oxygen and other reactive oxygen species (ROS) which, in turn,
destroy the malignant cell structures. Important prerequisites for
a successful application of PDT in cancer treatment comprise,
among others, a low dark toxicity, meaning that the photosensi-
tizer is not harmful to the target tissue without being irradiated,
and absorbance of longwave light, for it penetrates human tissue
deeper and causes less skin damage than shortwave light.4 Like-
wise, photosensitizers which are preferably or even selectively
accumulated in malignant cells are highly desirable too. Therefore,
new photosensitizers (dyes) fulfilling these prerequisites for an
efficient PDT need to get developed.
in solution which both make them suitable candidates as photo-
sensitizers for PDT.23 Encouraged by these results, we now report
on the first synthesis of a fully glycoconjugated magnesium(II)
porphyrazine, namely [2,3,7,8,12,13,17,18-octakis(6-deoxy-1,2:3,4-
di-O-isopropylidene-6-thio-a-D-galactopyranos-6-yl)porphyrazinato]
magnesium(II) (1) (Fig. 1). Recently, Williams24 and Horne25
reported the synthesis of some mono-glycoconjugated porphyrazi-
nes (Pz) of the A3B type in which the sugars are yoked to the
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
S
O
O
O
N
N
N
O
S
O
S
S
O
Mg
N
N
N
O
S
O
O
O
O
N
N
Previously, we and others have developed various synthetic
approaches toward a wide variety of glycoconjugated zinc(II)
phthalocyanines (Pc) for applications as photosensitizers5–17 (for
recent reviews about glycoconjugated Pc see Ref. 18–22). Some
O
O
O
O
S
S
O
O
O
O
O
O
O
O
O
1
O
O
⇑
Corresponding author. Tel.: +49 (0)7071 29 73035; fax: +49 (0)7071 29 5244.
E-mail address: thomas.ziegler@uni-tuebingen.de (T. Ziegler).
Figure 1. Glycoconjugated Mg(II)porphyrazine 1.
http://dx.doi.org/10.1016/j.tetlet.2015.12.076
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

496
T. Klein, T. Ziegler / Tetrahedron Letters 57 (2016) 495–497
benzene ring of the isoindole moiety of the A3B type porphyrazine
ring. These conjugates had been successfully applied as photosen-
sitizer for PDT. However, only a few examples of octa-substituted
Pz with thioether linkage at the periphery of the macrocycle
designed for medical purposes are described.26,27 To the best of
our knowledge, no octa-glycoconjugated or glycosylated por-
phyrazine of the A4 type, like 1, has been published so far and
we anticipated that a higher sugar content, as in 1, may positively
modulate the polarity, cell uptake, and aggregation behavior of
such photosensitizers.
Results and discussion
The most reliable method for the preparation of porphyrazines is
the tetramerization of maleonitriles under basic conditions and in
the presence of a metal ion (Linstead and similar methods).28–30
We chose sodium maleonitriledithiolate (2) (Fig. 2), for its two
thiolate groups are accessible for alkylations with electrophiles.
Maleonitrile 2 is also easily accessible in 2 steps from sodium
cyanide and carbon disulfide according to the method of Bähr and
Schleitzer.31
Figure 3. UV/Vis spectrum of porphyrazine 1 (12 lM) in DMSO.
the UV–Vis spectrum of the solid shows a very broad split Q-band.
The question, however, whether deprotection of 1 is mandatory for
its suitability for PDT or whether the protecting groups are just an
epithet must be answered through biological tests, for it is known
from glycosylated phthalocyanins that the protecting groups at the
sugar moieties can even enhance the biological activity in PDT.36,37
Treatment of maleonitrile 2 with 2.2 mol-equivalents of 1,2:3,4-
di-O-isopropylidene-6-O-trifluoromethanesulfonyl-a-D-galactopy-
ranose32,33 (3) in THF at room temperature for 48 h followed by
chromatographic purification gave 2,3-bis(6-deoxy-1,2:3,4-di-O-
isopropylidene-6-thio-
in 87% yield (Fig. 2). Using 6-bromo-6-deoxy-1,2:3,4-di-O-iso-
propylidene- -galactopyranose instead of 3 as alkylating agent
a-D
-galactopyranos-6-yl)maleonitrile34 (4)
Conclusion
a
-D
We have synthesized the first fully glycoconjugated A4 type
porphyrazine in an efficient 2-step process from easily accessible
sodium maleonitriledithiolate and diacetone galactose having a tri-
flyl leaving group at position 6. The porphyrazine was fully charac-
terized and showed an absorbance maximum for its Q-band of
673 nm making it a potential photosensitizer for applications in
PDT.
did not give 4 at all. The corresponding 6-iodo-6-deoxy-galactose,
prepared in situ from the bromide gave 4 in only poor 17% yield.
Next, when maleonitrile 4 was heated with in situ produced
magnesium bis(butan-1-olate) in butan-1-ol a smooth cyclote-
tramerization occurred and octa-glycoconjugated porphyrazine 1
was obtained in 53% yield as a fuscous blue amorphous material
after careful chromatographic purification.35 Porphyrazine 1 is
only slightly soluble in water (logPOW = 2.76) but exhibits an absor-
bance maximum for its Q-band of 673 nm (Fig. 3) and thus, makes
it suitable as photosensitizer for PDT. Unfortunately, the attempt to
selectively deprotect the sugar moieties of 1 (removal of the iso-
propylidene groups from the galactose moieties) under acidic con-
ditions5 (90% aqueous trifluoroacetic acid, room temperature, 2 h)
resulted in a dark blue and highly water soluble solid which could
not be identified by NMR- or MS-techniques. Most likely this can
be attributed to aggregation and the removal of the Mg2+ ion since
Acknowledgments
We thank the Karl & Anna Buck Stiftung – Germany and the
Deutsche Forschungsgemeinschaft (DFG) for financial support.
We also thank Dr. Kramer and Dr. Wistuba for recording the
NMR and MS data.
References and notes
1. Raab, O. Z. Biol. 1904, 39, 524–546.
2. von Tappeiner, H.; Jodlbauer, A. Dtsch. Arch. Klin. Med. 1904, 80, 427–487.
3. Jesionek, H.; von Tappeiner, H. Dtsch. Arch. Klin. Med. 1905, 82, 223–226.
4. Advances in Photodynamic Therapy: Basic, Translational, Clinical; Hamblin, M. R.,
Mróz, P., Eds., 1st ed.; Artech House: Norwood, 2008.
5. Crucius, G.; Hanack, M.; Ziegler, T. J. Porphyrins Phthalocyanines 2013, 17, 807–
813.
6. Iqbal, Z.; Ogunsipe, A.; Nyokong, T.; Lyubimtsev, A.; Hanack, M.; Ziegler, T. J.
Porphyrins Phthalocyanines 2012, 16, 413–422.
7. Iqbal, Z.; Lyubimtsev, A.; Hanack, M.; Ziegler, T. J. Porphyrins Phthalocyanines
2010, 14, 494–498.
8. Iqbal, Z.; Lyubimtsev, A.; Herrmann, T.; Hanack, M.; Ziegler, T. Synthesis 2010,
3097–3104.
9. Hanack, M.; Iqbal, Z.; Lyubimtsev, A.; Özcesmeci, I.; Özcesmeci, M.; Ziegler, T. J.
Porphyrins Phthalocyanines 2009, 13, 312–321.
10. Iqbal, Z.; Lyubimtsev, A.; Hanack, M.; Ziegler, T. Tetrahedron Lett. 2009, 50,
5681–5685.
11. Iqbal, Z.; Hanack, M.; Ziegler, T. Tetrahedron Lett. 2009, 50, 873–875.
12. Alvarez-Mico, X.; Calvete, M. J. F.; Hanack, M.; Ziegler, T. Tetrahedron Lett. 2006,
47, 3283–3286.
OSO2CF3
O
NC
CN
O
+
O
NaS
SNa
O
O
2
(1 eq.)
3
(2.2 eq.)
THF, 48 h
20 °C, 87%
NC
CN
S
Mg, I2, butan-1-ol
48 h, reflux, 53%
S
O
O
1
O
O
13. Ribeiro, A. O.; Tomé, J. P. C.; Neves, M. G. P. M. S.; Tomé, A. C.; Cavaleiro, J. A. S.;
Iamamoto, Y.; Torres, T. Tetrahedron Lett. 2006, 47, 9177–9180.
14. Choi, C.-F.; Huang, J.-D.; Lo, P.-C.; Fong, W.-P.; Ng, D. K. P. Org. Biomol. Chem.
2008, 6, 2173–2181.
O
O
O
O
O
O
15. Berthold, H. J.; Franke, S.; Thiem, J.; Schotten, T. J. Org. Chem. 2010, 75, 3859–
3862.
4
16. Silva, S.; Pereira, P. M. R.; Silva, P.; Almeida Paz, F. A.; Faustino, M. A. F.;
Cavaleiro, J. A. S.; Tome, J. P. C. Chem. Commun. 2012, 48, 3608–3610.
Figure 2. Synthesis of porphyrazine 1.

T. Klein, T. Ziegler / Tetrahedron Letters 57 (2016) 495–497
497
17. Lafont, D.; Zorlu, Y.; Savoie, H.; Albrieux, F.; Ahsen, V.; Boyle, R. W.; Dumoulin,
F. Photodiagn. Photodyn. Ther. 2013, 10, 252–259.
ethyl acetate (3 Â 50 mL). The combined extracts were washed with brine,
dried over sodium sulfate, filtered and concentrated. Chromatography of the
18. Singh, S.; Aggarwal, A.; Bhupathiraju, N. V. S. D. K.; Arianna, G.; Tiwari, K.;
Drain, C. M. Chem. Rev. 2015, 115, 10261–10306.
19. Hanack, M.; Crucius, G.; Calvete, M. J. F.; Ziegler, T. Curr. Org. Synth. 2014, 11,
59–66.
20. Lyubimtsev, A.; Iqbal, Z.; Crucius, G.; Syrbua, S.; Ziegler, T.; Hanack, M. J.
Porphyrins Phthalocyanines 2012, 16, 434–463.
21. Lourenco, L. M. O.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S.; Tomé, J. P. C.
Tetrahedron 2014, 70, 2681–2698.
residue with petrol ether/ethyl acetate (3:1) on silica gel gave 4 (3.44 g, 87%) as
20
an amorphous solid. [
a]
D
À103.8 (c 1.0, chloroform); ESI-TOF-HRMS m/z
calculated for [M+Na]+ 649.1860; found: 649.1859. 1H NMR 400.13 MHz
(CDCl3) d = 5.50 (d, 2H, J1,2 = 3.8 Hz, H-1gal), 4.63 (dd, 2H, J2,3 = 2.5 Hz,
J3,4 = 7.9 Hz, H-3gal), 4.32 (dd, 2H, H-2gal), 4.24 (dd, 2H, J4,5 = 1.9 Hz, H-4gal),
3.94 (ddd, 2H, J5,6a = 8.5 Hz, J5,6b = 5.4 Hz, H-5gal), 3.35 (dd, 2H, J6a,6b = À14.0 Hz,
H-6agal), 3.27 (dd, 2H, H-6bgal), 1.51, 1.45, 1.33, 1.32 (4s, 24H, CH3); 13C NMR
100.13 MHz (CDCl3) d = 121.5 (C@C), 112.3 (CN), 109.9, 109.0 (OACAO), 96.5
(C-1gal), 71.7 (C-4gal), 71.0 (C-3gal), 70.5 (C-2gal), 67.0 (C-5gal), 35.1 (C-6gal), 26.1,
26.0, 25.0, 24.5 (CH3).
22. Koifman, I. I.; Hanack, M.; Syrbu, S. A.; Lyubimtsev, A. V. Russ. Chem. Bull., Int.
Ed. 2013, 62, 896–917.
23. Lyubimtsev, A.; Iqbal, Z.; Crucius, G.; Syrbu, S.; Taraymovich, E. S.; Ziegler, T.;
Hanack, M. J. Porphyrins Phthalocyanines 2011, 15, 39–46.
24. Williams, D. B. G.; Mbatha, G. B. Dyes Pigm. 2011, 88, 65–74.
25. Horne, T. K.; Cronjé, M. J. Photochem. Photobiol. 2014, 90, 648–658.
26. Salvati, A.; Ristori, S.; Pietrangeli, D.; Oberdisse, J.; Calamai, L.; Martini, G.;
Ricciardi, G. Biophys. Chem. 2007, 131, 43–51.
27. Sholto, A.; Lee, S.; Hoffman, B. M.; Barrett, A. G. M.; Ehrenberg, B. Photochem.
Photobiol. 2008, 84, 764–773.
28. Cook, A. H.; Linstead, R. P. J. Chem. Soc. 1937, 929–933.
29. Tomada, H.; Saito, S.; Ogawa, S.; Shiraishi, S. Chem. Lett. 1980, 9, 1277–1280.
30. Rodríguez-Morgade, M. S.; Stuzhin, P. A. J. Porphyrins Phthalocyanines 2004, 8,
1129–1165.
31. Bähr, G.; Schleitzer, G. Chem. Ber. 1957, 90, 438–443.
32. Baryal, K. N.; Zhu, D.; Li, X.; Zhu, J. Angew. Chem., Int. Ed. Engl. 2013, 52, 8012–
8016.
33. Xie, W.; Tanabe, G.; Akai, J.; Morikawa, T.; Ninomiya, K.; Minematsu, T.;
Yoshikawa, M.; Wu, X.; Muraoka, O. Bioorg. Med. Chem. 2011, 19, 2015–2022.
34. A suspension of 2 (1.17 g, 6.3 mmol) and 3 (5.4 g, 13.8 mmol) in THF (60 mL)
was stirred at 20 °C for 48 h. Water (60 mL) was added and extracted with
35. A suspension of Mg (25 mg, 1.0 mmol) and a catalytic amount of iodine in
butan-1-ol (15 mL) was heated under reflux for 24 h until a clear solution was
formed. Maleonitrile
4 (627 mg, 1.0 mmol) was added and heating was
continued for another 24 h. The deep blue solution was cooled to room
temperature, filtered and concentrated. Chromatography with toluene/acetone
gradient (10:1–1:1) on silica gel gave 1 (338 mg, 53%) as a fuscous blue
amorphous solid. ESI-TOF-HRMS m/z calculated for [M+Na+H]2+ 1276.3843;
found: 1276.3829. 1H NMR 400.13 MHz (d6-acetone) d = 5.45 (d, 8H,
J1,2 = 4.9 Hz, H-1gal), 4.87 (d, 8H, J3,4 = 8.1 Hz, H-4gal), 4.66-4.61 (m, 16H, H-
6agal, H-3gal), 4.23 (dd, 8H, J2,3 = 2.3 Hz, H-2gal), 4.20-4.09 (m, 16H, H-5gal, H-
6bgal), 1.43, 1.35, 1.03, 0.46 (4s, 96H, CH3); 13C NMR 100.13 MHz (d6-acetone)
d = 158.3 (C@N), 141.2 (C@C), 109.7, 108.8 (OACAO), 97.4 (C-1gal), 72.8 (C-4gal),
71.9 (C-3gal), 71.5 (C-2gal), 68.5 (C-5gal), 35.6 (C-6gal), 26.5, 25.7, 25.0, 24.8
(CH3).
36. Ermeydan, M. A.; Dumoulin, F.; Basova, T. V.; Bouchu, D.; Gürek, A. G.; Ahsen,
V.; Lafont, D. New J. Chem. 2010, 34, 1153–1162.
37. Kimani, S. G.; Shmigol, T. A.; Hammond, S.; Phillips, J. B.; Bruce, J. I.; MacRobert,
A. J.; Malakhov, M. V.; Golding, J. P. Photochem. Photobiol. 2013, 89, 139–149.