symmetrical and unsymmetrical dyes. These dyes are usually
prepared by the condensation between squaric acid and
electron-rich aromatic, heteroaromatic, or olefinic compounds
in a one-step reaction.7 The success of the reaction depends
on the nucleophilicity of the aryl species, wherein only the
highly nucleophilic species was found to undergo the
condensation reaction.8 Recently,9 we have demonstrated that
quinaldinium salts with neutral and electron withdrawing
substituents give the corresponding squaraine dyes in quan-
titative yields, whereas the salts with electron-donating
substituents yield only the semisquaraine intermediates.
The objective of the present investigation has been to
design squaraine dyes for PDT applications that exhibit long
wavelength absorption and good cell permeability, since the
transport of the sensitizer through cell membrane is critical
to its effectiveness. The cellular uptake of both natural and
synthetic molecules can be enhanced by modification with
cationic peptides, proteins, lipids, encapsulation with lipo-
somes, and siderophores.10,11 Herein, we report the synthesis
of new squaraine dyes covalently linked to acetyl and cellular
recognition elements such as sugar and cholesterol (4b-e
and 5b-e) by making use of favorable electronic effects of
substituents. The presence of sugar and cholesterol units in
these dyes would render them amphiphilic and thereby
enhance their cell permeability and eventually their use as
sensitizers in PDT applications.
Scheme 1
As shown in Scheme 1, the reaction of 6-hydroxyquinal-
dine (1a) with 2,3,4,6-tetra-O-benzoyl-R-D-glucopyranosyl
bromide in the presence of NaOH and tetrabutylammonium
bromide (TBAB) gave the corresponding quinaldine 1b.
Subsequent reaction of 1b with sodium methoxide in
methanol yielded the corresponding sugar-linked quinaldine
derivative 1c. The reaction of 1a-c with methyl iodide at
100 °C in a sealed tube gave the corresponding quinaldinium
salts 2a-c in 90-95% yields (for details, see the Supporting
Information). The dye forming reaction between 2:1 equiv
of 2b and squaric acid was carried out in a mixture (1:1) of
n-butanol and benzene and was monitored by absorption
spectroscopy and product analysis. The absorption spectrum
of the reaction mixture after 0.5 h showed the formation of
a band at 500 nm corresponding to the semisquaraine 3b,
which increased with time (Figure S1, Supporting Informa-
tion). After about 7 h, the absorption spectrum showed the
formation of a new band at 740 nm, corresponding to the
symmetrical squaraine dye 4b, which, however, insignifi-
cantly increased with the time. The reaction mixture fol-
lowing workup and column chromatography after 30 h gave
semisquaraine 3b (80%) as the major product, along with
small amounts (10%) of the squaraine dye 4b. Similar
observations were made with the sugar-linked quinaldinium
salt 2c, which upon condensation with squaric acid gave the
corresponding semisquaraine 3c and the symmetrical dye 4c
in 85% and 10% yields, respectively. As reported previously,9
the reaction of the model quinaldinium salt 2a with squaric
acid, under similar reaction conditions, gave only the
semisquaraine intermediate 3a, in 95% yield. Interestingly,
the condensation reaction of the sugar-linked semisquaraine
derivatives 3b and 3c with 6-iodoquinaldinium salt in a
mixture (1:1) of n-butanol and benzene gave the correspond-
ing unsymmetrical dyes 5b and 5c in good yields (Scheme
1).
With a view to understand the role of electronic effects in
the squaraine dye formation reaction and to improve their
biological intake, we synthesized cholesteryl- and acetyl-
linked quinaldine derivatives 1d and 1e as shown in Scheme
2. Quaternization of these derivatives with methyl iodide
gave the corresponding quinaldinium salts 2d (95%) and 2e
(85%) in quantitative yields (Supporting Information). The
condensation between squaric acid and the cholesterol-linked
quinaldinium salt 2d was carried out using 1:2 equiv in a
mixture (1:1) of n-butanol and benzene. The progress of the
reaction was monitored by absorption spectroscopy as in the
earlier cases (Figure 1). As is evident from Figure 1, after
about 1 h, the absorption spectrum showed two absorption
bands at 505 and 740 nm, corresponding to the semisquaraine
intermediate 3d and the symmetrical squaraine dye 4d,
respectively. The intensity of both these bands increased with
(7) (a) Treibs, A.; Jacob, K. Angew. Chem., Int. Ed. Engl. 1965, 4, 694.
(b) Schmidt, A. H. Synthesis 1980, 961.
(8) (a) Law, K. Y.; Bailey, F. C. Can. J. Chem. 1986, 64, 2267. (b)
Law, K. Y.; Bailey, F. C. J. Org. Chem. 1992, 57, 3278. (c) Block, M. A.
B.; Khan, A.; Hecht, S. J. Org. Chem. 2004, 69, 184.
(9) Jyothish, K.; Arun, K. T.; Ramaiah, D. Org. Lett. 2004, 23, 3965.
(10) (a) Hussey, S. L.; He, E.; Peterson, B. R. J. Am. Chem. Soc. 2001,
123, 12712 and references therein. (b) Carreon, J. R.; Roberts, M. A.;
Wittenhagen, L. M.; Kelley, S. O. Org. Lett. 2005, 7, 99.
(11) (a) Bell, G. I.; Burant, C. F.; Takaka, J.; Gould, G. W. J. Biol. Chem.
1993, 268, 19161. (b) Mellanen, P.; Minn, H.; Greman, R.; Harkonen, P.
Int. J. Cancer 1994, 56, 622. (c) Chen, Y.; Janczuk, A.; Chen, X.; Wang,
J.; Ksebati, M.; Wang, P. G. Carbohydr. Res. 2002, 337, 1043. (d) Hussey,
S. L.; He, E.; Peterson, B. R. Org. Lett. 2002, 4, 415. (e) Chen, X.; Hui,
L.; Foster, D. A.; Drain, C. M. Biochemistry 2004, 43, 10918.
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Org. Lett., Vol. 8, No. 1, 2006