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Chemistry Letters Vol.38, No.4 (2009)
Liquid Crystallinity and Biological Activity of a Novel Amphiphilic Compound
Atsushi Yoshizawa,Ã1 Yuuka Takahashi,1 Rie Terasawa,1 Shota Chiba,1
Kenji Takahashi,2 Masaharu Hazawa,2 and Ikuo KashiwakuraÃ2
1Department of Frontier Materials Chemistry, Graduate School of Science and Technology,
Hirosaki University, 3 Bunkyo-cho, Hirosaki 036-8561
2Department of Radiological Life Sciences, Hirosaki University Graduate School of Health Sciences,
66-1 Hon-cho, Hirosaki 036-8564
(Received January 5, 2009; CL-090020; E-mail: ayoshiza@cc.hirosaki-u.ac.jp, ikashi@cc.hirosaki-u.ac.jp)
We have designed an amphiphilic compound in which
phenylpyrimidine and D-glucamine are connected via a flexible
spacer. The compound shows two thermotropic lamellar bilayer
mesophases with different layer spacings. The liquid-crystalline
compound showed cytostatic activity against A549 human lung
carcinoma cell lines, however an amphiphilic phenylpyrimidine
derivative, D-glucamine, and an equimolar mixture of them were
not active on cell lines under identical conditions.
Biological structure has links with liquid crystallinity.1 Cell
membranes are lamellar bilayer mesophases of phospholipids,
glycolipids, and cholesterol. Liquid-crystalline materials find a
new order in biomedical applications.2 Some lyotropic liquid-
crystalline materials that have structural affinity with cell mem-
branes have been applied to develop novel drug delivery sys-
tems. Recently, Tang, Du, et al. developed a novel polyethylene
glycol-phosphatidylethanolamine-based nanocarrier of doxoru-
bicin that increased cytotoxicity in vitro and enhanced anticanc-
er activity in vivo with low systematic toxicity.3 The results sup-
port the authors’ inference that 10-nm to 20-nm nanoassemblies
of phospholipids containing doxorubicin would improve the
drug’s penetration, accumulation, and anticancer activity.
Many amphiphilic polyhydroxy derivatives have been pre-
pared and their physical properties investigated.1,4–11 A relation-
ship between liquid crystallinity and immunosuppressive ability
of some amphiphilic compounds has been reported.12 However,
to our knowledge, the actions of liquid-crystalline compounds
against human cancer cells have never been reported. We have
investigated liquid crystal oligomers with a hierarchical struc-
ture,13 and recently, we found a lamellar to lamellar phase tran-
sition of an amphiphilic liquid crystal.14 We surmise that a
liquid-crystalline molecule that reorganizes its lamellar bilayer
structure according to the circumstances can penetrate layers
of tumor cells. For this study, we designed an amphiphilic com-
pound 1 in which phenylpyrimidine and D-glucamine are con-
nected via a flexible methylene spacer (Figure 1). We report here
its liquid crystallinity and anticancer activity.
Figure 2. Photomicrograph of the SmA to SmX phase transi-
tion of a homeotropically aligned sample of compound 1.
liquid. On cooling the smectic A changed to the smecic X
at 135 ꢀC, which was accompanied by appearance of a fine
Schlieren texture in the homeotropically aligned sample as
shown in Figure 2. This optical microscopic observation re-
vealed that the unidentified smectic X phase is a tilted smectic
phase. The relatively large enthalpy change of the SmA to
SmX transition indicates that the SmX phase is a higher ordered
smectic phase. It should be noticed that appearance of a tilted
smectic phase is not usual in amphiphilic liquid crystals with a
polyhydroxy unit, except in a few cases where some amphiphilic
propane-1,2-diol derivatives show the tilted smectic phase.4,15
The layer spacing obtained by X-ray diffraction studies
˚
increased from 43 to 49 A with decreasing temperature in the
smectic A phase, although it was not dependent on the temper-
16
˚
ature in the smectic X phase and the layer spacing was 55 A.
˚
The molecular length was estimated to be about 37 A for the
elongated structure using the MM2 model. The longer layer
spacings in the SmA and SmX phases than the molecular length
suggest that both smectic phases have an interdigitated structure.
Figure 3 portrays molecular organization models for the uniaxial
smectic A phase and the tilted smectic X phase. We assumed
intermolecular interactions between phenylpyrimidine units for
the smectic A phase (Figure 3a) and those between polyhydroxy
units for the smectic X phase (Figure 3b).
Competition between those intermolecular interactions
allows compound 1 to exhibit a tilted phase and to reorganize
from lamellar bilayer assemblies with hydrophilic parts in the
outer shell of each layer to those with hydrophobic units in the
outer shell.
Compound 1 showed the following phase sequence on the
first heating: Cry-136 ꢀC (56 kJ molÀ1)-unidentified smectic X-
141 ꢀC (5.3 kJ molÀ1)-smectic A-194 ꢀC (1.2 kJ molÀ1)-isotropic
OH OH
N
N
C8H17
O(CH2)6CONH
OH
OH
OH
Then we investigated whether compound 1 inhibits prolifer-
ation of A549 human lung cancer cells. The A549 cells
(4 Â 103 cells/mL) were placed at 1 mL per well in 24-well
1
Figure 1. Molecular structure of compound 1.
Copyright ꢀ 2009 The Chemical Society of Japan
Yoshizawa, Atsushi
