Optically active oligomer units in aggregates of a highly unsaturated, optically inactive carotenoid phospholipid

Article abstract of DOI:10.1002/chem.200401191

Enantiomers of glycerophospholipids show low or no optical activity. Accordingly, optical activity was not observed with the R enantiomer of a highly unsaturated carotenoyl lysophospholipid in solution. In spite of this, strong Cotton effects are detected

Full text of DOI:10.1002/chem.200401191

FULL PAPER
Optically Active Oligomer Units in Aggregates of a Highly Unsaturated,
Optically Inactive Carotenoid Phospholipid
Bente Jeanette Foss,[a] Hans-Richard Sliwka,*[a] Vassilia Partali,[a] Christian Kçpsel,[b]
Bernhard Mayer,[b] Hans-Dieter Martin,*[b] Ferenc Zsila,[c] Zsolt Bikadi,[c] and
Miklos Simonyi*[c]
Abstract: Enantiomers of glycerophos-
pholipids show low or no optical activi-
ty. Accordingly, optical activity was not
observed with the R enantiomer of a
highly unsaturated carotenoyl lyso-
phospholipid in solution. In spite of
this, strong Cotton effects are detected
in water. The amphiphilic carotenoid–
phospholipid monomers associate to
form aggregates, whose optical activity
is attributed to oligomeric entities.
These small helical assemblies cannot
exist independently. Yet, the calculated
octamer represents the simplest repeat-
ing primary unit that sufficiently ex-
presses the absorption properties and
supramolecular optical activity.
Keywords: carotenoids
·
helical
structures · molecular modeling ·
phospholipids
Introduction
detected in the olfactoric system.[4] Another reason for ne-
glecting chiroptical investigations of glycerolipids is their in-
visibility. (Phospho)lipids show notoriously low or no specif-
ic rotations, likewise, electronic optical activity (EOA) is
weak or absent due to the lack of chromophores.[5]
The chiroptical properties of glycerolipids have been rarely
investigated, while the two other groups of vital biomole-
cules, carbohydrates and proteins with their well-established
exclusive building blocks of d-sugars and l-amino acids,
have received a lot of attention. Despite the fact that the
biosynthesis of lipids also results in only one specific enan-
tiomer, a chiral, functional discrimination of enantiomeric
lipids has rarely been found. Membranes consist of pure
phospholipid enantiomers, but with respect to penetration
and other physical properties, phosphocholines behave as
achiral molecules.[1–3] It was only recently that a decisive
enantiomeric interaction between odorants and lipids was
The few natural chromophoric lipids contain ajenoic acids
C12:5, C14:5 in triglycerides[6] and parinaric acid C18:4 in
phophatidylcholines.[7] The circular dichroism (CD), or fluo-
rescence-detected CD (FDCD), of these lipids has not yet
been measured, nor have chiral lipids been prepared from
synthetic conjugated tetraenic fatty acids.[8] The acyl chains
in these unsaturated lipids are only partly accessible by
EOA spectroscopy. In various attempts to introduce chro-
mophores, phospholipids with stilbene, biphenyl, terphenyl,
and azobenzene fatty acids have been synthesized.[9–11] Like-
wise, a glycerophosphatidylcholine enantiomer with styryl-
thiophene acyl groups was synthesized, which was devoid of
optical activity.[12] Undoubtedly, the mentioned lipids con-
tain rather xenobiotic acyl groups and are, therefore, differ-
ent from lipids of naturally occurring fatty acids.
[a] B. J. Foss, H.-R. Sliwka, V. Partali
Norges Teknisk Naturvitenskapelige Universitet (NTNU) Institutt for
Kjemi
7491 Trondheim (Norway)
Fax : (+47)73-59-6255
E-mail: hrs@nvg.ntnu.no
For historical reasons optical activity is restricted to wave-
lengths from 200–800 nm. Although the accessible chiropti-
cal spectral range has successively been extended to both
lower and higher wavelengths, enantiomers continue to be
defined as “optically inactive” when no signal in the classical
wavelength scale is detected. Thus, the highly unsaturated
carotenoylphospholipid (R)-5 (in MeOH), which does not
exhibit EOA in the usual accessible range of the dichro-
graph, (see Figure 1a, c), is considered optically inactive.
[b] C. Kçpsel, B. Mayer, H.-D. Martin
Institut fꢀr Organische Chemie und Makromolelulare Chemie
Heinrich-Heine-Universitꢁt, 40225 Dꢀsseldorf (Germany)
Fax : (+49)211-81-14324
E-mail: martin@uni-duesseldorf.de
[c] F. Zsila, Z. Bikadi, M. Simonyi
Department of Bioorganic Chemistry, Chemical Research Center
1525 Budapest (Hungary)
Fax : (+361)325-9188
E-mail: msimonyi@chemres.hu
Chem. Eur. J. 2005, 11, 4103 – 4108
DOI: 10.1002/chem.200401191
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4103

However, (R)-5 shows optical activity in water (Figure 1a).
The chiroptical properties of (R)-5 result from the self-as-
sembly of optically inactive monomers to give supramolec-
ular structures.[13,14] By calculating the absorption and CD
spectra of a manifold of oligomeric structures, we found that
a helical oligomer composed of eight monomers may serve
as a basic unit that explains satisfactorily the spectroscopic
properties of (R)-5 aggregates.
We report here on the synthesis of lysophospholipid (R)-
5, on its chiroptical properties, and the calculation of a basic
aggregation unit.
Results and Discussion
Lysocarotenoylphosphatidyl choline ((R)-5) was synthesized
in low yield by reacting the natural (+)-(2R)-glycero-3-phos-
phocholine (3-sn-GPC) ((R)-1) with the rigid and fully chro-
mophoric carotenoic acid (C30-acid)[15,16] 2 in the presence
of the imidazole derivative
3
and 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU; 4)[17] (Scheme 1). Dissolved in
methanol, the carotenoid derivative (R)-5 did not show
EOA (Figure 1a, c).[18] A chiral perturbation of the polyene
chain is not expected to occur in (R)-5 and, in addition,
Cotton effects in the absorption region of the polyene chain
above 400 nm are difficult to detect.[19,20] In some colorless
glycerides, weak Cotton effects were observed around
220 nm (n–p* transitions of the ester group),[21–24] sometimes
with opposite signs for the same enantiomer.[25] The meas-
urement of the weak specific rotation of lysophospholipids
requires high compound concentrations (3–5%).[26] Such
deep orange colored solutions of (R)-5 are not transparent
and, therefore, hardly detectable in the polarimeter.[27]
Figure 1. CD spectra (a) and absorptions spectra (b) of (R)-5 in the range
300–600 nm and c) CD and absorption spectra of (R)-5 in the range 200–
400 nm; path length=1 cm, c=2ꢃ10À5 m (critical micelle concentration
of (R)-5: cM =1.5ꢃ10À3 m).[13]
Optically inactive enantiomers[28,29] have been, incorrectly,
called “cryptochiral”, because “chirality” frequently, but in-
admissibly, is considered to be equivalent with electronic op-
tical activity.[30–34] The more appropriate and descriptive
term “cryptoactive” for glyceride enantiomers without de-
tectable electronic optical activity has been largely ignor-
ed.[5] Nevertheless, we will rank the carotenoylglycerophos-
pholipid (R)-5 to the class of cryptoactive compounds or to
compounds with accidental opti-
cal inactivity.[35]
In water, the amphiphilic car-
otenoylphospholipid
(R)-5
forms clear, orange-colored dis-
persions, mostly of aggregates
with an average size of
6 nm.[13,14] The strong absorp-
tion band of the monomeric so-
lution observed at 445 nm in
methanol (p–p* transitions of
the polyene chain, Figure 1b),
splits in water into two exciton
bands, a prominent signal at
380 nm in the H-aggregate and
a slightly visible shoulder at
510 nm in the J-aggregate
region.[36,37] The association of
Scheme 1.
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Highly Unsaturated, Optically Inactive Carotenoid Phospholipids
FULL PAPER
monomers into aggregates accelerated at higher tempera-
ture, the intensity of the Cotton effect increased when the
sample was left to stand at 358C (Figure 1a). While the flat
line in the CD spectrum convincingly proves the lack of
Cotton effects in the molecular solution of (R)-5 (in metha-
nol) the CD spectrum of (R)-5 in water showed strong
Cotton effects (Figure 1a), a positive signal at 410 nm, a
strong negative band in the absorption region of the polyene
chain (445 nm), and again a positive band at 520 nm. Since
simply water was added to optically inactive (R)-5 the ob-
tained Cotton effects can only be generated from induced
optical activity, originating from a chiral association of (R)-5
monomers. In principle, the observed optical activity of the
aggregates could arise from a handed orientation of all mon-
omers in a possibly existing unilamellar vesicle.[13,14] Howev-
er, it is also possible that a few monomers first associate to
give small primary units, which then constitute the supra-
molecular structure. To determine the origin of EOA in the
aggregates, we tried to simulate the absorption and CD
spectra. At first sight, the experimental CD spectrum seems
to be a mixture of blue-shifted negative and red-shifted pos-
itive exciton couplets. The most simple model that explains
such spectral behavior would be a tetramer with both right-
and left-handed overlay angles. Molecular mechanics calcu-
lations were performed using the Sybyl 6.6 program[38] to
find a minimum-energy conformation. The calculated tet-
ramer (Figure 2) appeared to be in accordance with the
spectral data.
Figure 3. Optically active P-oligomer unit, built from eight optically inac-
tive (R)-5 monomers.
We conclude therefore that octamers form the primary
units leading to the observed chiroptical absorption.[44] The
configuration of these octamers is determined by the stereo-
genic center in the hydrophilic part of monomeric (R)-5.
The CD spectra express supramolecular chirality of the ag-
gregates resulting from a helical P orientation of the poly-
ene chain in the calculated oligomer (Figure 3).
Basic units in aggregates have rarely been reported,[45,46]
for example, the monomers of the mentioned styrylthio-
phene phospolipid create a tet-
ramer unit.[12] The formation of
aggregation units is consistent
with the observation of quan-
tized
aggregation
numbers
(AN),[47] where the total aggre-
gation number can only be a
multiple of monomers in the
primary aggregation unit.
Aggregates of chiral carote-
noids often show characteristic
exciton couplets in the CD
spectra, which are caused by
chromophores overlapping in
Figure 2. The simplest unit with both negative H-type and positive J-type arrangements.
However, the tetramer arrangement did not fully account
for the exciton interactions according to the excitation
model of Buss et al.[39] To account for these interactions two
tetrameric substructures were combined and optimized
using molecular dynamics (MD) and force-field-CVFF[40–42]
calculations in the Discover program.[43] The UV/Vis and
CD spectra of the aggregates could then be simulated with
the carotenoid acid 2 in the AM1-model by applying a con-
figuration interaction (CI) with three occupied and two un-
occupied MOs and considering singly as well as doubly ex-
cited configurations. The lowest excitation was calculated at
519 nm with a transition moment of 2.74 D. These values
were then used within the excitation model by employing
the dipole–dipole approximation. The computation resulted
finally in a structure (Figure 3), which satisfactorily explains
the recorded spectra (see Figure 4).
specific, ordered arrangements.[48–51] Such ordered arrange-
ments are not encountered in the oligomer discussed here.
The inadequate agreement of the maxima, minima, and
zero-point crossings of the CD spectrum with that of the ab-
sorption spectrum reflects the rather irregular structure of
the calculated oligomer. Further, it follows from Figure 3
that no defined H- or J-arrangements exist in the depicted
octamer. The interchromophoric geometry of the molecules
in the octamer causes a shift of the absorption maxima to
shorter as well as to longer wavelengths.
A basic unit, such as the selected octamer, cannot exist as
an independent entity in water, since the polar and nonpolar
groups are oriented in an unfavorable way. In addition, dy-
namic light scattering measurements did not detect oligo-
meric particles corresponding in size to the association of
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H.-R. Sliwka, H.-D. Martin, M. Simonyi et al.
tants. In a preliminary experiment, the membrane-opening
protein melittin[52] did not disrupt the membrane of (R)-5, as
demonstrated by the absence of energy and electron transfer
in flash photolysis experiments.
Conclusion
Reviewing our experimental results and molecular calcula-
tions, we conclude that the highly unsaturated, optically in-
active glycerophospholipid (R)-5 forms enantiomeric pri-
mary units of moderate size in water: an octameric oligomer
may represent the simplest repeating unit, satisfactorily ex-
pressing absorption properties and supramolecular EOA.
It appears reasonable to hypothesize that other (cryp-
to)optically active glycerolipid monomers also may associate
to give small, enantiomeric units within supramolecular as-
semblies.
Experimental Section
The product [(R)-5] was isolated by means of flash chromatography
(Silica 60 A 40–63 mm, SDS). The column was prepared with CHCl3, the
product dissolved in CHCl3 and eluted with CHCl3/CH3OH (80/20), grad-
ually increasing the amount of water and methanol to CHCl3/CH3OH/
H2O (40:50:10). Smaller amounts were purified on analytical DC plates
(Silika 60 F254, Merck) with CHCl3/CH3OH/H2O (40:50:10) as eluent.
The product yield was determined from the UV/Vis spectrum.[53]
(R)-1-(b-Apo-8’-carotenoyl)-3-glycerophosphocholin [(R)-5]: The inter-
mediate carotenoylimidazole was synthesized by reacting b-apo-8’-carote-
noic acid (2;[16] 77 mg, 0.18 mmol) with 1,1’-carbonyldiimidazole (3)
(292 mg, 1.8 mmol) dissolved in CHCl3 (10 mL). The reaction mixture
was stirred under nitrogen (208C, 4 h). sn-1-Glycerophosphocholine ((R)-
100 mg, 0.39 mmol), [aD18]=À 2.58, c=0,05 gmLÀ1 H2O, p=0.88,
Figure 4. Calculated and experimental CD (top) and absorption (bottom)
spectra of (R)-5; the calculated spectra are shifted by +40 nm for better
adjustment.
1
;
([a1D9]=À2.848, c=0.088 gmLÀ1 H2O[54]) and 1,8-diazabicyclo[5.4.0]undec-
7-ene (4) (119 mg, 0.78 mmol), dissolved in DMSO, were added to the so-
lution, and the reaction mixture was stirred under nitrogen (408C, 24 h).
The solution was washed with saturated NaCl (aq) to remove most of the
DMSO and then dried over Na2SO4. After evaporation of the solvent
under reduced pressure chromatographic work-up gave (R)-5 (5 mg,
4%). UV/Vis in MeOH and H2O: see Figure 1b, c. CD in MeOH and
eight monomers.[13,14] Therefore, we define the oligomer unit
as the lowest spatial extent of monomer association that dis-
plays all the spectroscopic and chiroptical properties of the
aggregate. Such basic units in aggregates could possibly be
compared with elementary (Bravais) units in crystals.
Aggregate formation is sensitive to subtle experimental
conditions. Besides the absorption at 380 nm, (Figure 1b),
aggregate dispersions absorbing at 390 or 400 nm were
sometimes observed suggesting the possible presence of
other oligomer structures in these higher absorbing aggre-
gates.[14]
H2O: see Figure 1a, c. The H, 13C, and 31P NMR spectra are given in ref-
1
erence [55]. No isomerization by acyl migration was detected.
Attempt at membrane disruption: Phospholipid (R)-5 in water was irradi-
ated with rose bengal as senzitizer. The transient absorption spectra of
carotenoid triplets (3car) or of carotenoid cation radicals (carC+) could
not be observed. Melittin (Bachem) was added and, after few minutes,
the solution was irradiated. Again, no energy or electron transfer occur-
red. The photophysics of (R)-5 and other water-dispersible carotenoids
will be published elsewhere.
Description of the calculation methods:
Calculation of the tetrameric structure: Molecular mechanics (MM) calcu-
lations were performed by using the Sybyl 6.6 program[38] on a Silicon
Graphics Octane workstation with an Irix 6.5 operating system. The MM
calculations were based on MMFF94 force field,[56] in which energy mini-
mization was applied by the conjugate gradient technique with
0.001 kcalmolÀ1 ꢄÀ1 gradient. Tetramers were built up from energy-mini-
mized monomers using the dock command of Sybyl.[38]
The few known Cotton effects of glycerophospholipid ag-
gregates arise from the ester carbonyl group located in the
hydrophilic part of molecules at the exterior of the aggre-
gates.[22,23] In contrast, the Cotton effects of (R)-5 are
formed by the hydrophobic polyene chromophores and cor-
respond to molecular interactions inside the aggregates (mi-
celles) or inside the membrane (lamellar vesicles). Aggre-
gates of (R)-5 should possess an enantiomorphous mem-
brane with the potential to differentiate enantiomeric reac-
Calculation of the octameric structure: Molecular dynamics (MD) calcula-
tions were performed by using the Discover 2.9.7 program[43] on an SGI
ORIGIN 2000 mainframe with an Irix 5.1 operating system. The applied
force filed was CVFF.[40–42] To determine the conformational space, the
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Highly Unsaturated, Optically Inactive Carotenoid Phospholipids
FULL PAPER
starting geometry was first equilibrated at 300 K for 500 ps followed by
slowly cooling to 100 K. The final geometry was obtained by applying the
steepest descent technique for 1000 steps and finally by applying the con-
jugate gradient with a 0.001 kcalmolÀ1 ꢄÀ1 gradient. The AM1 (MOPAC
93, Fujitsu Limited, Pentium III, 700 MHz, Windows NT4.0) method
with a CI of the three highest occupied and the two lowest unoccupied
MOs was used to calculate the excitation energies and transition mo-
ments. The individual transition moments were superimposed on the indi-
vidual molecules within the aggregates. Applying the principle of dipole–
dipole interactions,[57] an energy matrix was constructed and diagonalized
as usual. In this way the eigenvalues and, thus, the excitation energies of
the aggregates and the corresponding oscillatory and rotatory strengths
were obtained.
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Acknowledgements
We thank H. Ernst (BASF AG, Ludwigshafen) and S. Servi (Politecnico
di Milano) for a generous gift of C30-ester and (R)-glycerophosphocho-
line, respectively, and T. B. Melø and K. R. Naqvi (Department of Phys-
ics, NTNU) for carrying out the flash-photolysis experiments. Financial
support from the European Community (QLK2-CT-2002–90436) is ac-
knowledged.
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