Synthesis of alkyl glycerolipids with functional groups in their polar heads

Article abstract of DOI:10.1023/B:RUBI.0000043789.84688.c7

A number of alkyl glycerolipids with short-chain substituents at the C2 atom of glycerol and functional groups (carboxy and amino) in the polar head were synthesized. Cationic alkyl glycerolipids with a hydroxyl function in the hydrophilic moiety were also obtained.

Full text of DOI:10.1023/B:RUBI.0000043789.84688.c7

Russian Journal of Bioorganic Chemistry, Vol. 30, No. 5, 2004, pp. 454–458. Translated from Bioorganicheskaya Khimiya, Vol. 30, No. 5, 2004, pp. 507–511.
Original Russian Text Copyright © 2004 by Plyavnik, Maslov, Serebrennikova.
Synthesis of Alkyl Glycerolipids with Functional Groups
in Their Polar Heads
1
N. V. Plyavnik , M. A. Maslov, and G. A. Serebrennikova
Lomonosov State Academy of Fine Chemical Technology, pr. Vernadskogo 86, Moscow, 119571 Russia
Received June 23, 2003; in final form, November 24, 2003
Abstract—A number of alkyl glycerolipids with short-chain substituents at the C2 atom of glycerol and func-
tional groups (carboxy and amino) in the polar head were synthesized. Cationic alkyl glycerolipids with a
hydroxyl function in the hydrophilic moiety were also obtained.
Key words: alkyl glycerolipids, cationic lipids
1
INTRODUCTION
The synthesis of such compounds with various func-
tional groups appears to be topical owing to diverse and
high biological activities of alkyl glycerolipids. This
offers great opportunities in the creation of conjugates
of such lipids with other biologically active substances
and in the introduction of fluorescent and spin labels for
accomplishing biochemical and biophysical studies
[12, 13].
Currently, the direction of synthesis of various ana-
logues of natural lipids and their modified forms with
unnatural structures is intensively being developed. The
lipids of alkyl type (neutral or those with a positively
charged group, i.e., cationic lipids) can be assigned to
unnatural [1, 2]. An interest in the compounds of this
class is due to a wide spectrum of their biological activ-
ities. Effective antagonists of platelet activation factor
(PAF), a highly active lipid bioregulator, and com-
pounds with antibacterial, antitumor, and anti-HIV-1
activities were found among the cationic glycerolipids
with ether bond [3, 4]. Moreover, the possibility of their
use as mediators of transfection of various cells with
biologically active substances (polynucleotides, pep-
tides, hormones, etc.) [1, 5, 6] and as liposome compo-
nents [7] was shown.
It has been established up to date that the lipids with
ether bond (e.g., the known lipid preparation 1-octade-
cyl-2-methyl-sn-glycero-3-phosphocholine, ET-18-OMe,
and its phosphorless analogues) exert an inhibiting action
on metastasis and growth of various tumor cell lines due
to their effect on the activity of membrane-bound protein
kinase C and diacyl glycerol kinase [9, 10].
Numerous studies of lipids with ether bond allowed
the experimental revelation of some requirements to
their structures that determine with a great probability
their type of biological activity. It turned out that, in the
majority of cases, the alkyl lipids with a long-chain
oxyalkyl substituent (C10–C20) in position C1 of glyc-
erol backbone and a short-chain (C1–C4) in position C2
could exhibit antitumor properties. The presence of a
substituted phosphate or a cationic head of ammonium
or sulfonium type attached to the 1,2-dialkylglycerol
directly or through a spacer group is necessary at C3 of
glycerol [3, 11].
RESULTS AND DISCUSSION
We synthesized glycerolipids with ether bond that
not only met the requirements mentioned above but
also contained various functional groups in polar parts
of their molecules.
rac-1-Octadecyl-2-ethylglycerol (I‡) and rac-1-
octadecyl-2-allylglycerol (Ib) [4] were used as starting
compounds. They were reacted with 5-bromopentanoic
acid chloride to get lipids with hydroxy group in polar
moiety. After a chromatographic purification, rac-1-
octadecyl-2-ethyl/allyl-3-(5bromopentanoyl)glycerols
(IIa) and (IIb) were obtained in yield of 64–69%. The
subsequent reaction of the bromoderivatives with N,N-
dimethylaminoethanol was carried in DMSO in the
presence of NaI. The substitution of more reactive
iodine for bromine under the reaction conditions
allowed us to carry out the process more easily and to
obtain
rac-N-{4-[(2-ethoxy/allyloxy-3-octadecyl-
oxy)prop-1-yloxycarbonyl]butyl}-N,N-dimethyl-N-(2-
hydroxyethyl)ammonium iodides (IIIa) and (IIIb) in
57–59% yields.
The synthesis of cationic lipids with N+H3 group in
polar head (Va)–(Vd) was achieved by the acylation of
dialkylglycerols (Ia) and (Ib) with Boc-aminounde-
canoic or Boc-aminocaproic acids in pyridine in the
presence of DCC (see scheme). The yields of (IVa)–
(IVd) were 55–68%. The subsequent removal of Boc
protective group with trifluoroacetic acid in chloroform
resulted in rac-1-octadecyl-2-ethyl/allyl-3-(6-ammoni-
1
Corresponding author; phone: +7 (095) 434-8544; e-mail:
httos.mitht@g23.relcom.ru
1068-1620/04/3005-0454 © 2004 MAIK “Nauka /Interperiodica”

SYNTHESIS OF ALKYL GLYCEROLIPIDS WITH FUNCTIONAL GROUPS
455
OC18H37
OR
OH
(I‡), (Ib)
Br(CH2)4COCl
BocNH(CH2)nCOOH
OC18H37
OR
OC18H37
OR
OOC(CH2)4Br
OOC(CH2)nNHBoc
(II‡), (IIb)
(IV‡)–(IVd)
(CH3)2NCH2CH2OH
CF3COOH
OC18H37
OC18H37
CH3
OR
OR
OOC(CH2)4N+CH2CH2OH
OOC(CH2)nNH+3CF3COO–
I–
CH3
(V‡)–(Vd)
1. Et3N
(III‡), (IIIb)
2. (CH2CO)2O
OC18H37
OR
OOC(CH2)5NHCO(CH2)2COOH
(VI‡), (VIb)
(I), (II), (III), (VI): R = C2H5 (‡), R = CH2CH=CH2 (b),
(IV), (V): n = 10, R = C2H5 (‡), R = CH2CH=CH2 (b);
n = 5, R = C2H5 (c), R = CH2CH=CH2 (d).
oundecanoyl)glycerol trifluoroacetates (Va) and (Vb) (Sigma, United States); 11-aminoundecanoic acid, and
and rac-1-octadecyl-2-ethyl/allyl-3-(6-ammoniohex- sodium iodide (Merck, Germany); and triethylamine
1
anoyl)glycerol trifluoroacetates (Vc) and (Vd) in 78–
87% yields.
(Vekton, Russia). H NMR spectra (δ, ppm, spin cou-
pling constants J, Hz) were registered on a pulse Fou-
rier-transform Bruker MSL-200 spectrometer
(200 MHz) in deuterochloroform with tetramethylsi-
lane as an internal standard. Mass spectra were
obtained on a time-of-flight Finnigan MAT 900XL-
TRAP mass spectrometer (San Jose, CA, United
States) with electrospray ionization (ESI). Silufol UV-
254 (Chemapol, Czech Republic) was used for TLC;
detection was made with phosphomolybdic acid. The
following solvent systems were used for TLC: (A) 2 : 1
petroleum ether–ether, (B) 3 : 1 chloroform–methanol,
(C) 20 : 1 chloroform–methanol, (D) 7 : 1 chloroform–
methanol, and (E) 10 : 1 chloroform–methanol. Silica
gel L 40/100 µm (Chemapol, Czech Republic) was
used for column chromatography.
Carboxyl function was introduced in glycerolipid
molecule by the successive treatment of ammonium
salts (Vc) and (Vd) with triethylamine and succinic
anhydride in the presence of catalytic quantity of N,N-
dimethylaminopyridine in DMSO. rac-1-Octadecyl-2-
ethyl/allyl-3-(6-succinylamidohexanoyl)glycerols (VIa)
and (VIb) were obtained in 68 and 65% yields, respec-
tively.
The homogeneity and structure of all the com-
pounds synthesized were confirmed by 1H NMR spec-
troscopy and mass spectrometry.
Thus, we synthesized a number of alkyl glycerolip-
ids with various functional groups (hydroxy, carboxy,
and amino) in hydrophilic moiety.
rac-1-Octadecyl-2-ethyl-3-(5-bromopentanoyl)gly-
cerol (IIa). Pyridine (0.5 ml) and then dropwise a solu-
tion of 5-bromopentanoyl chloride (0.4 g, 2 mmol) in
anhydrous chloroform (2 ml) were added to a cooled to
EXPERIMENTAL
We used distilled solvents and the following 0°ë solution of rac-1-octadecyl-2-ethylglycerol (I‡)
reagents: DMSO, N,N-dimethylaminoethanol, and suc- (0.75 g, 2 mmol) in anhydrous chloroform (3 ml). The
cinic anhydride (Reakhim, Russia); 5-bromovaleric mixture was stirred for 14 h at 20°ë; diluted with chlo-
acid (Fluka, Switzerland); 6-aminocaproic acid roform (20 ml); washed with 1% HCl (3 × 20 ml) and
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 30 No. 5 2004

456
PLYAVNIK et al.
water (2 × 20 ml); dried with Na2SO4; and evaporated. 1.65–1.77 (2 H, m, éëéëç2ëç2), 1.81–1.93 (2 ç, m,
ëç2ëç2N+), 2.46 (2 ç, Ú, J 7.0, éëéëç2), 3.34 [6 H,
s, N+(ëç3)2], 3.42 (2 H, t, J 6.7, éëç2ëç2), 3.44–3.50
(2 H, m, ëç2éë18ç37), 3.57–3.77 (5 H, m, ëçéAll,
N+ëç2ëç2éç, CH2ëç2N+), 4.05–4.17 (5 ç, m,
ëçHaéëé, éëç2ëç=ëç2, and N+ëç2ëç2éç),
4.25 (1 H, dd, J 6.9 and 11.6, ëçHbéëé), 5.16 (1 H,
ddt, J 1.3, 1.7, and 10.3, éëç2ëç=ëHça), and 5.27
(1 H, ddt, J 5.7, 10.3, and 17.2, éëç2ëç=ëç2).
The residue was chromatographed on a silica gel col-
umn eluted with chloroform to get target (IIa); yield
1
0.68 g (64%); Rf 0.6 (Ä); ç NMR: 0.86 [3 H, t, J
6.8,(ëç2)15ëç3), 1.17 (3 H, t, J 7.1, éëç2ëç3), 1.23
[30 H, br s, (ëç2)15ëç3], 1.47–1.59 (2 H, m,
éëç2ëç2), 1.71–1.91 [4 H, m, (ëç2)2ëç2Br], 2.35
(2 H, t, J 7.0, éëéëç2), 3.35–3.46 (7 H, m,
ëç2éëç2ëç2, CHOEt, and ëç2Br), 3.60 (2 H, q, J
7.1, éëç2ëç3), 4.07 (1 H, dd, J 5.8 and 10.6,
ëçHaéëé), and 4.25 1 H, dd, J 3.9 and 10.6,
ëçHbéëé).
rac-1-Octadecyl-2-ethyl-3-[11-(N-tert-butoxycar-
bonyl)aminoundecanoyl]glycerol (IVa). DCC (0.19 g,
0.96 mmol) and then rac-1-octadecyl-2-ethylglycerol
(0.2 g, 0.54 mmol) were added to a solution of 11-Boc-
aminoundecanoic acid (0.24 g, 0.8 mmol) in anhydrous
pyridine (1.2 ml). The mixture was kept for 1.5 h at
25°ë and evaporated. The residue was dissolved in
chloroform (8 ml), and dicyclohexylurea that was not
dissolved was filtered off. This operation was repeated
3 times, and the resulting substance was purified by
chromatography on a silica gel column eluted with 20 : 1
chloroform–methanol mixture to give (IVa); yield
0.24 g (68%); Rf 0.45 (C); MS, m/z: 556.8 [å – ÇÓÒ]+,
rac-1-Octadecyl-2-allyl-3-(5-bromopentanoyl)gly-
cerol (IIb). According to the previous procedure, from
rac-1-octadecyl-2-allylglycerol (Ib) (0.51 g, 1.3 mmol)
pyridine (0.5 ml) and 5-bromopentanoyl chloride
(0.26 g, 1.3 mmol), (IIb) was obtained; yield 0.5 g
1
(69%); Rf 0.6 (A); H NMR: 0.82 [3 H, t, J 6.2,
(ëç2)15ëç3], 1.22 [30 H, br s, (ëç2)15ëç3], 1.46–1.55
(2 H, m, éëç2ëç2), 1.71–1.91 [4H, m, (ëç2)2ëç2Br],
2.32 (2 H, t, J 6.1, éëéëç2), 3.35–3.46 (6 H, m,
ëç2éëç2ëç2 and ëç2Br), 3.60–3.71 (1 H, m, CHO-
Allyl), 4.02–4.11 (3 H, m, ëçHaéëé and
éëç2ëç=ëç2), 4.22 (1 H, dd, J 4.7 and 12.4,
ëçHbéëé), 5.09–5.29 (2 H, m, éëç2ëç=ëç2), and
5.75–5.95 (1 H, m, éëç2ëç = ëç2).
rac-N-{4-[(2-Ethoxy-3-octadecyloxy)prop-1-yloxy-
carbonyl]butyl}-N,N-dimethyl-N-(2-hydroxyethyl)-
ammonium iodide (IIIa). Sodium iodide (0.37 g) and
N,N-dimethylethanol (0.1 ml, 1 mmol) were added to a
solution of (IIa) (0.45 g, 0.84 mmol) in DMSO (2 ml).
The mixture was kept for 5 h at 70°ë, diluted with chlo-
roform (20 ml), washed with water (4 × 15 ml), and
dried with Na2SO4. The residue after the solvent
removal was chromatographed on a silica gel column
eluted with 3 : 1 chloroform–methanol mixture. Yield
of (IIIa) was 0.33 g (58.9%); Rf 0.5 (B); MS, m/z: 544.7
1
678.9 [å + Na]+; ç NMR: 0.86 [3 H, t, J 6.6,
(ëç2)15ëç3)], 1.17 (3 H, t, J 6.7, éëç2ëç3), 1.23–1.31
[42 H, m, (ëç2)15ëç3 and (ëç2)6], 1.42 [9 H, s,
ë(ëç3)3], 1.45–1.65 (6 H, m, éëç2ëç2,
éëéëç2ëç2, and ëç2ëç2N), 2.30 (2 H, t, J 7.3,
éëéëç2), 3.00–3.13 (2 H, m, ëç2N), 3.35–3.49 (4
H, m, ëç2éëç2ëç2), 3.61 (2 H, q, J 6.7, éëç2ëç3),
3.57–3.65 (1 H, m CHOEt, overlapped with q at 3.61),
4.07 (1 H, dd, J 5.6 and 11.8, ëçHaéëé), 4.22 (1 H,
dd, J 4.2 and 11.8, ëçHbéëé), and 4.39–4.56 (1 H,
m, NH).
rac-1-Octadecyl-2-allyl-3-[11-(N-tert-butoxycarbo-
nyl)aminoundecanoyl]glycerol (IVb) was obtained as
described for (IVa) from 11-Boc-aminoundecanoic
acid (0.32 g, 1.05 mmol), DCC (0.26 g, 1.26 mmol),
and rac-1-octadecyl-2-allylglycerol (Ib) (0.27 g,
0.7 mmol); yield 0.36 g (64%); Rf 0.45 (C); MS, m/z:
[M]+; 1H NMR: 0.88 [3 H, t, J 6.9, (ëç2)15ëç3], 1.19
(3 H, t, J 7.3, éëç2ëç3), 1.23 [30 H, br s,
(ëç2)15ëç3], 1.50–1.61 (2 H, m, éëç2ëç2), 1.69–1.95
[4 H, m, (ëç2)2ëç2N+], 2.48 (2 H, t, J 6.1, éëéëç2),
3.38 [6 H, s, N+(ëç3)2], 3.43–3.50 (4 H, m,
ëç2éëç2ëç2), 3.58–3.69 (5 H, m, ëçéëç2ëç3
1
668.1 [å]+, 690.1 [å + Na]+; ç NMR: 0.86 [3 H, t,
J 7.0, (ëç2)15ëç3], 1.21–1.33 [42 H, m, (ëç2)15ëç3
and (ëç2)6], 1.41 [9 H, s, ë(ëç3)3], 1.45–1.65 (6 H, m,
éëç2ëç2, éëéëç2ëç2, and ëç2ëç2N), 2.30 (2 H,
t, J 7.7, éëéëç2), 3.01–3.15 (2 H, m, ëç2N), 3.41
(2 H, t, J 6.7, éëç2ëç2), 3.45–3.50 (2 H, m,
ëç2éë18ç37), 3.64–3.72 (1 H, m, CHOAllyl), 4.08
(1 H, dd, J 5.7 and 11.6, ëçHaéëé), 4.10 (2 H, ddt, J
1.3, 1.7, and 5.7, éëç2ëç=ëç2), 4.22 (1 H, dd, J 4.2
and 11.6, ëçHbéëé), 4.42–4.52 (1 H, m, NH), 5.15
(1 H, ddt, J 1.3, 1.7, and 10.3, éëç2ëç=ëHça), 5.25
(1 H, ddt, J 1.7, 1.7, and 17.2, Oëç2ëç=ëHçb), and
and
N+ëç2ëç2éç),
3.75–3.81
[2H,
m,
(CH2)3ëç2N+], 4.09 (1 H, dd, J 5.9 and 11.8,
ëçHaéëé), 4.13–4.22 (2 H, m, N+ëç2ëç2éç), and
4.26 (1 H, dd, J 4.2 and 11.8, ëçHbéëé).
rac-N-{4-[(2-Allyloxy-3-octadecyloxy)prop-1-yloxy-
carbonyl]butyl}-N,N-dimethyl-N-(2-hydroxyethyl)-
ammonium iodide (IIIb) was obtained as described
for (IIIa) from triester (IIb) (0.36 g, 0.67 mmol), NaI
(0.29 g) and N,N-dimethylethanol (0.08 ml, 0.8 mmol); 5.86 (1 H, ddt, J 5.7, 10.3, and 17.2, éëç2ëç=ëç2).
yield 0.26 g (57.1%); Rf 0.5 (B); MS, m/z: 556.2 [M]+;
rac-1-Octadecyl-2-ethyl-3-[6-(N-tert-butoxycar-
1H NMR: 0.86 [3 H, t, J 6.8, (ëç2)15ëç3], 1.24 [30 H,
bonyl)aminohexanoyl]glycerol (IVc) was obtained as
br s, (ëç2)15ëç3], 1.47–1.59 (2 H, m, éëç2ëç2),
described for (IVa) from rac-1-octadecyl-2-ethylglyc-
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 30 No. 5 2004

SYNTHESIS OF ALKYL GLYCEROLIPIDS WITH FUNCTIONAL GROUPS
457
erol (Ia) (0.18 g, 0.48 mmol), 6-Boc-aminohexanoic [3 H, t, J 7.0, (ëç2)15ëç3], 1.21–1.34 [42 H, m,
acid (0.15 g, 0.63 mmol), and DCC (0.15 g,
(ëç2)15ëç3 and (ëç2)6], 1.54–1.68 (6 H, m, éëç2ëç2,
éëéëç2ëç2, and ëç2ëç2NH+3 ), 2.30 (2 H, t, J 7.7,
éëéëç2ëç2), 2.83–2.96 ëç2NH+3 ), 3.41 (2 H, t, J 6.8,
0.75 mmol); yield 0.18 g (63%), Rf 0.53 (C); MS, m/z:
1
587.1 [å – ç]+; ç NMR: 0.85 [3 H, t, J 6.4,
(ëç2)15ëç3], 1.16 (3 H, t, J 7.3, éëç2ëç3), 1.20–1.29
[32 H, m, (ëç2)15ëç3 and éëé(ëç2)2ëç2], 1.41 [9 H,
s, ë(ëç3)3], 1.47–1.65 (6 H, m, éëç2ëç2,
éëéëç2ëç2, and ëç2ëç2N), 2.31 (2 H, t, J 7.3,
éëéëç2ëç2), 3.02–3.12 (2 H, m, ëç2N), 3.41 (2 H,
t, J 6.8, éëç2ëç2), 3.42–3.47 (2 H, m, ëç2éë18ç37),
3.60 (2 H, q, J 7.3, éëç2ëç3), 3.54–3.66 (1 H, m
CHOEt, overlapped with q at 3.61), 4.06 (1 H, dd, J 5.6
and 11.5, ëçHaéëé), 4.22 (1 H, dd, J 4.3 and 11.9,
ëçHbéëé), and 4.46–4.57 (1 H, m, NH).
éëç2ëç2), 3.45–3.50 (2 H, m, ëç2éë18ç37), 3.64–
3.72 (1 H, m CHOAllyl), 4.08 (1 H, dd, J 5.7 and 11.6,
ëçHaéëé), 4.10 (2 H, ddt, 1.3, 1.7, and 5.7,
éëç2ëç=ëç2), 4.22 (1 H, dd, J 4.2 and 11.6,
ëçHbéëé), 5.86 (1 H, ddt, J 5.7, 10.3, and 17.2,
éëç2ëç=ëç2), and 7.84 (3 H, br s, NH+3 ).
rac-1-Octadecyl-2-ethyl-3-[6-ammoniohexanoyl)-
glycerol trifluoroacetate (Vc) was obtained as
described for (Va) from (IVc) (0.14 g, 0.24 mmol) and
trifluoroacetic acid (0.15 ml). The substance was chro-
matographed on silica gel eluting with 10 : 1 chloro-
form–methanol; yield 0.12 g (80%); Rf 0.2 (E); MS, m/z:
rac-1-Octadecyl-2-allyl-3-[6-(N-tert-butoxycarbo-
nyl)aminohexanoyl]glycerol (IVd) was obtained as
described for (IVa) from rac-1-octadecyl-2-allylglyc-
erol (Ib) (0.15 g, 0.4 mmol), 6-Boc-aminohexanoic
acid (0.14 g, 0.6 mmol), and DCC (0.15 g, 0.75 mmol);
yield 0.13 g (55%), Rf 0.53 (C); MS, m/z: 697.3 [å]+,
556.2 [å]+, 557.3 [å + ç]+; 1ç NMR: 0.86 [3 H, t, J 6.8,
(ëç2)15ëç3], 1.17 (3 H, t, J 7.0, éëç2ëç3), 1.20–1.30
[32 H, m, (ëç2)15ëç3 and éëé(ëç2)2ëç2], 1.48–1.75
(6 H, m, éëç2ëç2, éëéëç2ëç2, and ëç2ëç2N),
2.29 (2 H, t, J 7.3, éëéëç2ëç2), 2.82–2.95 (2 H, m,
1
620.1 [å + Na]+; ç NMR: 0.86 [3 H, t, J 6.8,
(ëç2)15ëç3], 1.19–1.31 [32 H, m, (ëç2)15ëç3 and
éëé(ëç2)2ëç2], 1.42 [9 H, s, ë(ëç3)3], 1.46–1.75
(6 H, m, éëç2ëç2, éëéëç2ëç2, and ëç2ëç2N),
2.31 (2 H, t, J 7.3, éëéëç2ëç2), 3.02–3.14 (2 H, m,
ëç2N), 3.36–3.75 (5 H, m, ëç2éëç2ëç2 and CHO-
Allyl), 4.02–4.15 (3 H, m, ëçHaéëé and
éëç2ëç=ëç2), 4.23 (1 H, dd, J 4.3 and 11.9, ëçH-
béëé), 4.46–4.54 (1 H, m, NH), 5.11–5.32 (2 H, m,
éëç2ëç=ëç2), and 5.78–6.01 (1 H, m,
éëç2ëç=ëç2).
ëç2NH+3 ), 3.41 (2 H, t, J 6.4, éëç2ëç2), 3.42–3.50
(2 H, m, ëç2éë18ç37), 3.60 (2 H, q, J 7.0,
éëç2ëç3), 3.56–3.66 (1 H, m, CHOEt, overlapped
with q at 3.60), 4.05 (1 H, dd, J 5.6 and 11.5,
ëçHaéëé), 4.20 (1 H, dd, J 3.8 and 11.5, ëçHbéëé),
and 8.1 (3 H, br s, NH+3 ).
rac-1-Octadecyl-2-ethyl-3-[6-ammoniohexanoyl)-
glycerol trifluoroacetate (Vd) was obtained as
described for (Va) from (IVd) (0.1 g, 0.16 mmol) and
trifluoroacetic acid (0.1 ml). The substance was chro-
matographed on silica gel eluting with 10 : 1 chloro-
form–methanol; yield 0.08 g (78%); Rf 0.2 (E); MS,
rac-1-Octadecyl-2-ethyl-3-[11-ammonioundecan-
oyl)glycerol trifluoroacetate (Va). Trifluoroacetic
acid (0.2 ml) was added to a solution of (IVa) (0.19 g,
0.29 mmol) in chloroform (1 ml). The mixture was
stirred for 1.5 h at 40°ë and evaporated. The residue
was chromatographed on a silica gel column eluted
with 7 : 1 chloroform–methanol mixture to give (Va);
yield 0.17 g (87%); Rf 0.42 (D); MS, m/z: 556.2 [å]+;
m/z: 568 [å – ç]+, 569.1 [å]+; 1ç NMR: 0.85 [3 H, t,
J 6.8, (ëç2)15ëç3], 1.19–1.31 [32 H, m, (ëç2)15ëç3
and éëé(ëç2)2ëç2], 1.47–1.77 (6 H, m, éëç2ëç2,
éëéëç2ëç2, and ëç2ëç2N), 2.32 (2 H, t, J 6.8,
1ç NMR: 0.85 [3 H, t, J 6.5, (ëç2)15ëç3], 1.17 (3 H,
t, J 7.0, éëç2ëç3), 1.21–1.36 [42 H, m, (ëç2)15ëç3
and (ëç2)6], 1.48–1.69 (6 H, m, éëç2ëç2,
éëéëç2ëç2, and ëç2ëç2NH+3 ), 2.30 (2 H, t, J 7.3,
éëéëç2ëç2), 2.82–2.95 (2 H, m, ëç2NH+3 ), 3.41
éëéëç2ëç2), 2.86–2.97 (2 H, m, ëç2NH+3 ), 3.40
(2 H, t, J 6.8, éëç2ëç2), 3.42–3.50 (2 H, m,
ëç2éë18ç37), 3.58–3.71 (1 H, m CHOAllyl), 4.03–
4.13 (3 H, m, ëçHaéëé and éëç2ëç=ëç2), 4.21
(1 H, dd, J 4.3 and 11.5, ëçHbéëé), 5.15 (1 H, ddt,
J 1.3, 1.7, and 10.2, éëç2ëç=ëHça), 5.26 (1 H, ddt,
J 1.3, 1.7, and 10.2, Oëç2ëç=ëHçb), 5.87 (1 H, ddt,
J 5.6, 10.2, and 17.5, éëç2ëç=ëç2), and 6.25 (3 H,
(2 H, t, J 6.8, éëç2ëç2), 3.43–3.48 (2 H, m,
ëç2éë18ç37), 3.61 (2 H, q, J 7.0, éëç2ëç3), 3.58–
3.65 (1 H, m CHOEt, overlapped with q at 3.61), 4.07
(1 H, dd, J 5.8 and 11.6, ëçHaéëé), 4.23 (1 H, dd, J
br s, NH+3 ).
4.2 and 11.6, ëçHbéëé), and 7.84 (3 H, br s, NH+3 ).
rac-1-Octadecyl-2-ethyl-3-[6-succinylamidohex-
anoyl)glycerol (VIa). Triethylamine (0.14 ml,
9.9 mmol) was added to a solution of (Vc) (0.11 g,
0.19 mmol) in anhydrous chloroform (0.4 ml). The
mixture was stirred for 20 min at 0°ë and 1 h at 20°C
rac-1-Octadecyl-2-allyl-3-[11-ammonioundecan-
oyl)glycerol trifluoroacetate (Vb) was obtained as
described for (Va) from (IVb) (0.35 g, 1.01 mmol) and
trifluoroacetic acid (0.2 ml); yield 0.21 g (81%), Rf 0.42
(D); MS, m/z: 568 [å – ç]+, 569.1 [å]+; 1ç NMR: 0.86 and evaporated. The residue was dissolved in chloro-
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 30 No. 5 2004

458
PLYAVNIK et al.
form (0.2 ml), and succinic anhydride (0.04 g, 866, and 03-03-32482, and the grants: Scientific
0.39 mmol), DMSO (0.3 ml), and a catalytic amount of Research of High Schools on the Priority Directions of
DMAP were added. The reaction mixture was kept for Science and Technology, subsection Medicinal and
5 h at 80°ë, diluted with chloroform (25 ml), washed Biologically Active Substances no. 203.05.04.005,
with water (4 × 15 ml), dried with Na2SO4, and evapo- Carrying out the Collective Basic Studies on the Basis
of Educational Scientific Center on Physiologically
Active Substances no. I0563, and the President’s Grant
for the Support of Leading Scientific Schools of Russia
no. NSh-2013.2003.3.
rated. The residue was chromatographed on a silica gel
column eluted with 20 : 1 chloroform–methanol to get
(VIa); yield 0.08 g (67.8%); Rf 0.7 (D); MS, m/z: 608.1
[å + Na]+; 1ç NMR: 0.85 [3 H, t, J 6.8, (ëç2)15ëç3],
1.16 (3 H, t, J 7.3, éëç2ëç3), 1.19–1.33 [32 H, m,
(ëç2)15ëç3 and éëé(ëç2)2ëç2], 1.40–1.68 (6 H, m,
éëç2ëç2, éëéëç2ëç2, and ëç2ëç2N), 2.32 (2 H,
t, J 7.3, éëéëç2ëç2), 2.42–2.51 (2 H, m, NCOCH2),
2.61–2.70 (2 H, m, ëç2ëééç), 3.18–3.29 (2 H, m,
ëç2N), 3.38–3.48 (4H, m, ëç2éëç2ëç2), 3.56–3.68
(3 H, m, éëç2ëç3 and CHOEt), 4.07 (1 H, dd, J 5.6
and 11.9, ëçHaéëé), 4.23 (1 H, dd, J 4.3 and 11.5,
ëçHbéëé), and 6.05 (1 H, m, NH).
REFERENCES
1. Fuhrhop, J.H. and Tank, H., Chem. Phys. Lipids, 1987,
vol. 43, pp. 193–199.
2. Grumpton, S.G., Goz, B., and Ishaq, K.S., Anticancer
Res., 1988, vol. 8, pp. 1361–1365.
3. Konstantinova, I.D. and Serebrennikova, G.A., Usp.
Khim., 1996, vol. 65, pp. 581–598.
4. Konstantinova, I.D., Zaitseva, N.M., Ushakova, I.P., and
Serebrennikova, G.A., Izv. Ross. Acad. Nauk, Ser. Khim.,
1994, no. 10, pp. 1826–1829.
rac-1-Octadecyl-2-allyl-3-[6-succinylamidohexan-
oyl)glycerol (VIb) was obtained as described for (VIa)
from (Vd) (0.08 g, 0.13 mmol), triethylamine (0.1 ml),
and succinic anhydride (0.026 g, 0.26 mmol); yield
0.05 g (65.4%); Rf 0.7 (D); 1H NMR: 0.86 [3 H, t, J 6.8,
(ëç2)15ëç3], 1.18–1.31 [32 H, m, (ëç2)15ëç3 and
éëé(ëç2)2ëç2], 1.45–1.70 (6 H, m, éëç2ëç2,
éëéëç2ëç2, and ëç2ëç2N), 2.32 (2 H, t, J 7.2,
éëéëç2ëç2), 2.44–2.52 (2 H, m, NCOCH2), 2.62–
2.71 ëç2ëééç), 3.19–3.30 (2 H, m, ëç2N), 3.42
(2 H, t, J 6.8, éëç2ëç2), 3.44–3.50 (2 H, m,
ëç2éë18ç37), 3.62–3.74 (1 H, m, CHOAllyl), 4.04–
4.14 (3 H, m, ëçHaéëé and éëç2ëç=ëç2), 4.24
(1 H, dd, J 3.8 and 11.5, ëçHbéëé), 5.16 (1 H, ddt,
J 1.3, 1.7, and 10.3, éëç2ëç=ëHça), 5.26 (1 H, ddt,
J 1.3, 1.7, and 17.1, Oëç2ëç=ëHçb), 5.88 (1 H, ddt,
ddt, J 5.6, 10.2, and 17.5, éëç2ëç=ëç2), and 5.99–
6.10 (1 H, m, NH).
5. Ballas, N., Zakai, N., Sela, I., and Loyter, A., Biochim.
Biophys. Acta, 1988, vol. 939, pp. 8–18.
6. Innes, C.L., Smith, P.B., Lanqenbach, R., Tindall, K.R.,
and Boone, L.R., J. Virol., 1990, vol. 64, pp. 957–964.
7. Duzgunes, N., Goldstein, J.A., Friend, D.S., and Fel-
gner, P.L., Biochemistry, 1989, vol. 28, pp. 9179–9184.
8. Sablina, M.A., Ushakova, I.P., and Serebrenni-
kova, G.A., Khim.–Farm. Zh., 1993, vol. 27, pp. 3–13.
9. Marasco, C.J., Piantadosi, C., Meyer, K.L., Morris-
Natschke, S., Ishaq, K.S., Small, G.W., and Daniel, L.W.,
J. Med. Chem., 1990, vol. 33, pp. 985–992.
10. Goddat, J., Coste, H., Vilgrain, I., Chambaz, E., and
Driguez, H., Lipids, 1992, vol. 27, pp. 331–336.
11. Maslov, M.A., Sycheva, E.V., Morozova, N.G., and
Serebrennikova, G.A., Izv. Ross. Acad. Nauk, Ser. Khim.,
2000, no. 3, pp. 485–500.
12. Kertscher, P., Ruger, H.-J., Gawrisch, K., and Nuhn, P.,
Pharmazie, 1980, vol. 35, no. 1, pp. 10–14.
ACKNOWLEDGMENTS
13. Heyes, J.A., Niculescu-Duvaz, D., Cooper, R.G., and
Springer, C.J., J. Med. Chem., 2002, vol. 45, pp. 105–
114.
This work was supported by the Russian Foundation
for Basic Research, project nos. 01-03-33234, 00-15-
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 30 No. 5 2004