Mendeleev Commun., 2019, 29, 29–31
HO
OH
i
HO
ii
TsO
O
O
42.0
OH
O
O
Me
Me
4
4
4
1.5
1.0
0.5
Me
(85%)
Me
1
2 (96%)
2
iii
R = 0.958
2
R = 0.973
Me
OH
Cl
R2N
O
2
1
3
O
40.0
9.5
39.0
Me
Me
Me
Me
Me
vi
Me
3
2
R = 0.974
3
a–c (80–89%)
Me
iv, v
0
.0
0.1
0.2
0.3 0.4
0.5
Compound/DPPC molar ratio
5
(88%)
R2N
OH
OH
a–c (77–83%)
Figure 1 Plot of Tm vs. compound/DPPC molar ratio: (1) 6a, (2) 6b and
3) 6c.
(
4
the dependence indicates that during the experiment there was
no solubilization (destruction) of the lipid vesicles in the studied
concentration range.
vii
Me
Me
The zpotential of DPPC vesicles is a valuable indicator for
the incorporation of foreign compounds into the lipid bilayer.
It depends weakly on the concentration and type of common
R2N
O
Me
O
Me
a R + R = (CH2)4
b R = Et
c R + R = (CH2)5
2
7
Me
Me
electrolyte in the solution. When embedded in the bilayer,
compounds 6a–c should normally change the zpotential of the
vesicles. The results of the zpotential measurement for com
pound/DPPC mixtures in different ratio (see Online Supple
mentary Materials) are shown in Figure 2. The point 0.0 on the
abscissa axis corresponds to the zpotential value for the pristine
DPPC vesicle suspension (~1.5 mV) which is consistent with the
6
a–c (69–75%)
Scheme 1 Reagents and conditions: i, Me CO, TsOH, room temperature;
ii, TsCl, pyridine, room temperature; iii, R NH, 100°C; iv, 1 m HCl, room
temperatute; v, MeONa, MeOH, room temperature; vi, CCl , PPh , reflux;
vii, NaH, abs. THF, reflux.
2
2
4
3
2
6
to evaluate quantitatively the compounds 6a–c interaction with
published data. Compounds 6a,b decrease the zpotential of
the DPPC vesicles by about 3 mV, while 6c decreases its value
by 6.5 mV when the molar ratio 1:2 (compound/DPPC) is
reached. Such relatively small changes in the zpotential indicate
the preservation of the lipid bilayer structure. The dependence
reaches plateau with an increase of the molar ratio of compound/
DPPC to the value above 1:2, which implies the saturation of the
vesicles in agreement with the data obtained by turbidimetry.
Thus, for the first time, a biomimetic approach to the design
of membrane anchors was proposed and developed based on the
construction of compounds structurally similar to archaeal lipids
on an aminoglyceride platform with geraniol fragments. New
lipidlike watersoluble meroterpenes capable of incorporating
into the phospholipid bilayer were synthesized. The ability of the
compounds to interact with the lipid bilayer of model DPPC
membranes has been studied by turbidimetry as well as by
laser Doppler microelectrophoresis. The results unambiguously
demonstrate the ability of the synthesized compounds to be
inserted into the DPPC membranes. The zpotential of the DPPC
vesicles is changed due to meroterpenes binding to the DPPC
vesicles. The range of the zpotential change (~1.5–6.5 mV)
phospholipid bilayer by the turbidimetry method.23 It is well
2
4
known that binding of amphiphilic substances with a bilayer
is accompanied by a change in the packing density of lipids,
which ultimately can lead to solubilization of the vesicles. The
gel–liquid crystals phase transition temperature T is a sensitive
indicator for the lipid molecules state in the bilayer. In this
2
5
m
25
study T was determined by measuring the optical density of the
m
25
aqueous lipid dispersion with temperature increase (see Online
Supplementary Materials). This approach is not affected by
scattering particles, because the phase transition is recorded as a
sharp decrease in absorption within a certain narrow temperature
range typical of the chosen lipid. Therefore, it is useful for
screening the membraneactive compounds.
Figure 1 shows the dependence of the vesicle phase transition
temperature Tm on the amount of 6a–c introduced, which is
linear up to a compound/DPPC molar ratio of 1:2. A decrease
in T with an increase in the concentration of compounds 6a–c
m
indicates their interaction with DPPC vesicles. As well, a decrease
of Tm may be caused by disorder in the packaging of the lipid
acyl chains, which testifies to the incorporation of 6a–c into the
lipophilic part of the bilayer.26 Finally, the linear character of
2
1
0
1
1
-(2,3-Bisgeranyloxypropyl)piperidine 6c: yield 3.02 g (70%). H NMR
(
CDCl ) d: 1.60 (m, 6H, CH CH CH ), 1.66 (s, 6H, Me), 1.68 (m, 16H,
Me, CH N), 1.83 (m, 2H, CHCH O), 2.09 (m, 10H, CH CH and NCH ),
.98 (d, 4H, OCH , J 6.8 Hz), 5.08 (m, 2H, =CH), 5.26 (m, 1H, CH),
.44 (m, 2H, =CH). C NMR (CDCl ) d: 16.48, 17.70, 23.03, 25.72,
6.39, 32.46, 39.63, 44.47, 45.50, 66.41, 113.30, 120.99, 121.54, 124.06,
31.63, 140.03. IR (n/cm ): 3365 (=CH), 2967 (Me), 2928 (Me), 2857
CH ), 1720 (=CH), 1670 (C=C), 1446 (=CH), 1376 (Me), 1256 (C–N),
3 2 2 2
2
2
2
2
2
2
3
–1
3
5
2
1
2
1
3
1
3
–2
–
–
3
4
–1
(
2
1
4
140, 1065, 928 (C–O–C), 902 (=CH), 570 (=CH). MS (MALDI), m/z:
32.5 [M+H] , 465.5 [M+Na] , 469.5 [M+K] (calc., m/z: 431.4 [M] ).
–5
3
+
+
+
+
0
.0
0.2
0.4
0.6
0.8
1.0
Found (%): C, 77.02; H, 10.98; N, 3.56. Calc. for C H NO (%): C, 77.90;
H, 11.44; N, 3.24.
28
49
2
Compound/DPPC molar ratio
For characteristics of compounds 6a,b, see Online Supplementary
Materials.
Figure 2 zpotential of DPPC vesicles in the presence of (1) 6a, (2) 6b
and (3) 6c.
–
30 –