3,28-Bis-O-polyfluorobenzoylbetulin. Synthesis, Molecular Structure, and Cytotoxicity

Article abstract of DOI:10.1134/S107042801810007X

Treatment of betulin with 2,3,4,5-tetrafluoro- and pentafluorobenzoyl chlorides in triethylamine afforded 3,28-bis-O-polyfluorobenzoylbetulins. According to the X-ray diffraction data, all six-membered rings in the 3,28-bis-O-pentafluorobenzoylbetulin molecule appear in a chair conformation, and the five-membered ring has an envelope conformation with the C¹⁷ atom deviating from the plane formed by the other four carbon atoms. Unlike betulin itself, the obtained bis-esters showed no cytotoxic effect on human lung adenocarcinoma cell line A549 and human glioblastoma cell line U251.

Full text of DOI:10.1134/S107042801810007X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 10, pp. 1480–1485. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © Yu.G. Trishin, A.N. Fedorov, K.A. Lyssenko, D.S. Prokof’eva, Yu.S. Rudenok, V.V. Pavlova, 2018, published in Zhurnal
Organicheskoi Khimii, 2018, Vol. 54, No. 10, pp. 1468–1475.
3
,28-Bis-O-polyfluorobenzoylbetulin.
Synthesis, Molecular Structure, and Cytotoxicity
a
a
b
c
Yu. G. Trishin ,* A. N. Fedorov , K. A. Lyssenko , D. S. Prokof’eva ,
a
a
Yu. S. Rudenok , and V. V. Pavlova
a
Higher School of Technology and Energy, St. Petersburg State University of Industrial Technologies and Design,
ul. Ivana Chernykh 4, St. Petersburg, 198095 Russia
*
e-mail: trish@YT4470.spb.edu
b
Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
ul. Vavilova 28, Moscow, 119991 Russia
c
Institute of Experimental Pharmacology, Kuz’molovskii, Leningrad oblast, 188663 Russia
Received May 7, 2018
Abstract—Treatment of betulin with 2,3,4,5-tetrafluoro- and pentafluorobenzoyl chlorides in triethylamine
afforded 3,28-bis-O-polyfluorobenzoylbetulins. According to the X-ray diffraction data, all six-membered rings
in the 3,28-bis-O-pentafluorobenzoylbetulin molecule appear in a chair conformation, and the five-membered
17
ring has an envelope conformation with the C atom deviating from the plane formed by the other four carbon
atoms. Unlike betulin itself, the obtained bis-esters showed no cytotoxic effect on human lung adenocarcinoma
cell line A549 and human glioblastoma cell line U251.
DOI: 10.1134/S107042801810007X
The chemistry of terpenoids in Russia has a long
history, and considerable advances have been achieved
in this field [1]. Betulin (1) is a pentacyclic triterpenoid
of the lupane series, and it has been extensively studied
in recent time in many research centers of Novosibirsk,
Ufa, Perm, Moscow, and St. Petersburg. Betulin
exhibits high and diverse biological activity, in partic-
ular anti-inflammatory, choleretic, antiviral, antitumor,
immunomodulatory, etc. [2, 3], and efficiently inhibits
chemically induced carcinogenesis in vivo [4]. Betulin
is among the most accessible terpenoids; its concen-
tration in Betula Pendula Roth. birch bark reaches
derivatives have been synthesized [8–11]. Taking into
account that more than 20% of commercial pharma-
ceuticals contain fluorine atoms [12], we have synthe-
sized 3,28-bis-O-(2,3,4,5-tetrafluorobenzoyl)betulin 2
and 3,28-bis-O-(pentafluorobenzoyl)betulin 3 by reac-
tion of betulin with a slight excess of 2,3,4,5-tetra-
fluoro- or pentafluorobenzoyl chloride in triethylamine
(Scheme 1). Compounds 2 and 3 were isolated in 78
and 69% yield, respectively, as light brown solids
readily soluble in benzene, chloroform, and methylene
chloride and poorly soluble in hexane, ethyl acetate,
acetone, and ethanol.
1
3
5% [2]. The ease of isolation and purification of
The structure of 2 and 3 was confirmed by IR, H,
1
3
19
19
betulin provides the possibility of obtaining new bio-
logically active compounds based thereon. Esterifica-
C, and F NMR, and ESI mass spectra. The
F
NMR spectra of 2 and 3 contained two sets of signals
3
28
tion of betulin at the hydroxy groups on C and C
with equal intensities, indicating the presence of two
3
28
afforded a wide series of O-acyl derivatives some of
which turned out to be promising as hepatoprotective,
anti-inflammatory, antiulcer, immunomodulatory, and
anti-HIV agents [5–7].
polyfluorobenzoyloxy groups on C and C . Signals of
fluorines in the 2,3,4,5-tetrafluorobenzoyloxy group on
2
8
C of 2 were located at δ –133.79, –137.86, –147.44,
F
and –153.36 ppm, and those of the 2,3,4,5-tetrafluoro-
3
Betulin esters containing fluorine atoms in the acyl
moiety have been studied to a considerably lesser
extent than their nonfluorinated analogs. Up to now,
only a few 28-O- and 3,28-bis-O-fluoroacyl betulin
benzoyloxy group on C , at δ –134.08, –138.11,
F
–147.94, and –153.57 ppm. Likewise, the pentafluoro-
2
8
benzoyloxy group on C of 3 was represented by
signals at δ –137.94, –148.67, and –160.37 ppm, and
F
1
480

3
,28-BIS-O-POLYFLUOROBENZOYLBETULIN.
1481
Scheme 1.
Me
H C
2
F
F
O
R
F
F
Cl
Et N
3
+
OH
Me
Me
Me
Me
HO
Me
1
Me
H C
2
F
F
F
Et N
3
Me
Me
O
F
F
O
Me
F
O
F
F
R
O
Me
Me
R
2
, 3
2
, R = H; 3, R = F.
3
that on C , at δ –138.59, –149.43, and –160.55 ppm.
3,28-bis-O-trifluoroacetylbetulin [9]. The signal of 3-H
(d.d) was located even in a weaker field than that in the
spectrum of 3,28-bis-O-trifluoroacetylbetulin [9] by
F
1
In the H NMR spectra of these compounds, the CH O
protons resonated as two doublets at δ 4.60, 4.14 ( J =
1.0 Hz) (2) and 4.62, 4.17 ppm ( J = 11.0 Hz) (3).
These signals were shifted 0.8 ppm downfield from the
corresponding signals of initial betulin; analogous
downfield shift was observed in the spectrum of
2
2
2
3
1
1.57 ppm (δ 4.75 ppm, J = 10.8, 5.1 Hz) (2) and
3
1.63 ppm (δ 4.81 ppm, J = 11.3, 5.0 Hz) (3). The
1
3
C chemical shifts of 2 and 3 almost did not differ
from those reported for 3,28-bis-O-trifluoroacetyl-
3
0
C
2
9
C
2
0
C
2
1
1
9
C
C
1
2
C
1
8
C
22
C
1
1
13
C
C
1
17
C
C
2
8
2
2
9
C
O
C
C
3
1
0
14
O
C
C
10
F
1
6
C
1
31
3
F
C
C
2
5
3
2
C
8
15
38
44
9
C
3
3
3
6
C
C
C
F
C
26
C
2
3
34
C
F
C
4
1
5
O
O
C
7
39
43
3
7
5
4
C
C
C
C
F
C
C
23
42
C
6
40
C
3
5
24
C
C
8
C
C
F
4
6
F
F
F
4
1
C
7
F
Fig. 1. Structure of the molecule of lup-20(29)-ene-3β,28-diyl bispentafluorobenzoate (3) according to the X-ray diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

1
482
TRISHIN et al.
Fig. 2. A fragment of crystal packing of lup-20(29)-ene-3β,28-diyl bispentafluorobenzoate (3).
3
28
betulin [10]; exceptions were the signals of C and C
which appeared 2–3 ppm upfield.
whereas one C F group of the second molecule is
6 5
involved in a series of short C···C and F···F contacts
with the perfluorinated substituent of the neighboring
molecule (Fig. 2).
The molecular structure of 3,28-bis-O-(pentafluoro-
benzoyl)betulin 3 was determined by X-ray analysis.
Single crystals of 3 were obtained by crystallization
from ethyl acetate–acetone (1:1). Compound 3 crystal-
lized in the chiral point symmetry group (C2) with two
independent molecules in a unit cell (Fig. 1). The
structures of two independent molecules were almost
identical; the only difference was mutual arrangement
The cytotoxicity of 3,28-bis-perfluorobenzoate 3
in vitro was studied in comparison to betulin 1 against
human lung adenocarcinoma A549 and human glio-
blastoma U251 cell lines. The cytotoxic activity was
quantitatively expressed by the cell viability percent-
age at concentrations of the tested compounds of
5, 10, and 15 μM (Table 1). The cell viability was
estimated by counting their overall amount in wells in
48 h after addition of compound 1 or 3 (sulfo-
rhodamine B assay). The results showed no effect of
compound 3 on the survival of A549 and U251 cells up
to a concentration of 15 μM. Further increase of the
3
28
of the C F CO substituents on C and C with respect
6
5
2
to the pentacyclic skeleton. The bond lengths and
dihedral angles in the betulin fragments of two in-
dependent molecules coincided with each other within
the experimental error and were similar to those found
for other betulin derivatives, e.g., 3,28-bis-O-trifluoro-
acetylbetulin [9] and 3,28-O-diacetylbetulin [13]. All
six-membered rings adopt a chair conformation, but
the more flexible five-membered ring, unlike the above
noted betulin bis-esters, has an envelope conformation
Table 1. Effect of compounds 1 and 3 on the viability of
A549 and U251 tumor cells
Cell viability, %
1
7
Compound Concentration,
with the C atom deviating by ~0.7 Å from the plane
no.
μM
1
8
19
21
22
A549
U251
formed by the C , C , C , and C atoms.
1
05
10
95.1±7.2
75.5±4.5
32.8±1.1
102.0±7.6
93.9±8.7
101.0±1.9
93.2±5.7
51.0±6.8
The observed difference in the torsion angles
determining orientation of the C F CO groups with
6
5
2
respect to the central part of molecule 3 is likely to
originate from the difference in the intermolecular
interaction systems. The prefluorinated substituents in
one of the two independent molecules form mainly
short C–H···F contacts with the pentacyclic skeleton,
1
5
20.4±4.0
3
05
105.8±10.7
100.0±13.1
94.5±7.0
1
1
0
5
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

3
,28-BIS-O-POLYFLUOROBENZOYLBETULIN.
1483
concentration was impossible because of low solubility
of compounds 2 and 3. On the other hand, betulin
showed an appreciable cytotoxic effect even at a con-
centration of 10 μM. Thus, the acylation of betulin at
the 3-OH and 28-OH groups with perfluorobenzoyl
residues suppresses the cytotoxic activity against the
examined cancer cell lines. Analogous results have
recently been obtained [11] by studying the cytotoxi-
city of betulin and its mono- and bis-esters with
different benzoyl groups (including 4-fluorobenzoyl
and 4-trifluoromethylbenzoyl) against several human
tumor cell lines (MGC-803, PC3, Bcap-37, A375,
MCF-7) by MTT assay.
Crystallographic Data Centre (CCDC entry
no. 1834265).
Betulin (1) was isolated by extraction from the
bark of Betula Pendula Roth. birch. The outer birch
bark with a moisture content of less than 5% was
finely crumbled and Soxhlet extracted with a 1 :1
mixture of petroleum ether (bp 70–100°C) and toluene.
The extract was cooled to 10°C, and the precipitate
was filtered off and dried in air. The crude product
(
yellowish powder) was recrystallized twice from
ethanol. Loose white powder, mp 251–252°C; pub-
lished data [15]: mp 256–258°C. According to the
1
H NMR data, the product contained ≥95% of the main
substance.
EXPERIMENTAL
Pentafluorobenzoic and 2,3,4,5-tetrafluorobenzoic
acids were commercial products (P&M) with a purity
of 99%. The corresponding acid chlorides were
prepared by treatment of the acids with phosphorus
pentachloride (pure grade, Reakhim) [16].
1
13
19
The H, C, and F NMR spectra were recorded on
a Bruker Avance 400 spectrometer at 400.13, 100.61,
and 375.50 MHz, respectively, using CDCl as solvent.
Signals in the C NMR spectra were assigned on the
basis of DEPT and H– C HMQC experiments. The
F chemical shifts are given relative to CFCl . The IR
3
1
3
1
13
2
,3,4,5-Tetrafluorobenzoyl chloride. Yield 69%,
1
9
19
3
bp 63°C (13 mm). F NMR spectrum, δ , ppm:
F
spectra were measured from solutions in chloroform
on a Shimadzu FTIR-8400S spectrometer. The mass
spectra (electrospray ionization) were obtained on
a Bruker micrOTOF 10223 instrument; samples were
introduced as solutions in methanol. The elemental
compositions were determined with a Carlo Erba 1106
analyzer. The optical rotations were measured at
λ 589 nm on an Optical Activity AA-55 polarimeter
using a 3-mL cell.
–133.79, –136.80, –143.14, –152.59.
Pentafluorobenzoyl chloride. Yield 78%, bp 60°C
19
(
20 mm). F NMR spectrum, δ , ppm: –137.62 (2F),
F
–
145.14 (1F), –159.10 (2F).
Triethylamine was preliminarily dried over solid
sodium hydroxide, distilled, and stored over metallic
sodium.
Lup-20(29)-ene-3β,28-diyl bis-2,3,4,5-tetra-
fluorobenzoate (2). 2,3,4,5-Tetrafluorobenzoyl
chloride, 2.4 g (11.29 mmol), was added dropwise with
stirring to a suspension of 2.0 g (4.52 mmol) of betulin
in 20 mL of triethylamine, cooled to 5°C. The mixture
was stirred for 20 h at room temperature and for 2 h at
Crystallographic data for ester 3. Monoclinic crys-
tal system, space group C2; C H F O , M 830.82;
4
4
48 10
4
unit cell parameters (120 K): a = 51.449(9), b =
7
7
.1538(14), c = 22.116 (3) Å; β = 105.379(13)°; V =
3
3
848(2) Å ; d
= 1.406 g/cm ; Z (Z′) = 8 (2).
calc
6
0°C, washed with 5% aqueous HCl (100 mL), and
Intensities of 27321 reflections (Rint = 0.0793) were
measured on a Bruker Smart APEX II CCD automated
extracted with 80 mL of chloroform. The extract was
washed with distilled water and dried over MgSO , the
diffractometer at 120 K (Mo K radiation, graphite
4
α
solvent was distilled off on a rotary evaporator, and the
residue was recrystallized from ethanol and dried
under reduced pressure. Yield 2.8 g (78%), mp 116–
monochromator, ω-scanning, 2θmax = 58°). The struc-
ture was solved by the direct method and was refined
2
against F by the full-matrix least-squares method in
2
0
anisotropic–isotropic approximation using 17170 re-
flections. The positions of hydrogen atoms were deter-
mined by difference electron density syntheses and
were refined according to the riding model. Final
divergence factors: wR = 0.1630; R = 0.0707 [for
118°C, [α] = –23.3° (c = 0.013, CHCl ). IR spectrum,
D
3
–
1
ν, cm : 1719 (C=O), 1627 (C=C), 1239 (C–F).
H NMR spectrum, δ, ppm: 0.92 s, 0.95 s, 0.98 s,
1
1.04 s, and 1.10 s (15H, CH
2.10 m (24H, CH, CH ), 2.51 m (1H, 19-H), 4.14 d
); 1.73 s (3H, 30-H), 0.81–
3
2
1
2
2
8
342 reflections with I > 2σ(I)]; goodness of fit 0.951.
and 4.60 d (2H, 28-H, JHH = 11.0 Hz), 4.64 d and
3
The calculations were performed using SHELXTL
PLUS software package [14]. The X-ray diffraction
data for compound 3 were deposited to the Cambridge
4.74 d (2H, 20-H), 4.75 d.d (1H, 3-H, JHH = 5.1,
1
3
10.8 Hz), 7.63 m (1H, Harom). C NMR spectrum, δ ,
C
24
2
7
26
25
ppm: 14.79 (C ), 16.06 (C ), 16.16 (C ), 16.61 (C ),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

1
1
(
(
3
(
6
1
1
1
484
TRISHIN et al.
6
30
11
2
8.18 (C ), 19.13 (C ), 20.83 (C ), 23.61 (C ), 25.16
Cytotoxicity assay of betulin and lup-20(29)-ene-
3β,28-diyl bispentafluorobenzoate (3) in vitro.
Human lung adenocarcinoma A549 and human glio-
blastoma U251 cell lines were obtained from the
Russian Vertebrate Cell Culture Collection (Institute of
Cytology, Russian Academy of Sciences, St. Peters-
burg, Russia). Cells were cultivated at 37°C in a humid
1
2
15
23
16
C ), 27.04 (C ), 28.01 (C ), 29.50 (C ), 29.70
2
1
7
22
10
13
C ), 34.11 (C ), 34.54 (C ), 37.11 (C ), 37.75 (C ),
4
1
8
14
8.03 (C ), 38.38 (C ), 40.94 (C ), 42.79 (C ), 46.59
1
7
19
18
9
5
C ), 47.75 (C ), 48.81 (C ), 50.29 (C ), 55.39 (C ),
2
8
3
29
4.87 (C ), 83.79 (C ), 110.08 (C ), 113.05 and
13.25 (CHarom), 115.09 and 115.55 (Carom); 140.10,
42.11, 142.59, 142.72, 145.21, 146.59, 147.79,
atmosphere containing 5% of CO in DMEM complete
2
2
0
medium (Biolot, Russia) with addition of 10% of
fetal bovine serum (Gibco), 2 mmol of a solution
of L-glutamine, 100 unit/mL of penicillin, and
49.16 m (FC); 149.86 (C ), 161.92 and 162.58
C=O). F NMR spectrum, δ , ppm: –133.79, –137.86,
147.44, –153.36 [28-OC(O)C HF ]; –134.08,
6 4
138.11, –147.94, –153.57 [3-OC(O)C HF ]. Mass
spectrum: m/z 817.3480 [M + Na] . Found, %:
C 66.60; H 6.44. C H F O . Calculated, %: C 66.49;
1
9
(
–
–
F
1
3
00 mg/mL of streptomycin. The cells were recultured
times a week. Tests were carried out between the 3rd
6
4
+
and 7th reculture.
4
4
50
8
4
H 6.34. M + Na 817.3474.
The cultured A549 and U251 cells were inoculated
in 96-well microplates in amounts of 8 000 and
Lup-20(29)-en-3β,28-diyl bispentafluoroben-
zoate (3). Pentafluorobenzoyl chloride, 1.3 g
1
8000 cells per well, respectively (cell suspension
volume 100 μL), and incubated for 24 h before the
addition of compounds to be tested. Stock solutions of
(
5.63 mmol), was added dropwise with stirring to
a suspension of 1.0 g (2.25 mmol) of betulin in 10 mL
of triethylamine, cooled to 5°C. The mixture was
stirred for 20 h at room temperature and for 3 h at
1
and 3 were prepared by dissolving the compounds in
acetone to a concentration of 1 mM and were stored at
4
3
°C. Solutions with concentrations of 10, 20, and
0 μM were prepared immediately before addition to
6
0°C, washed with 5% aqueous HCl (50 mL), and
extracted with chloroform (50 mL). The extract was
washed with distilled water and dried over MgSO , the
wells using complete culture medium and were added
in an amount of 100 μL to the wells containing
cultured cells, so that the final concentrations of 1 and
4
solvent was distilled off on a rotary evaporator, and the
residue was recrystallized from ethanol, and dried
under reduced pressure. Yield 1.3 g (69%), mp 138–
3
in the wells were 5, 10, and 15 μM, and the final
2
0
concentration of acetone therein did not exceed 1.5%,
which did not affect the cell viability. All experiments
were carried out in triplicate. Those wells to which
only complete culture medium (100 μL) was added
without a compound to be tested were used as control.
Wells containing 200 μL of complete culture medium
were used as blanks. The microplates were incubated
for 48 h at 37°C in a humid atmosphere containing 5%
of carbon dioxide.
1
40°C, [α] = –13.4° (c = 0.013, CHCl ). IR spectrum,
D
3
–
1
ν, cm : 1731 (C=O), 1655 (C=C), 1227 (C–F).
H NMR spectrum, δ, ppm: 0.87 d (1H, 5-H, J
1
3
=
HH
9
2
.78 Hz), 0.91 s (6H), 0.98 s (3H), 1.03 s (3H), 1.05–
.09 m (23H, CH, CH ), 1.10 s (3H), 1.73 s (3H,
2
3
0
C H ), 2.50 m (1H, 19-H), 4.17 d and 4.62 d (2H,
2
4
3
2
8-H, J = 11.04 Hz), 4.64 d and 4.74 d (2H, 29-H),
HH
3
13
.81 d.d (1H, 3-H, J = 5.0, 11.3 Hz). C NMR
HH
2
7
26
spectrum, δ , ppm: 14.79 (C ), 16.04 (C ), 16.14
C
2
5
24
6
30
11
The cells in wells were fixed by adding a solution
of trichloroacetic acid, the wells were then repeatedly
washed with running water, and a 0.4% solution of
sulforhodamine B was added in keeping with the
manufacturer protocol (TOX6, Sigma). The unbound
dye was removed by washing with 1% acetic acid, and
the bound dye was dissolved in Tris [2-amino-2-(hy-
droxymethyl)propane-1,3-diol, 10 mM]. The optical
density of the content of the wells was measured at
λ 510 nm against blank using a BioTeck Instruments
Epoch microplate reader (US).
(
2
(
3
C ), 16.46 (C ), 18.16 (C ), 19.12 (C ), 20.82 (C ),
3.65 (C ), 25.14 (C ), 26.95 (C ), 27.84 (C ), 29.43
C ), 29.55 (C ), 34.08 (C ), 34.42 (C ), 37.09 (C ),
7.76 (C ), 37.92 (C ), 38.38 (C ), 40.92 (C ), 42.77
C ), 46.50 (C ), 47.72 (C ), 48.83 (C ), 50.26 (C ),
5.40 (C ), 65.54 (C ), 84.63 (C ), 110.09 (C ),
36.00‒147.20 (C
58.86 (C=O). F NMR spectrum, δ , ppm: –137.94
2
12
15
23
1
6
21
7
22
10
1
3
4
1
8
1
4
17
19
18
9
(
5
28
3
29
5
1
1
2
0
), 149.80 (C ), 159.51 and
arom
1
9
F
(
2F, o-F), –148.67 (1F, p-F), –160.37 (2F, m-F)
[
28-OC(O)C F ]; –138.59 (2F, o-F), –149.43 (1F, p-F),
6
5
–
160.55 (2F, m-F) [3-OC(O)C F ]. Mass spectrum:
6 5
+
m/z 853.3250 [M + Na] . Found, %: C 63.47; H 5.96.
C H F O . Calculated, %: C 63.61; H 5.82. M + Na
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 17-03-01215).
4
4
48 10
4
8
53.3285.
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1485
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