Synthesis of aminopropylamino derivatives of betulinic and oleanolic acids

Article abstract of DOI:10.1134/S1068162013020064

Triterpenoids with the following amine fragments in C3 and C28 positions were synthesized on the basis of betulinic and oleanolic acids: (3-aminopropoxy)-, 3-acetyl-(3-aminopropyl)amino-, 6-[bis(3-aminopropyl)amino] hexylamino-, and (3-aminopropyl)-4-aminophenylsulfonyl-4-phenylamino. Amide of betulonic acid with 4,4′-diaminodiphenylsulfonic substituent was shown to exhibit no antitumor effect, but to have a pronounced anti-inflammatory activity.

Full text of DOI:10.1134/S1068162013020064

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2013, Vol. 39, No. 3, pp. 329–337. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © G.V. Giniyatullina, O.B. Kazakova, N.I. Medvedeva, I.V. Sorokina, N.A. Zhukova, T.G. Tolstikova, G.A. Tolstikov, 2013, published in Bioorganicheskaya
Khimiya, 2013, Vol. 39, No. 3, pp. 369–377.
Synthesis of Aminopropylamino Derivatives of Betulinic
and Oleanolic Acids
1
G. V. Giniyatullinaa, O. B. Kazakovaa, , N. I. Medvedevaa, I. V. Sorokinab,
N. A. Zhukovab, T. G. Tolstikovab, and G. A. Tolstikovb
a Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences, pr. Oktyabrya 71, Ufa, 45054 Russia
b Vorozhtsov Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
Received May 25, 2012; in final form, July 10, 2012
Abstract—Triterpenoids with the following amine fragments in C3 and C28 positions were synthesized on the
basis of betulinic and oleanolic acids: (3ꢀaminopropoxy)ꢀ, 3ꢀacetylꢀ(3ꢀaminopropyl)aminoꢀ, 6ꢀ[bis(3ꢀamiꢀ
nopropyl)amino]hexylaminoꢀ, and (3ꢀaminopropyl)ꢀ4ꢀaminophenylsulfonylꢀ4ꢀphenylamino. Amide of
betulonic acid with 4,4'ꢀdiaminodiphenylsulfonic substituent was shown to exhibit no antitumor effect, but
to have a pronounced antiꢀinflammatory activity.
Keywords: triterpenoids, amides, cyanoethylation, aminopropylamino derivatives, antiꢀinflammatory activity
DOI: 10.1134/S1068162013020064
1
INTRODUCTION
with hydrogen. Cyanoethylation of amines with the
subsequent reduction of the nitrile group is known to
result in the preparation of monoꢀNꢀ or bisꢀNꢀpropylꢀ
amines depending on the structure and reaction conꢀ
ditions [11].
Derivatives of betulinic acid with longꢀchain subꢀ
stituents in position C28 are known as effective antiviꢀ
ral agents [1, 2]. In general, syntheses of amides and
ureides with amino acids, diamines, and peptides are
described [3]. The triterpenoid structures with
branched fragments in their side chains are of interest,
for example, dioxalates of 3,28ꢀpolyethyleniminobetꢀ
ulin [4] and hydroxyl/amino derivatives of betulinic
acid (esters with 2,3ꢀdihydroxyꢀ2ꢀhydroxymethylproꢀ
RESULTS AND DISCUSSION
We applied the aforementioned approach to the
synthesis of a new group of triterpenoids which conꢀ
tained various alkanepolyamine fragments. Amides of
betulonic and oleanonic acids with aliphatic and aroꢀ
matic diamines were used as starting compounds
(Schemes 1 and 2). Exhaustive cyanoethylation of the
pane, 2ꢀaminoꢀ2,3ꢀdihydroxymethylpropane,
Nꢀ
(1,1ꢀbis(hydroxymethyl)ꢀ2ꢀhydroxyethyl)formamide,
and others). The antitumor activity of these derivatives
is several times higher than that of betulinic acid [5, 6].
Aminopropoxy derivatives of betulin, erythrodiol,
uvaol, and oleantriol were synthesized by cyanoethyꢀ
lation of hydroxyl groups of the triterpenoids and subꢀ
sequent reduction of the cyanoethyl fragments, and
high antitumor activity of these compounds towards
large number of human tumor cell lines in vitro was
shown [7]. Derivatives of lupane and ursane with variꢀ
ous substituents in positions C3 and C28 are also
promising modifiers of biological reactions with antiꢀ
oxidative, antiꢀinflammatory, and cytoprotective
activity [8–10].
terminal NH2ꢀgroup with the formation of bisꢀ
pionitrile (III) was observed during the interaction of
amide of betulonic acid ( ) with acrylonitrile in dioxꢀ
Nꢀproꢀ
V
ane. Products of biscyanoethylation were found even
at equimolar amounts of the diamine and acryloniꢀ
trile. The monosubstituted derivative (VI) was formed
from amide (V), probably due to steric factors. As it
was previously reported [12, 13], we found no products
of the cyanoethylation of the triterpenic skeleton of
compounds (II) and (
groups were identified in the 13C NMR spectra at
118.6 and 119.4 ppm. The resonances from C7' and
C10' of bisnitrile (III) and C1' of nitrile (VI) were
observed in the region of 49.7–49.9 ppm, whereas
the resonances from C8' and C11' of nitrile (III) and
V). Resonances from the nitrile
One of the new approaches to the introduction of
longꢀchain branched substituents in position C28 of
triterpenic acids involves synthesis of amides, interacꢀ
tion of their terminal amino groups with acrylonitrile,
and subsequent reduction of cyanoethyl derivatives
δ
δ
1
C2' of derivative (VI) were found at
δ 12.2, 12.3, and
Corresponding author: fax: (347)235ꢀ6066; eꢀmail:
obf@anrb.ru.
17.3 ppm, respectively.
329

330
GINIYATULLINA et al.
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SYNTHESIS OF AMINOPROPYLAMINO DERIVATIVES
331
29
30
20
19 21
22
12
26
13
18
28
11
25
17
16
i
COCl
CONH(CH2)6NH2
14
15
1
4
9
2
3
10
8
7
5
27
6
O
O
(XV)
(XVI)
24
23
N
N
ii
NH2
iii
CONH(CH2)6N
CONH(CH2)6N
NH2
O
HO
(XVII)
(XVIII)
Reaction conditions:
i, NH2(CH2)6NH2, Et3N, chloroform; ii, CH2=CHCN, 1,4ꢀdioxane, 40%
КOH; iii, LiAlH4, THF.
Scheme 2.
Bisamino derivative (IV) was prepared by reduction 3.08–3.34 ppm (H1'''). Steroid compounds of this
of compound (III) by lithium aluminum hydride in type exhibit an antimicrobial activity [16].
boiling THF with a yield of 74%. The CONꢀbond was
not reduced under the reaction conditions, possible
owing to the bulk substituent at the C17 atom. Proꢀ
longed reduction (for 20 h) of amide (III) by lithium
aluminum hydride did not affect the amide bond,
although the amide of acetyl betulinic acid was conꢀ
verted into the corresponding amine under similar
conditions [14]. At the same time, the stability of
amides of glycyrrhetic acid towards the reduction by
lithium aluminum hydride is well known [15]. The
type of triterpenic backbone and steric factors were
probably important for every concrete case. Resoꢀ
We used amide of betulonic acid with 4,4'ꢀdiaminꢀ
odiphenylsulfonic substituent (XII) as one more comꢀ
pound for the formation of a branched derivative
(Scheme 1). Note that amide of deoxycholic acid with
4,4'ꢀdiaminodiphenylsulfonic substituent was tested
as an anticancer agent [17]. Therefore, we synthesized
the analogous derivative of betulonic acid in order to
study the effect of 4,4'ꢀdiaminodiphenylsulfonic subꢀ
stituent on the antitumor and antiꢀinflammatory
activity.
Aromatic amines are known to be cyanoethylated
only after heating to 100–180°С for many hours in the
presence of salts of Cu, Zn, Co, or Ni [18]. Cyanoethꢀ
ylation of amide (XII) to derivative (XIII) according to
nances from CNꢀgroups at
δ 118.4 and 119.4 were
absent in the 13C NMR spectrum of compound (IV),
but resonances from the C9' and C12' aminomethylꢀ
the method [19] required the presence of Сu(ОАс)2
.
ene groups were observed at
of the reduction of compound (VI) was characterized
as its ꢀdiacetate (VIII).
Exhaustive cyanoethylation of amide of oleanonic
acid XVI to [6ꢀbis(2ꢀcyanoethyl)amino)hexyꢀ
lamino]oleanꢀ12ꢀene (XVII) with its subsequent
reduction to ꢀhydroxyꢀ28ꢀ{6ꢀ[bis(3ꢀaminoproꢀ
pyl)amino]hexylamino}oleanꢀ12ꢀene XVIII was
performed according to a similar scheme (Scheme 2).
Structures of compounds (XVII and (XVIII) were
δ 39.2 ppm. The product
Reduction of compound (XIII) by lithium aluminum
hydride in boiling THF yielded 56% of lupene derivaꢀ
tive (XIV) with the unreduced sulfogroup. Resonances
from the H2'' and H1'' protons of the aminomethylene
groups were found in the 1H NMR spectrum of comꢀ
pound (XIV) in the area of δ 1.21–2.00 and 3.60–3.75
ppm as multiplets.
O,N
(
)
3β
(
)
The antitumor properties of 4,4'ꢀdiaminodipheꢀ
nylsulfonic amide of betulonic acid (XII) were examꢀ
ined on female mice of the C57BL/6 line with the
intramuscularly transplanted Lewis lung carcinoma
)
confirmed by their NMR and IR spectra.
Sequential cyanoethylation of amide of betulinic
(2 ×
106 cells). Compound (XII) was daily introduced
acid (IX) and catalytic hydrogen reduction of tricyano on the cancer visualization stage from the 10th to
derivative ( ) result in the formation of lupane trisꢀ 16th day after the cancer transplantation at a dose of
X
amino derivative (XI). The broadened resonances 50 mg/kg (see Experimental). The mixture of antituꢀ
from aminomethylene groups are observed in its mor agents that imitated polychemotherapy (PCT)
1H NMR spectrum at
δ 2.64–2.88 ppm (H3''') and served as a standard of the antitumor activity [20]. The
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332
GINIYATULLINA et al.
Table 1. Dynamics of growth of the Lewis lung carcinoma in the C57BL/6 mice in the course of treatment with compound
XII
(
)
The cancer volume (V, cm3; %) in the course of the treatment with agent (XII
)
1
Group
10 day
12 day
14 day
17 day
3
3
3
3
V, cm
V, %
V, cm
V, %
V, cm
V, %
V, cm
V, %
251
Control
PCT
XII
1.33 0.07
1.12 0.08
1.02 0.05**
0
0
0
2.05 0.13
54
27
63
2.78 0.18
109
55
4.67 0.22
1.42 0.10**
1.66 0.09*
1.74 0.13***
3.08 0.18*** 175
4.16 0.17### 308
(
)
2.51 0.13### 146
***
p
p
≤
≤
0.001; **
0.001;
p
p
≤
≤
0.01 – relative to the control group;
0.01 – relative to the PCT group;
###
##
1
1 days after the cancer transplantation.
Table 2. Values of the edema index for a leg of mice with the induced inflammation
Group
Dose, mg/kg
Edema index, %
Relative edema index, %
Control
XII
–
100
100
20
19.80 1.58
15.15 1.18*
14.54 1.40*
14.17 2.57
100
75
(
)
Betulonic acid
Indomethacin
73
72
*
P < 0.05 differences with the control are significant.
control group was treated with a waterꢀtween mixture. indomethacin (the wellꢀknown nonꢀsteroid antiꢀ
Volumes of tumor nodes were measured during the inflammatory agent) (28%) that was administered in
treatment with compound (XII). The dynamics of the the effective dose. No considerable differences in the
growth of transplants was presented as a percentage of antiꢀinflammatory activity were found between betuꢀ
their starting sizes before the administration of the lonic acid and its derivative (XII). This fact pointed to
agents (Table 1).
the leading role of the triterpene backbone in the realꢀ
ization of this activity.
As follows from Table 1, compound (XII) exhibited
no antitumor effect: the average sizes of the transplants
of experimental and control groups did not signifiꢀ
cantly differ. We noted a negative tendency to
advanced growth of the transplants in the experimenꢀ
tal group in comparison with the control group (taking
into account the differences between the groups before
the administration of the compound). At the end of
the experiment, sizes of the cancer in mice that were
treated with compound (XII) were 1.2 times higher
than those in the control group, whereas they were
1.4 times lower in the PCT group. Previously, we demꢀ
onstrated that betulonic acid that was administered to
mice with the Lewis lung carcinoma according to the
same scheme exhibited no antitumor activity [21].
Thus, the introduction of 4,4'ꢀdiaminodiphenylsulꢀ
fonic fragment in betulonic acid did not result in the
appearance of the target activity.
Thus, triterpenoids with the following amine fragꢀ
ments: (3ꢀaminopropooxy)ꢀ, 3ꢀacetylꢀ(3ꢀaminoproꢀ
pyl)aminoꢀ,
6ꢀ[bis(3ꢀaminopropyl)amino]hexylꢀ
aminoꢀ, and (3ꢀaminopropyl)ꢀ4ꢀaminophenylsulfoꢀ
nylꢀ4ꢀphenylamino in positions C3 and C28, were
synthesized on the basis of betulinic and oleanolic
acids. No antitumor effect was shown to appear after
the attachment of 4,4'ꢀdiaminodiphenylsulfonic subꢀ
stituent to betulonic acid, but this derivative preserved
the antiꢀinflammatory activity specific for betulonic
acid.
EXPERIMENTAL
IR spectra were recorded on an IRPrestigeꢀ21 Shiꢀ
madzu spectrophotometer (Japan) in a paste with
Vaseline oil. The absorption band of valence oscillaꢀ
tions of the nitrile group in IR spectra of compounds
Antiꢀinflammatory properties of compound (XII
were studied on a model of inflammation which was
induced by the subplanar administration of histamine The 1Н and 13C NMR spectra (
)
(
III)
and (VI) was observed in the region of 2260 cm–1.
δ, ppm) were recorded on
(see Experimental). The results are given in Table 2. a Bruker AMꢀ300 spectrometer (300.13 and 75.47 MHz,
Compound (XII) was shown to exhibit a significant respectively) in deuterochloroform (if otherwise indiꢀ
antiꢀinflammatory effect; the leg edema was decreased cated) with trimethyl silane as an internal standard.
by 25% in comparison with the control. The proꢀ Melting points were determined on a Boetius device.
nouncement of this effect corresponded to that of Optical absorption was measured on a PerkinꢀElmer
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SYNTHESIS OF AMINOPROPYLAMINO DERIVATIVES
333
241 MC polarimeter in a 1ꢀdecimeter tube. TLC was (C6'), 49.9, 51.3, 55.2, 122.3 (C12), 145.1 (C14),
carried out on Sorbfil plates (ZAO Sorbpolimer, Rusꢀ 177.7 (C28), 217.2 (C3).
sia) in the chloroform–ethyl acetate system (40 : 1).
Substances were detected by treatment with 10%
H2SO4 (heating for 2–3 min at 100–120°С). The eleꢀ
Found, %: C 77.79, H 10.67, N 4.81. Calc. for
C36H60N2O2 (
N 5.07.
M 552.881), %: C 78.21, H 10.94,
ment analysis was performed on a EuruEAꢀ3000
CHNSꢀanalyzer using acetanilide as a main standard.
The column chromatography was carried out on neuꢀ
tral Al2O3 (Reakhim, Russia). Oleanolic acid was isoꢀ
lated as described in [22] and oxidized to oleanonic
acid by the Jones reagent in acetone. Betulonic acid
was synthesized from betulin as described in [23].
Technique of the synthesis of compounds (III), (VI),
and (XVII). The mixture of amide (II), ( ), or XVI)
(1 mmol) acrylonitrile (8 mL), and 40% KOH
(0.3 mL) in dioxane (15 mL) was stirred for 14 h at
V
(
20°С and poured into ice (50 g) with HCl (5 mL). The
precipitate was filtered, washed with water to pH 7,
dried in air, and fractionated on a column with Al2O3
that was subsequently eluted with benzene and chloroꢀ
form.
Chlorides of betulonic acid (I) and oleanonic acid
(XV) were prepared by treatment with oxalyl chloride
in chloroform [24]. The Raney Nickel catalyst was
prepared according to [25].
3,28ꢀDioxoꢀ28ꢀ{6ꢀ[bis(2ꢀcyanoethyl)amino]hexylꢀ
amino}lupꢀ20(29)ꢀene (III). The yield of compound
(
III) 0.37 g (74%); Rf 0.32; mp 143–145°
С. [α]2D0
6ꢀAminohexylamide of betulonic (II) and oleanonic
(XVI) acids. Diaminohexane (0.16 g, 1 mmol) and,
then, triethyl amine (0.3 mL, dropwise) were added to
the solution of chloride of betulonic or oleanonic acids
(0.46 g, 1 mmol) in anhydrous CHCl3 (30 mL). The
reaction mixture was boiled for 8 h, washed with 5%
1
+12° (с 0.02, CH3СОСН3); H NMR: 0.86, 0.92,
0.96, 1.04, 1.13 (15 H, 5s, 5CH3), 1.20–2.00 (29 H,
CH2, CH, H2', H3', H4', H5'), 1.69 (3 H, s, H30),
2.08–2.34 (5 H, m, H13, H16, H6'), 2.49–2.68 (4 H,
m, H7', H10'), 3.04–3.27 (7 H, m, H19, H1', H8',
H11'), 4.62 and 4.75 (2 H, both broadened s, H29),
5.57–5.68 (1H, m, CONH); 13C NMR: 12.2 (C8'),
12.3 (C11'), 14.4, 15.4, 17.5, 19.4, 20.1, 21.5, 21.7,
22.9, 25.5 (C3'), 25.9, 29.2 (C2'), 29.4 (C5'), 29.7
(C4'), 30.7, 32.2, 32.7, 33.6, 36.7, 37.3, 37.5, 38.4,
38.5, 40.5, 42.5, 46.0 (C1'), 46.5, 48.0, 49.8 (C7'), 49.9
(C10'), 50.0, 51.1, 51.6 (C6'), 55.0, 55.4, 109.4 (C29),
118.6 (C9'), 119.4 (C12'), 150.7 (C20), 175.9 (C28),
218.6 (C3).
HCl (2 × 50 mL) and cold water (50 mL), dried over
СаСl2, and evaporated in vacuum. The residue was
fractionated on a column with Al2O3 that was eluted
with benzene and chloroform.
3,28ꢀDioxoꢀ28ꢀ(6ꢀaminohexylamino)lupꢀ20(29)ꢀ
ene (II). The yield of compound (II) was 0.48 g (87%);
1
mp 188–190
°
C. [α]2D0 –36
°
(c
0.07, CHCl3); H
NMR: 0.86, 0.92, 0.96, 1.04, 1.13 (15
H, 5s, 5CH3),
1.20–2.13 (32 H, CH2, CH, H2', H3', H4', H5',
NH2), 1.67 (3 H, s, H30), 2.32–2.58 (5 H, m, H13,
H16, H6'), 3.03–3.32 (3 H, m, H19, H1'), 4.58 and
4.72 (2 H, both broadened s, H29), 5.75–5.88 (1 H,
m, CONH); 13C NMR: 14.5, 15.9, 16.1, 19.1, 19.4,
20.9, 21.4, 23.5, 25.5, 25.9 (C4'), 26.5 (C2'), 26.6
(C3'), 29.3, 29.7, 30.8, 33.7, 34.1, 36.8, 37.7, 38.4,
39.6, 40.6, 42.4 (C5'), 45.8 (C1'), 46.6, 47.3 (C6'),
49.3, 49.9, 50.0, 54.9, 55.5, 109.3 (C29), 150.9 (C20),
176.1 (C28), 218.2 (C3).
Found, %: C 76.12, H 9.72, N 8.12. Calc. for
C42H66N4O2 (
N 8.50.
M 659.008), %: C 76.55, H 10.09,
3,28ꢀDioxoꢀ28ꢀ[(2ꢀcyanoethyl)amino]lupꢀ20(29)ꢀ
ene (VI). The yield of compound (VI) 0.34 g (68%);
R
f 0.43; mp 94–96° ° (с 1.0, CH3Сl);
С. [α]2D0 +24
1H NMR: 0.86, 0.92, 0.96, 1.04, 1.13 (15 H, 5s, CH3),
1.18–2.03 (21 H, CH2, CH3), 1.69 (3 H, s, H30),
2.18–2.67 (5 H, m H13, H16, H2'), 3.01–3.18 (1 H,
m, H19), 3.42–3.53 (2 H, m, H1'), 4.62 and 4.78 (2 H,
both broadened s, H29), 5.57–5.68 (1 H, m, CONH);
13C NMR: 14.2, 15.3, 17.3 (C2'), 18.6, 19.3, 20.0,
21.6, 22.8, 25.4, 29.2, 29.8, 30.1, 30.4, 32.2, 32.6,
33.5, 36.6, 37.0, 37.3, 38.0, 40.4, 42.5, 46.5, 47.8, 49.7
(C1'), 50.9, 51.4, 55.4, 109.4 (C29), 119.1 (C3'), 150.2
(C20), 178.4 (C28), 217.9 (C3).
Found, %: C 77.84, H 10.62, N, 4.72. Calc. for
C36H60N2O2 (
5.07.
М 552.881), %: C 78.21, H 10.94, N
3,28ꢀDioxoꢀ28ꢀ(6ꢀaminohexylamino)oleanꢀ12ꢀene
(XVI). The yield of compound (XVI) 0.33 g (62%);
R
f 0.42; mp 150–152° ° (с 1.02, CHCl3);
С. [α]2D0 +21
1H NMR : 0.78, 0.89, 0.93, 1.01, 1.03, 1.11, 1.14
(21 H, 7s, CH3), 1.20–2.12 (32 H, CH2, CH, H2',
H3', H4', H5', NH2), 2.42–2.62 (2 H, m, H6'), 2.74–
2.84 (1 H, m, H11), 2.93–3.03 (2 H, m, H1'), 5.18–
5.34 (1 H, broadened s, H12), 5.78–5.88 (1 H, m,
CONH); 13C NMR: 14.0, 15.0, 16.8, 17.9, 19.5, 21.4,
22.6, 23.5, 24.8, 25.5 (C3'), 26.4 (C2'), 26.5 (C4'),
27.1, 29.6, 30.6, 31.6, 32.6, 32.9, 34.0, 36.6, 39.1
(C5'), 39.3, 42.1, 42.3, 45.8 (C1'), 46.2, 46.7, 47.3
Found, %: C 77.82, H 9.56, N 5.24. Calc. for
C33H50N2O2 (
M 506.769), %: C 78.21, H 9.94, N 5.53.
3,28ꢀDioxoꢀ28ꢀ{6ꢀ[bis(2ꢀcyanoethyl)amino]hexylꢀ
amino}oleanꢀ12ꢀene (XVII). The yield of compound
(
XVII) 0.50 g (78%); Rf 0.31; mp 86
⎯88°С;
[α]2D0
1.1, CHCl3); 1H NMR: 0.78, 0.89, 0.93, 1.01,
+34° (с
1.03, 1.11, 1.14 (21 H, 7s, CH3), 1.20–2.12 (30 H,
CH2, CH, H2', H3', H4', H5'), 2.14–2.26 (2 H, m,
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GINIYATULLINA et al.
H6'), 2.49–2.68 (4 H, m, H7', H9'), 2.74–2.84 (1 H, 17.9, 19.5, 20.1, 21.4, 22.6, 23.5, 24.2, 24.8, 25.3
m, H11), 3.03–3.28 (6 H, m, H1', H8', H10'), 5.18– (C3'), 25.6, 27.1, 28.7 (C5'), 29.1 (C2'), 29.6 (C4'),
5.34 (1 H, broadened s, H12), 5.88–5.98 (1 H, m, 30.1, 30.6, 31.6, 32.6, 32.9, 34.0, 34.2 (C8'), 34.4
CONH); 13C NMR: 12.0 (C8'), 12.3 (C11'), 14.0,
15.0, 16.8, 17.9, 19.5, 21.4, 22.6, 23.5, 24.8, 25.5
(C3'), 26.4 (C2', C4'), 27.1, 29.6, 27.2, 30.6, 31.6,
32.6, 32.9, 34.0, 36.6, 39.1 (C5'), 39.3, 42.1, 42.3, 45.8
(C1'), 46.2, 46.7, 47.3 (C6'), 47.9 (C7', C10'), 48.1,
51.3, 55.2, 118.4 (C9'), 119.4 (C12'), 121.8 (C12),
144.8 (C14), 177.5 (C28), 218.1 (C3).
(C11'), 36.6, 39.1 (C9'), 39.3 (C12'), 42.1, 42.3, 45.8
(C1'), 46.2, 46.7, 47.3 (C6'), 47.9 (C7', C10'), 51.3,
55.2, 77.8 (C3), 121.8 (C12), 144.8 (C14), 177.5
(C28).
Found, %: C 74.63, H 11.45, N 7.89. Calc. for
C42H78N4O2 (
8.35.
M 671.103), %: C 75.17, H 11.71, N
Found, %: C 76.13, H 9.64, N 8.17. Calc. for
3βꢀAcetoxyꢀ28ꢀoxoꢀ28ꢀ[3ꢀacetylꢀ(3ꢀaminopropyl)ꢀ
C42H66N4O2 (
8.50.
M 659.008), %: C 76.55, H 10.09, N
amino]lupꢀ20(29)ꢀene (VIII). Compound (VIII) was
prepared from compound (VI) similarly to compound
(
IV). Further, the reaction mixture was boiled for 8 h
Synthesis of compounds (IV) and (XVIII). LiAlН4
(467.4 mg, 12.3 mmol) was added to the solution of
compound (III) or (XVII) (1 mmol) in anhydrous tetꢀ
rahydrofuran with intensive stirring. The reaction
mixture was boiled for 3 h and diluted with water
(3 mL). The precipitate of Al(OH)3 was filtered off,
with acetic anhydride (1.3 mL) and poured into 5%
solution of HCl (100 mL). The precipitate was filꢀ
tered, washed with water, dried, and recrystallized
from ethanol. The yield of compound (VIII) 0.42 g
(70%); Rf 0.34; mp 128–130° ° (с 0.13,
С. [α]2D0 +11
and the water layer was washed with chloroform (3 ×
CHСl3); 1H NMR: 0.86, 0.92, 0.96, 1.04, 1.13 (15 H,
5s, CH3), 1.18–2.03 (25 H, CH2, CH, H2', NH), 1.69
(3 H, s, H30), 2.08 and 2.31 (6 H, 2s, 2 Ac), 2.18–2.71
(3 H, m, H13, H16), 3.23–3.53 (5 H, m, H19, H3',
H1'), 4.42–4.45 (1 H, m, H3), 4.62 and 4.78 (2 H,
both broadened s, H29); 13C NMR: 14.2, 15.3, 17.4,
18.6, 19.3, 20.0, 21.6, 22.8, 25.4, 29.8, 30.1, 30.4,
32.2, 32.6, 33.5, 34.3 (C2'), 36.6, 37.0, 37.3, 38.0, 39.7
(C3'), 40.4, 42.5, 43.4 (C1'), 45.7, 46.2, 46.5, 47.8,
50.9, 51.4, 55.4, 80.8 (C3), 109.4 (C29), 150.2 (C20),
170.4 (CH3CO), 172.4 (NHꢀСОСН3), 178.4 (C28).
60 mL), dried over СаСl2, and evaporated in vacuum.
The residue was fractionated on a column with SiО2
that was subsequently eluted with chloroform and
methanol.
3βꢀHydroxyꢀ28ꢀoxoꢀ28ꢀ{6ꢀ[bis(3ꢀaminopropyl)amiꢀ
no]hexylamino}lupꢀ20(29)ꢀene (IV). The yield of
compound (IV) 0.49 g (74%);
[α]2D0 +9
R
f 0.13; mp 250–252°С.
1
°
(с
0.51, CH3ОН); H NMR (CD3OD):
0.86, 0.92, 0.96, 1.04, 1.13 (15 H, 5s CH3), 1.18–2.03
(38 H, CH2, CH3, H2', H3', H4', H5', H8', H11', 2
NH2), 1.69 (3 H, s, H30), 2.18–2.48 (5 H, m H13,
H16, H6'), 2.46–2.67 (4 H, m H7', H10'), 3.05–3.28
(2 H, m, H19, H3), 3.31–3.48 (6 H, m, H1', H9',
H12'), 4.62 and 4.78 (2 H, both broadened s, H29),
5.52–5.73 (1 H, m, CONH); 13C NMR (CD3OD):
14.4, 15.4, 17.6, 19.3, 20.1, 21.8, 22.9, 23.6, 25.4
(C3'), 25.6, 28.9 (C5'), 29.2 (C2'), 29.9 (C4'), 30.1,
30.3, 30.7, 32.3, 32.7, 33.5, 34.2 (C8', C11'), 35.2,
36.7, 37.3, 37.7, 38.3, 39.2 (C9'), 39.2 (C12'), 40.5,
42.6, 46.4 (C1'), 46.5, 48.1, 49.7 (C7', C10'), 51.1,
51.7 (C6'), 55.7, 77.3 (C3), 109.8 (C29), 150.7 (C20),
176.8 (C28).
Found, %: C 74.07, H 9.85, N 4.26. Calc. for
C37H60N2O2 (
4.69.
M 569.912), %: C 74.45, H 10.13, N
3βꢀHydroxyꢀ28ꢀoxoꢀ28ꢀ(6ꢀaminohexylamino)lupꢀ
20(29)ꢀene (IX). NаВН4 (120 mg, 3.12 mmol) was
added to the solution of compound (II) (0.66 g,
1 mmol) in isopropanol (20 mL) for 10 min. The reacꢀ
tion mixture was kept for 2 h and diluted with 30%
solution of HCl (72 mL). The precipitate was filtered,
washed with water, dried, and recrystallized from ethꢀ
anol. The yield of compound (IX) 0.40 g (80%);
R
f 0.18; mp 68⎯70° ° (с 0.38, СНСl3);
С. [α]2D0 +4
Found, %: C 74.82, H 11.26, N 7.94. Calc. for
1H NMR: 0.76, 0.82, 0.92, 0.96, 1.04 (15 H, 5s, CH3),
1.12–2.13 (32 H, CH2, CH, H2', H3', H4', H5',
NH2), 1.67 (3 H, s, H30), 2.39–2.57 (5 H, m, H13,
H16, H6'), 3.03–3.38 (4 H, m, H3, H19), 4.58 and
4.72 (2 H, both broadened s, H29), 5.75–5.88 (1 H,
m, CONH); 13C NMR: 14.6, 15.3, 16.1, 18.2, 19.4,
20.9, 25.6, 25.9 (C3'), 27.4, 27.9 (C2'), 28.0 (C4'),
28.1 (C5'), 28.2, 28.3, 29.4, 29.7, 30.9, 33.8, 34.4,
37.2, 37.6, 38.4, 38.7 (C1'), 38.8 (C6'), 39.6, 40.7,
42.4, 46.6, 50.1, 50.6, 55.4, 55.5, 78.9 (C3), 109.2
(C29), 150.9 (C20), 176.1 (C28).
C42H78N4O2 (M 671.013), %: C 75.37, H 11.71, N
8.35.
3βꢀHydroxyꢀ28ꢀoxoꢀ28ꢀ{6ꢀ[bis(3ꢀaminopropyl)amiꢀ
no]hexylamino}oleanꢀ12ꢀene (XVIII). The yield of
compound (XVIII) 0.41 g (62%); Rf 0.22; mp 125–
127° ° (с 0.48, CH3ОН);
С. [α]2D0 +67
1H NMR
(CD3OD): 0.78, 0.89, 0.93, 1.01, 1.03, 1.11, 1.14
(21 H, 7s, CH3), 1.20–2.03 (41 H, CH2, CH, H2',
H3', H4', H5', H8', H11', 2NH2), 2.14–2.26 (2 H, m,
H6'), 2.49–2.68 (4 H, m, H7', H10'), 2.74–2.84 (1 H,
m, H11), 3.09–3.25 (7 H, m, H3, H1', H9', H12'),
5.28–5.44 (1 H, broadened s, H12), 5.89–5.98 (1 H,
m, CONH); 13C NMR (CD3OD): 14.0, 15.0, 16.8,
Found, %: C 77.64, H 10.88, N 4.72. Calc. for
C36H62N2O2 (
N 5.05.
M 554.897), %: C 77.92, H 11.26,
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
No. 3
2013

SYNTHESIS OF AMINOPROPYLAMINO DERIVATIVES
335
3
β
ꢀ(2ꢀCyanoethoxy)ꢀ28ꢀoxoꢀ28ꢀ{6ꢀ[bis(2ꢀcyanoꢀ 8 h with a backflow condenser, washed with 5% HCl
ethyl)amino]hexylamino}lupꢀ20(29)ꢀene (X). was preꢀ 50 mL) and cold water ( 50 mL), and dried
pared from compound (IX) similarly to compound over СаСl2. The solvent was evaporated in vacuum,
(
2
×
1 ×
(
III). The yield of compound (
X) 0.41 g (74%);
and the residue was fractionated on a column with
Al2O3 that was eluted with chloroform. The yield of
compound (XII) 0.40 g (85%); Rf 0.30. mp 114–
R
f 0.57; mp 149 151
1H NMR: 0.76, 0.82, 0.92, 0.96, 1.04 (15 H, 5s, CH3),
1.12–2.03 (30 H, CH2, CH, H2', H3', H4', H5'), 1.67
⎯
°С;
[α]2D0 +13
°
(с
1.0, CHCl3);
1
115°
С. [α]2D0 –19
°
(с
0.05, CHCl3); H NMR: 0.81,
(3 H, s, H30), 2.39–2.51 (5 H, m, H13, H16, H6'), 0.94, 0.97, 0.98, 1.02 (15 H, 5s, CH3), 1.21–2.00 (24
2.54–2.62 (4 H, m, H8', H8''), 2.64–2.68 (4 H, m,
H7', H7''), 3.08–3.34 (5 H, m, H19, H1', H2'''), 3.69–
3.78 (2 H, m, H1'''), 4.58 and 4.72 (2 H, both broadꢀ
ened s, H29), 5.75–5.88 (1 H, m, CONH); 13C NMR:
14.6, 15.3, 16.1 (C8', C8''), 18.2, 19.2 (C2'''), 19.5,
20.9, 25.6, 25.9 (C3'), 26.5 (C2'), 27.9 (C4', C5'), 28.0,
28.3, 29.4, 29.7, 30.9, 33.8, 34.4, 37.1, 37.2, 37.6,
38.4, 38.7 (C1'), 39.6, 40.7, 42.4, 46.7, 50.1, 50.6,
55.4, 55.5, 55.8 (C6'), 55.9 (C7'), 56.0 (C7''), 65.9
(C1'''), 67.0, 87.7 (C3), 109.2 (C29), 117.3 (C3'''),
118.2 (C9'), 118.3 (C9''), 150.9 (C20), 176.1 (C28).
H, CH2, CH, NH, NH2), 1.69 (3 H, s, H30), 2.28–
2.55 (3 H, m, H13, H16), 3.02–3.18 (1 H, m, H19),
4.58 and 4.71 (2 H, both broadened s, H29), 6.40–
6.58 (2 H, m, H9', H10'), 7.52–7.98 (6 H, m, H2',
H3', H5', H6', H8', H11'); 13C NMR: 11.8, 14.7, 16.1,
19.5, 20.0, 21.2, 21.9, 26.0, 26.8, 30.0, 31.1, 33.7,
34.0, 34.5, 37.3, 37.9, 38.1, 40.0, 41.1, 43.0, 46.8,
47.6, 50.3, 50.5, 55.3, 57.2, 109.7 (C20), 114.4 (C2',
C9'), 120.1 (C6', C10'), 128.4 (C8'), 128.7 (C11'),
128.8 (C3'), 129.8 (C5'), 136.4 (C7'), 137.6 (C4'),
143.7 (C1'), 151.1 (C29), 151.9 (C12'), 175.5 (C28),
218.0 (C3).
Found, %: C 75.11, H 9.63, N 9.25. Calc. for
C45H71N5O2 (
9.81.
M 714.087), %: C 75.69, H 10.02, N
Found, %: C 71.62, H 7.78, N 3.63, S 4.17. Calc.
for C42H56N2O5S (
4.07, S 4.60.
M 700.973), %: C 72.06, H 8.20, N
3β
ꢀ(3ꢀAminopropoxy)ꢀ28ꢀoxoꢀ28ꢀ{6ꢀ[bis(3ꢀamiꢀ
nopropyl)amino]hexylamino}lupꢀ20(29)ꢀene (XI).
Compound ( ) (1 mmol) was dissolved in methanol
3,28ꢀDioxoꢀ28ꢀ[(2ꢀcyanoethyl)ꢀ4ꢀaminophenylsulꢀ
fonylꢀ4ꢀphenylamino]lupꢀ20(29)ꢀene (XIII). The mixꢀ
ture of amide (XII) (0.48 g, 1 mmol), acrylonitrile
(4 mL), and Cu(OAc)2 (0.2 g) in dioxane (15 mL) was
X
(30 mL), and NiꢀRaney (0.96 g) was added to the
solution. The reaction mixture was kept in an autoꢀ
clave at 100 atmospheres for 8 h. The catalyst was filꢀ
tered off and the filtrate was diluted with water. The
precipitate was washed with water to pH 7, dried, and
recrystallized from ethanol. The yield of compound
boiled for 20 h at 90°С, cooled, and poured onto ice
(50 g) with HCl (5 mL). The precipitate was filtered,
washed with water to pH 7, dried in air, and fractionꢀ
ated on a column with Al2O3 that was subsequently
eluted with benzene and chloroform. The yield of
compound (XIII) 0.56 g (80%); Rf 0.43; mp 188–
(
XI) 0.41 g (88%);
R
f 0.07; mp 208–210
°
С. [α]2D0 –5
°
1
(c 0.45, CH3ОН); H NMR (CD3OD): 0.82, 0.90,
0.92, 0.96, 1.04 (15 H, 5s, CH3), 1.12–2.03 (47 H,
CH2, CH, H2', H3', H4', H5', H8', H8'', H2''', 3NH2),
2.14–2.19 (4 H, m, H7', H7''), 2.39–2.51 (5 H, m,
H13, H16, H6'), 2.64–2.88 (6 H, m, H9', H9'', H3'''),
3.08–3.34 (5 H, m, H19, H1', H1'''), 4.62 and 4.78
(2 H, both broadened s, H29), 5.75–5.88 (1 H, m,
CONH); 13C NMR (CD3OD): 14.2, 14.7, 14.8, 16.9,
19.8, 21.5, 21.7, 22.2, 22.4, 24.7, 25.9 (C3'), 26.1,
26.7, 27.9 (C2'), 28.0 (C4'), 28.1 (C5'), 28.7 (C20),
31.9 (C8'), 32.0 (C8''), 33.4, 36.0 (C2'''), 37.1, 37.4,
37.6, 38.6 (C1'), 38.7 (C9'), 38.8 (C9''), 38.9 (C3'''),
39.6, 41.3, 42.8, 46.7, 48.5, 48.6, 49.3, 54.3, 54.6, 55.7
(C7', C7''), 58.6 (C6'), 65.4 (C1'''), 86.2 (C3), 109.2
(C29), 150.9 (C20), 176.1 (C28).
1
190°
С. [α]2D0 +2
°
(с
0.55, CHCl3); H NMR: 0.81,
0.94, 0.97, 0.98, 1.02 (15 H, 5s, CH3), 1.21–2.00
(22 H, CH2, CH, NH), 1.69 (3 H, s, H30), 2.48–2.68
(5 H, m, H13, H16, H2''), 2.98–3.18 (1 H, m, H19),
3.61–3.74 (2 H, m, H1''), 4.53 and 4.69 (2 H, both
broadened s, H29), 6.51–6.65 (1 H, m, CONH),
6.40–6.58 (2 H, m, H9', H10'), 7.52–7.98 (6 H, m,
H2', H3', H5', H6', H8', H11'); 13C NMR: 11.7, 14.7,
16.1, 19.5, 20.0, 21.2, 21.4 (C2''), 21.9, 26.0, 26.8,
30.0, 31.1, 33.7, 34.0, 34.5, 37.3, 37.9, 38.1, 40.0,
41.1, 43.0, 45.7 (C1''), 46.8, 47.6, 50.3, 50.5, 55.3,
57.2, 109.7 (C20), 114.4 (C2', C9'), 118.6 (C3''), 120.1
(C6', C10'), 128.4 (C8'), 128.7 (C11'), 128.8 (C3'),
129.8 (C5'), 136.4 (C7'), 137.6 (C4'), 143.7 (C1'),
151.1 (C29), 151.9 (C12'), 175.5 (C28), 218.0 (C3).
Found, %: C 73.85, H 11.31, N 9.27. Calc. for
C45H85N5O2 (
N 9.62.
M 728.198), %: C 74.22, H 11.76,
Found, %: C 72.96, H 7.64, N 5.23, S 4.02. Calc.
for C45H59N3O4S (
5.69, S 4.34.
M 738.037), %: C 73.23, H 8.06, N
3,28ꢀDioxoꢀ28ꢀ(4ꢀaminophenylsulfonylꢀ4ꢀphenyꢀ
lamino)lupꢀ20(29)ꢀene (XII). 4,4'ꢀDiaminodiphenylꢀ
sulfone (1 mmol) was added to the solution of chloride
of betulonic acid (
CHCl3 (30 mL), then, triethyl amine (3 mL) was
3βꢀHydroxyꢀ28ꢀoxoꢀ28ꢀ[(3ꢀaminopropyl)ꢀ4ꢀamiꢀ
I) (0.47 g, 1 mmol) in anhydrous
nophenylsulfonylꢀ4ꢀphenylamino]lupꢀ20(29)ꢀene (XIV)
was prepared from compound (XIII) as described for
added dropwise. The reaction mixture was boiled for compound (IV). The yield of compound (XIV) 0.53 g
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
No. 3
2013

336
GINIYATULLINA et al.
(72%); Rf 0.19; mp 196⎯198° ° (с 0.06,
С. [α]2D0 –8
CH3ОН); 1H NMR (CD3OD): 0.81, 0.94, 0.97, 0.98,
1.02 (15 H, 5s, CH3), 1.21–2.00 (26 H, CH2, CH,
H2'', NH2, NH), 1.69 (3 H, s, H30), 2.47–2.74 (5 H,
rate group of mice at a dose of 100 mg/kg. The control
animals received the waterꢀTween mixture in the
equivalent volume. Every group involved 8 mice. The
value of edema was determined 5 h after the histamine
introduction from the difference in the masses of the
m, H13, H16, H3''), 2.98–3.20 (1 H, m, H19), 3.60– inflamed and the healthy leg. The inflammatory index
3.75 (2 H, m, H1''), 4.54 and 4.67 (1 H, both broadeꢀ was calculated for every animal as a ratio of this differꢀ
ned s, H29), 6.52–6.63 (1 H, m, CONH), 6.40–6.58 ence to the mass of the healthy leg. The results were
(2 H, m, H9', H10'), 7.52–7.98 (6 H, m, H2', H3', processed using the STATISTIKA 6 software. The difꢀ
H5', H6', H8', H11'); 13C NMR (CD3OD): 11.7, 14.7,
16.1, 19.5, 20.0, 21.2, 21.9, 26.0, 26.8, 29.1 (C2''),
30.0, 31.1, 33.7, 34.0, 34.5, 37.3, 37.9, 38.1, 40.0,
41.1, 42.4 (C3''), 43.0, 46.0 (C1''), 46.8, 47.6, 50.3,
50.5, 55.3, 57.2, 78.4 (C3), 109.8 (C20), 114.6 (C2'),
114.7 (C9'), 120.2 (C6', C10'), 128.6 (C8'), 128.9
(C11'), 129.0 (C3'), 130.1 (C5'), 136.1 (C7'), 137.2
(C4'), 143.4 (C1'), 151.2 (C29), 151.6 (C12'), 175.7
(C28).
ferences with
p < 0.05 were considered as significant.
The edema value was calculated for every experimenꢀ
tal group relatively to the control (100%).
ACKNOWLEDGMENTS
This study was supported by the Russian Foundaꢀ
tion for Basic Research, project no. 11ꢀ03ꢀ12144.
Found, %: C 72.46, H 8.11, N 5.21, S 3.87. Calc.
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M 742.069), %: C 72.84, H 8.56, N
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larly transplanted (2 ×
106 cells in 0.1 mL of physiologꢀ
ical solution). Compound (XII) was daily adminisꢀ
tered to the experimental group of mice at a dose of
50 mg/kg in an aqueous suspension with Tween from
10th to 16th day after the transplantation. The total
dose was 350 mg/kg. The following mixture of PCTꢀ
imitated antitumor agents was once administered to
the comparison group: doxorubicine (4 mg/kg),
cyclophosphan (50 mg/kg), vincristine (0.4 mg/kg),
and prednisolone (5 mg/kg) [20]. The waterꢀTween
mixture was administered to the control group in the
equivalent volume. Every group consisted of 11–
14 animals.
The volumes of tumor nodes were measured by a
bar in three mutually perpendicular directions before
and in the course of the administration of compound
(
XII).
Studies of the antiꢀinflammatory activity on the
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,
model of histamineꢀinduced inflammation. The inflamꢀ
matory activity was determined according to a
decrease in edema of a mouse leg. The edema was
induced by the subplanar administration of 0.1% soluꢀ
tion of histamine. The waterꢀTween suspension of
compound (XII) was administered in a stomach at a
dose of 100 mg/kg one hour before the phlogogene
administration. The indomethacin reference agent
(Fluka) was administered in the same way at a dose of
20 mg/kg. Betulonic acid was administered to a sepaꢀ
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Translated by L. Onoprienko
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