Synthesis of new betulonic and oleanonic acid amides

Article abstract of DOI:10.1007/s10600-011-9832-5

Amides of betulonic and oleanonic acids with diethylenetriamine, triethylenetetramine, and spermidine were synthesized. Antitumor activity in vitro was not found for the conjugate of betulonic acid with diethylenetriamine.

Full text of DOI:10.1007/s10600-011-9832-5

Chemistry of Natural Compounds, Vol. 47, No. 1, March, 2011 [Russian original No. 1, January–February, 2011]
SYNTHESIS OF NEW BETULONIC AND
OLEANONIC ACID AMIDES
G. V. Giniyatullina, O. B. Kazakova,*
E. V. Salimova, and G. A. Tolstikov
UDC 547.824:542.91:548.737
Amides of betulonic and oleanonic acids with diethylenetriamine, triethylenetetramine, and spermidine were
synthesized. Antitumor activity in vitro was not found for the conjugate of betulonic acid with
diethylenetriamine.
Keywords: triterpenoids, betulonic acid, oleanolic acid, polyamines, amides, antitumor activity.
Triterpene acids with long O- and N-containing side chains have shown promise for developing antiviral and antitumor
agents. Thus, a dipeptide of betulonic acid with a phenylalanine unit affects the early stages of the viral reproduction cycle, is
highly active against Herpes simplex virus, and has immunostimulating activity greater than that of Freund’s incomplete
adjuvant [1, 2].
R
N
NH
CONH
NHR
CONH
NH
2
e
O
HO
3
, 9
7
3
9
: R = H
: R = Boc
f
a, b
NH
2
COOH
CONH
NH
a, d
O
O
1
5
a, c
R
N
NHR
NH
NH
2
e
CONH
N
CONH
NH
R
O
HO
4
, 10
8
4
: R = H
f
1
0: R = Boc
a. (COCl) , CHCl , 2 h; b. NH (CH ) NH(CH ) NH , Et N, CHCl , 60°C, 4 h; c. NH (CH ) NH(CH ) NH(CH ) NH , Et N, CHCl ,
2
3
2
2 2
2 2
2
3
3
2
2 2
2 2
2 2
2
3
3
6
0°C, 5 h; d. NH (CH ) NH(CH ) NH , Et N, CHCl , 60°C, 6 h; e. NaBH , isopropanol, 2 h; f. Boc O, CH Cl , 5 h.
2 2 3 2 4 2 3 3 4 2 2 2
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, pr. Oktyabrya, 71,
fax: (347) 235 60 66, e-mail: obf@anrb.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 62–65, January–
February, 2011. Original article submitted April 13, 2010.
6
8
0009-3130/11/4701-0068 ©2011 Springer Science+Business Media, Inc.

TABLE 1. Antitumor Activity in vitro of 3 (10–5 M) Against 60 Human Cancer Cell Lines
Cell line
Percent growth
Cell line
Percent growth
Lung cancer
A549/ATCC
EKVX
Leukemia
95.49
99.41
107.24
109.94
104.33
108.73
99.93
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
Kidney cancer
786-0
A498
100.49
100.10
83.89
100.28
80.10
HOP-62
NCI-H226
NCI-H322M
NCI-H23
NCI-H460
NCI-H522
HOP-92
63.11
111.44
88.03
108.91
96.12
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578T
ÂÒ-549
ACHN
CAKI-1
RXF 393
SN12C
TK-10
133.93
107.47
127.77
79.65
108.91
96.12
120.27
112.46
96.23
129.27
104.82
89.75
UO-31
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
Prostate cancer
PC-3
101.98
107.25
117.89
111.81
103.65
134.40
114.64
110.06
122.58
93.29
96.50
103.94
115.48
119.07
114.07
108.67
T-47D
MDA-MB-468
Ovarian cancer
IGROV1
110.41
93.33
OVCAR-3
82.59
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
109.04
108.73
115.84
111.69
110.84
DU-145
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
105.99
84.85
96.34
94.27
94.56
93.55
101.00
R
N
COOH
a, b
CONH
NH
2
O
O
2
6
a. (COCl) , CHCl , 2 h; b. NH (CH ) NH(CH ) NH , Et N, CHCl , 60°C, 4 h.
2
3
2
2 2
2 2
2
3
3
The activities of esters of acetylbetulinic acid with 2,3-dihydroxy-2-hydroxymethylpropane, 2-amino-3-hydroxy-2-
hydroxymethylpropane, and N-(1,1-bis(hydroxymethyl)-2-hydroxyethyl)formamide are seven times greater than that of betulinic
acid against HTB-92 liposarcoma and 518A2 melanoma. Furthermore, they are also active against HIV-1 [3]. Derivatives of
oleanolic and ursolic acids exhibit antitumor activity against leukemia and HT-29 colon cells [4, 5]. 2-Cyano-3,12-dioxooleana-
1
,9(11)-dien-28-oic acid (CDDO) and its methyl ester and imidazolide are active against leukemia, multiple myeloma, breast,
lung, and osteosarcoma cells and are undergoing Phase I clinical trials [6, 7].
6
9

Stepwise elaboration of the side chain is usually used to synthesize triterpenoids with polyamine substituents. However,
such structures can be synthesized by introducing commercially available alkanepolyamines. Herein we report the synthesis
of amides of betulonic (1) and oleanonic (2) acids obtained via reaction of their acid chlorides with diethylenetriamine,
triethylenetetramine, and spermidine. Compounds 3–6 were synthesized in 48–54% yields after purification by column
1
3
chromatography. Their structures were confirmed by NMR spectroscopy. Thus, the C-28 resonance in C NMR spectra was
located at ꢀ 176 ppm. The H-28 resonance in PMR spectra appeared at ꢀ 6.26–6.41 ppm as a multiplet. Resonances of
methylene protons introduced into the structure of the alkanepolyamines gave multiplets at ꢀ 2.74–3.62.
Derivatives of betulinic acid 7 and 8 were synthesized via reduction of the C-3 ketone of amides 3 and 4 by NaBH4.
Considering the anticancer activity of betulonic acid amide that contains an N-Boc-protected lysine [8], we prepared
N-Boc-amides 9 and 10. Strong singlets in the PMR spectra of these compounds at 1.28–1.52 ppm corresponded to the
tert-butoxycarbonyl protons.
The antitumor activity in vitro (cytotoxicity) of 3 was studied at the National Cancer Institute (USA) against 60 cell
lines of nine different human tumors (lung, colon, CNS, ovarian, kidney, prostate, brain, leukemia, and melanoma) by the
literature method [9–12]. Preliminary testing of the activity was carried out in cell cultivation medium at a final concentration
–
5
of 10 M for 48 h, after which the growth of the treated cells was estimated compared with that of untreated control cells.
Table 1 presents the percent growth of treated cells compared with control cells (negative values correspond to cell death). It
can be seen that 3-oxo-28-(diethylenetriamino)-carbonyl-lup-20(29)-ene (3) did not exhibit antitumor activity.
EXPERIMENTAL
PMR and 13C NMR spectra were recorded in CDCl and CD OD with TMS internal standard on a Bruker AM-300
3
3
spectrometer (Germany, 300 and 75.5 MHz, respectively, ꢀ, ppm, SSCC, Hz). Melting points were determined on a Boetius
microstage. Optical absorption was measured on a Perkin–Elmer 241 MC polarimeter (Germany) in a 1-dm tube. TLC was
performed on Sorbfil plates (ZAO Sorbpolimer, Russia) using CHCl :EtOAc (40:1). Compounds were detected by H SO
3
2
4
solution (10%) with subsequent heating at 100–120°C for 2–3 min. We used oleanolic acid, diethylenetriamine,
triethylenetetramine, and spermidine (Aldrich Chemical Co.). Betulonic acid (1) was synthesized from betulin [13]. Oleanolic
acid was oxidized to oleanonic acid (2) by Jones reagent in acetone as before [14]. Betulonic and oleanonic acid chlorides
were prepared by the standard method [15] by reaction with oxalylchloride in CHCl3.
Preparation of 3–5. A solution of betulonic acid chloride (0.46 g, 1 mmol) in dry CHCl (30 mL) was treated with
3
diethylenetriamine, triethylenetetramine, or spermidine (1 mmol) and dropwise with Et N (3 mL); refluxed (TLC monitoring);
3
washed with HCl solution (5%, 2 ꢁ 50 mL) and H O (50 mL); and dried over CaCl . The solvent was removed in vacuo. The
2
2
solid was chromatographed over a column of Al O with elution by benzene.
2
3
N - 3 a - [ 2 - ( 2 - A m i n o e t h y l a m i n o ) e t h y l ] - 1 - i s o p ro p e n y l - 5 a , 5 b , 8 , 8 , 11 a - p e n t a m e t h y l - 9 -
2
0
oxoperhydrocyclopenta[a]chrysen-3a-carboxamide (3). Yield 0.27 g (54%), R 0.32, mp 158–160°C, [ꢂ] +21° (c 0.23,
f
D
CHCl ). C H N O (MW 539.842).
3
34 57 3 2
PMR spectrum (CDCl , ꢀ, ppm): 0.86, 0.92, 0.96, 1.04, 1.13 (15H, 5s, 5CH ), 1.10–2.18 (24H, m, CH , CH, NH,
3
3
2
NH ), 1.69 (3H, s, H-30), 2.35–2.56 (3H, m, H-13, H-16), 2.74–2.89 (6H, m, H-2ꢃ, H-3ꢃ, H-4ꢃ), 3.03–3.17 (1H, m, H-19),
2
3
.33–3.47 (2H, m, H-1ꢃ), 4.62 and 4.75 (1H each, both br., H-29), 6.26–6.37 (1H, m, CONH).
1
3
C NMR spectrum (ꢀ, ppm): 14.5, 15.8, 15.9, 16.1, 19.4, 19.6, 20.9, 21.4, 25.6, 26.6, 27.4, 29.4, 30.9, 33.4, 33.7,
4.0, 36.9, 37.8, 38.3, 38.7, 39.6, 40.7, 42.5, 46.6, 47.2, 49.3, 50.0, 50.1, 55.0, 55.7, 109.4 (C-29), 150.7 (C-20), 176.7
3
(
CONH), 217.7 (C-3).
N-3a-2-[2-(2-Aminoethylamino)ethylamino]ethyl-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-9-
2
0
oxoperhydrocyclopenta[a]chrysen-3a-carboxamide (4). Yield 0.24 g (48%), R 0.34, mp 173–175°C, [ꢂ] +19° (c 0.35,
f
D
CHCl ). C H N O (MW 582.911).
3
36 62 4 2
PMR spectrum (CDCl , ꢀ, ppm): 0.86, 0.92, 0.96, 1.04, 1.13 (15H, 5s, 5CH ), 1.10–2.18 (25H, m, CH , CH, 2NH,
3
3
2
NH ), 1.69 (3H, s, H-30), 2.35–2.56 (3H, m, H-13, H-16), 2.71–2.85 (4H, m, H-3ꢃ, H-4ꢃ), 2.89–2.98 (4H, m, H-2ꢃ, H-5ꢃ), 3.03–
2
3
.17 (1H, m, H-19), 3.25–3.62 (4H, m, H-1ꢃ, H-6ꢃ), 4.62 and 4.75 (1H each, both br., H-29), 6.28–6.41 (1H, m, CONH).
1
3
C NMR spectrum (ꢀ, ppm): 14.6, 15.9, 16.0, 19.4, 19.7, 21.0, 21.5, 25.7, 26.6, 29.3, 29.4, 30.9, 33.7, 34.1, 36.9,
3
1
7.8, 38.4, 39.6, 40.2, 40.5, 40.7, 42.5, 45.7, 46.7, 47.3, 47.4, 49.0, 50.0, 53.1, 53.9, 55.0, 55.7, 109.4 (C-29), 150.9 (C-20),
76.6 (CONH), 218.0 (C-3).
7
0

N - 3 a - [ 3 - ( 4 - A m i n o b u t y l a m i n o ) p ro p y l ] - 1 - i s o p ro p e n y l - 5 a , 5 b , 8 , 8 , 11 a - p e n t a m e t h y l - 9 -
2
0
oxoperhydrocyclopenta[a]chrysen-3a-carboxamide (5). Yield 0.3 g (52%), R 0.28, mp 154–157°C, [ꢂ] +29° (c 0.6,
f
D
CHCl ). C H N O (MW 581.923).
3
37 63 3 2
PMR spectrum (CDCl , ꢀ, ppm): 0.86, 0.92, 0.96, 1.04, 1.13 (15H, 5s, 5CH ), 1.10–2.18 (30H, m, CH , CH, H-2ꢃ,
3
3
2
H-3ꢃ, H-6ꢃ, NH, NH ), 1.69 (3H, s, H-30), 2.35–2.56 (3H, m, H-13, H-16), 2.74–2.89 (6H, m, H-4ꢃ, H-5ꢃ, H-7ꢃ), 3.03–3.17 (1H,
2
m, H-19), 3.33–3.47 (2H, m, H-1ꢃ), 4.62 and 4.75 (1H each, both br., H-29), 6.26-6.37 (1H, m, CONH).
1
3
C NMR spectrum (ꢀ, ppm): 14.4, 15.1, 15.9, 16.0, 19.3, 19.5, 20.9, 21.4, 25.5, 26.1, 26.5, 27.2, 29.3, 29.4, 30.8,
3.6, 34.0, 36.8, 36.9, 37.0, 37.4, 37.6, 38.3, 38.6, 39.5, 40.6, 42.4, 46.6, 47.2, 48.9, 49.9, 50.0, 55.4, 109.3 (C-29), 150.7
3
(
C-20), 176.2 (CONH), 217.9 (C-3).
N-5-[2-(2-Aminoethylamino)ethyl]-1,2,8,8,15,19,19-heptamethyl-18-oxopentacyclo[12.8.0.02,11.05,10.015,20]-
docos-11-en-5-carboxamide (6). A solution of oleanonic acid chloride (0.46 g, 1 mmol) in dry CHCl (30 mL) was treated
3
with diethylenetriamine (1 mmol) and dropwise with Et N (3 mL), refluxed (TLC monitoring), washed with HCl solution
3
(
5%, 2 ꢁ 50 mL) and H O (50 mL), and dried over CaCl . The solvent was removed in vacuo. The solid was chromatographed
over a column of Al O with elution by benzene. Yield 0.26 g (48%), R 0.39, mp 125–128°C, [ꢂ] +67° (c 0.48, CHCl3).
2 2
2
0
2
3
f
D
C H N O (MW 539.842).
3
4 57 3 2
PMR spectrum (CDCl , ꢀ, ppm): 0.78, 0.89, 0.93, 1.01, 1.03, 1.11, 1.14 (21H, 7s, 7CH ), 1.20–2.12 (25H, m, CH ,
3
3
2
CH, NH, NH ), 2.76–2.87 (7H, m, H-11, H-2ꢃ, H-3ꢃ, H-4ꢃ), 3.12–3.22 (2H, m, H-1ꢃ), 5.39–5.52 (1H, br., H-12), 5.89–5.98 (1H,
2
m, CONH).
13C NMR spectrum (ꢀ, ppm): 14.0, 15.0, 16.8, 19.5, 21.2, 22.5, 23.4, 23.7, 25.4, 25.6, 26.2, 27.1, 29.2, 29.6, 30.5,
3
(
1.7, 32.9, 33.8, 34.0, 36.1, 36.6, 38.9, 39.2, 41.1, 41.7, 46.1, 46.4, 46.7, 47.4, 55.1, 122.4 (C-12), 143.9 (C-14), 177.8
CONH), 215.9 (C-3).
Synthesis of 7 and 8. A solution of 3 or 4 (1 mmol) in isopropanol (20 mL) was stirred, treated over 10 min with
NaBH (50 mg, 1.3 mmol), stored for 2 h, and diluted with HCl solution (30 mL, 10%). The solid was filtered off, washed with
4
H O, dried, and recrystallized from MeOH.
2
N - 3 a - [ 2 - ( 2 - A m i n o e t h y l a m i n o ) e t h y l ] - 9 - h y d r o x y - 1 - i s o p r o p e n y l - 5 a , 5 b , 8 , 8 , 11 a -
2
0
pentamethylperhydrocyclopenta[a]chrysen-3a-carboxamide (7). Yield 0.49 g (92%), R 0.27, mp 213–215°C, [ꢂ] +13°
f
D
(
c 0. 35, CH OH). C H N O (MW 541.858).
3 34 59 3 2
PMR spectrum (CD OD, ꢀ, ppm): 0.86, 0.92, 0.96, 1.04, 1.13 (15H, 5s, 5CH ), 1.10–2.03 (25H, m, CH , CH, NH,
3
3
2
NH ), 1.69 (3H, s, H-30), 2.35–2.56 (3H, m, H-13, H-16), 2.68–2.81 (6H, m, H-2ꢃ, H-3ꢃ, H-4ꢃ), 3.03–3.17 (1H, m, H-19),
2
3
.23–3.47 (3H, m, H-3, H-1ꢃ), 4.62 and 4.75 (1H each, both br., H-29), 6.03–6.14 (1H, m, CONH).
1
3
C NMR spectrum (ꢀ, ppm): 14.6, 15.3, 16.1, 18.2, 19.4, 19.6, 20.9, 21.4, 25.6, 27.4, 27.9, 29.4, 30.9, 33.7, 34.4,
3
1
6.9, 37.1, 37.4, 37.7, 38.4, 38.8, 40.7, 42.4, 46.7, 48.9, 49.3, 50.1, 50.6, 55.3, 55.6, 78.9 (C-3), 109.4 (C-29), 150.7 (C-20),
76.7 (CONH).
N-3a-2-[2-(2-Aminoethylamino)ethylamino]ethyl-9-hydroxy-1-isopropenyl-5a,5b,8,8,11a-
2
0
pentamethylperhydrocyclopenta[a]chrysen-3a-carboxamide (8). Yield 0.49 g (92%), R 0.25, mp 221–223°C, [ꢂ] +5°
f
D
(
c 1.25, CH OH). C H N O (MW 584.926).
3 36 64 4 2
PMR spectrum (CD OD, ꢀ, ppm): 0.86, 0.92, 0.96, 1.04, 1.13 (15H, 5s, 5CH ), 1.10–2.18 (26H, m, CH , CH, 2NH,
3
3
2
NH ), 1.69 (3H, s, H-30), 2.35–2.56 (3H, m, H-13, H-16), 2.71–2.85 (4H, m, H-3ꢃ, H-4ꢃ), 2.89–2.98 (4H, m, H-2ꢃ, H-5ꢃ), 3.03–
2
3
.17 (1H, m, H-19), 3.25–3.62 (5H, m, H-3, H-1ꢃ, H-6ꢃ), 4.62 and 4.75 (1H each, both br., H-29), 6.28–6.41 (1H, m, CONH).
1
3
C NMR spectrum (ꢀ, ppm): 14.6, 15.9, 16.0, 19.4, 19.7, 21.0, 21.5, 25.7, 26.6, 29.3, 29.4, 30.9, 33.7, 34.1, 36.9,
3
1
7.8, 38.4, 39.6, 40.2, 40.5, 40.7, 42.5, 45.7, 46.7, 47.3, 47.4, 49.0, 50.0, 53.1, 53.9, 55.0, 55.7, 78.8 (C-3), 109.4 (C-29),
50.9 (C-20), 176.6 (CONH).
Synthesis of 9 and 10. A solution of 3 or 4 (1 mmol) in CH Cl (20 mL) was treated with di-tert-butylbicarbonate
2
2
(
349 mg, 1.59 mmol or 465 mg, 2.12 mmol), stirred at room temperature for 12 h, and evaporated in vacuo. The solid was
chromatographed over Al O with elution by CHCl .
2
3
3
N-3a-[2-tert-Butylformyl-(2-tert-butylformylaminoethyl)aminoethyl]-1-isopropenyl-5b,8,8,11a-tetramethyl-9-
2
0
oxoperhydrocyclopenta[a]chrysen-3a-carboxamide (9). Yield 0.32 g (60%), R 0.80, mp 124–127°C, [ꢂ] +21° (c 0.04,
f
D
CHCl ). C H N O (MW 740.075).
3
44 73 3 6
PMR spectrum (CDCl , ꢀ, ppm): 0.86, 0.92, 0.96, 1.04, 1.13 (15H, 5s, 5CH ), 1.20–2.00 (21H, m, CH , CH), 1.48
3
3
2
(
9H, s, CH ), 1.52 (9H, s, CH ), 1.69 (3H, s, H-30), 2.35–2.56 (3H, m, H-13, H-16), 3.03–3.17 (1H, m, H-19), 3.22–3.48 (8H,
3 3
m, H-2ꢃ, H-3ꢃ, H-4ꢃ, H-5ꢃ), 4.62 and 4.75 (1H each, br., H-29), 5.91–6.09 (1H, m, NH-6ꢃ), 6.48–6.59 (1H, m, CONH).
7
1

1
3
C NMR spectrum (ꢀ, ppm): 14.4, 15.8, 15.9, 19.4, 19.5, 20.9, 21.4, 23.5, 25.5, 26.5 (3CH ), 26.7 (3CH ), 27.3,
3
3
2
1
9.4, 30.8, 31.1, 33.4, 33.7, 34.0, 36.8, 37.6, 38.2, 39.5, 40.6, 42.4, 46.5, 47.2, 49.9, 50.0, 54.6, 54.7, 54.9, 55.4, 80.6, 85.0,
09.3 (C-29), 146.7, 150.8 (C-20), 156.7, 176.6 (CONH), 217.8 (C-3).
N-3a-2-tert-Butylformyl-[2-tert-butylformyl(2-tert-butylformylaminoethyl)aminoethyl]aminoethyl-1-
isopropenyl-5b,8,8,11a-tetramethyl-9-oxoperhydrocyclopenta[a]chrysen-3a-carboxamide (10). Yield 0.37 g (64%), R
f
0
.79, mp 174–176°C, [ꢂ] D2 0 +20° (c 0.67, CHCl ). C H N O (MW 883.259).
3 51 86 4 8
PMR spectrum (CDCl , ꢀ, ppm): 0.86, 0.92, 0.96, 1.04, 1.13 (15H, 5s, 5CH ), 1.20–2.00 (21H, m, CH , CH), 1.28
3
3
2
(
9H, s, 3CH ), 1.35 (9H, s, 3CH ), 1.41 (9H, s, 3CH ), 1.69 (3H, s, CH ), 2.35–2.56 (3H, m, H-13, H-16), 2.92–3.02 (4H, m,
3 3 3 3
H-3ꢃ, H-6ꢃ), 3.03–3.17 (5H, m, H-19, H-4ꢃ, H-5ꢃ), 3.22–3.48 (4H, m, H-2ꢃ, H-7ꢃ), 4.58 and 4.75 (1H each, br., H-29), 5.90–6.07
(
1H, m, NH-9ꢃ), 6.48–6.59 (1H, m, CONH).
1
3
C NMR spectrum (ꢀ, ppm): 14.5, 15.9, 16.0, 19.4, 19.6, 21.0, 21.4, 23.6, 25.6, 26.6 (3CH ), 26.7 (3CH ), 26.8
3
3
(
3CH ), 28.4, 29.4, 30.9, 33.4, 33.7, 34.1, 36.9, 37.7, 38.3, 39.6, 40.7, 42.3, 45.4, 46.6, 47.3, 49.9, 50.0, 54.3, 54.5, 54.7, 54.9,
3
5
5.4, 55.7, 80.6, 80.7, 84.6, 109.3, 150.0, 150.9 (C-20), 156.4, 156.7, 176.7 (CONH), 218.0 (C-3).
The procedure for testing the antitumor activity in vitro of 3 is given at the website www.dtp.nci.nih.gov.
ACKNOWLEDGMENT
The work was supported financially by the RFBR (Project No. 08-03-00868). We thank the National Cancer Institute
NCI) for determining the antitumor activity of 3 in vitro.
(
REFERENCES
1
.
.
G. A. Tolstikov, N. I. Petrenko, N. V. Elantseva, E. E. Shulꢃts, E. A. Plyasunova, T. N. Ilꢃicheva, O. A. Borisova,
T. K. Pronyaeva, and A. G. Pokrovskii, RF Pat. No. 2,211,843 (2003).
A. G. Pokrovskii, O. A. Plyasunova, T. N. Ilꢃicheva, O. A. Borisova, N. V. Fedyuk, N. I. Petrenko,
V. Z. Petukhova, E. E. Shulꢃts, and G. A. Tolstikov, Khim. Interesakh Ustoich. Razvit., 9, 485 (2001).
E. Selzer, B. Jansen, and R. Paschke, US Pat. Appl. 2008/0214516 (2008).
L. Cipak, L. Grausova, E. Miadokova, L. Novotny, and P. Rauko, Arch. Toxicol., 80, 429 (2006).
E. M. Juan, J. M. Planas, V. Ruiz-Gutierrez, H. Daniel, and U. Wenzel, Br. J. Nutr., 100, 36 (2008).
X. Gao, D. Deeb, H. Jiang, Y. Liu, S. A. Dulchavsky, and S. C. Gautam, J. Neuro-Oncol., 84, 147 (2007).
A. Petronelli, G. Pannitteri, and U. Testa, Anti-Cancer Drugs, 20, 880 (2009).
B. B. Saxena, L. Zhu, M. Hao, E. Kisilis, M. Katdare, O. Oktem, A. Bomshteyn, and P. Rathnam, Bioorg.
Med. Chem., 14, 6349 (2006).
2
3
4
5
6
7
8
.
.
.
.
.
.
9
.
M. C. Alley, D. A. Scudiero, P. A. Monks, M. L. Hursey, M. J. Czerwinski, D. L. Fine, B. J. Abbott, J. G. Mayo,
R. H. Shoemaker, and M. R. Boyd, Cancer Res., 48, 589 (1988).
1
1
1
1
0.
1.
2.
3.
M. R. Grever, S. A. Schepartz, and B. A. Chabner, Semin. Oncol., 19, 622 (1992).
M. R. Boyd and K. D. Paull, Drug. Dev. Res., 34, 91 (1995).
R. H. Shoemaker, Nature Rev., 6, 813 (2006).
O. B. Flekhter, L. R. Nigmatullina, L. A. Baltina, L. T. Karachurina, F. Z. Galin, F. S. Zarudii, G. A. Tolstikov,
E. I. Boreko, N. I. Pavlova, S. N. Nikolaeva, and O. V. Savinova, Khim.-farm. Zh., 36, 26 (2002).
L. F. Tietze and T. Eicher, Preparative Organic Chemistry [translated from Ger.], Mir, Moscow, 1999.
O. B. Flekhter, E. I. Boreko, L. R. Nigmatullina, E. V. Tretꢃyakova, N. I. Pavlova, L. A. Baltina, S. N. Nikolaeva,
O. V. Savinova, V. F. Eremin, F. Z. Galin, and G. A. Tolstikov, Bioorg. Khim., 30, 89 (2004).
1
1
4.
5.
7
2