Synthesis, Structures, and Acute Toxicity of Gossypol Nonsymmetrical Aldehyde Derivatives

Article abstract of DOI:10.1134/S1068162010030167

Nonsymmetrical aldehyde derivatives of gossypol, a yellow polyphenolic pigment of cottonseed, were synthesized by reactions with ammonia, aniline, 4-aminoantipyrine, and barbituric acid. Their structures were determined by UV spectrophotometry and IR and

Full text of DOI:10.1134/S1068162010030167

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2010, Vol. 36, No. 3, pp. 390–395. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © K.Z. Tilyabaev, F.G. Kamaev, N.L. Vypova, A.M. Yuldashev, B.T. Ibragimov, S.A. Talipov, 2010, published in Bioorganicheskaya Khimiya, 2010, Vol. 36,
No. 3, pp. 423–428.
Synthesis, Structures, and Acute Toxicity of Gossypol
Nonsymmetrical Aldehyde Derivatives
K. Z. Tilyabaev1, F. G. Kamaev, N. L. Vypova, A. M. Yuldashev, B. T. Ibragimov, and S. A. Talipov
Sadykov Institute of Bioorganic Chemistry, Uzbek Academy of Sciences, Mirzo Ulugbek str. 83, Tashkent, 100125 Uzbekistan
Received June 21, 2009; in final form, September 8, 2009
Abstract—Nonsymmetrical aldehyde derivatives of gossypol, a yellow polyphenolic pigment of cottonseed,
were synthesized by reactions with ammonia, aniline, 4ꢀaminoantipyrine, and barbituric acid. Their strucꢀ
tures were determined by UV spectrophotometry and IR and 1H NMR spectroscopy methods. Their acute
toxicities in white mice were compared with those of gossypol and the corresponding symmetrical analogues.
It was demonstrated that in general, the fewer free aldehyde groups available in the gossypol derivative, the
lower its acute toxicity. Only in the case of a nonsymmetrical gossypol derivative bearing a 4ꢀaminoantipyrine
residue did we observe a deviation from the above correlation: its symmetrical counterpart was even more
toxic, but still less toxic than gossypol.
Key words: acute toxicity, gossypol, gossypol symmetrical and nonsymmetrical aldehyde derivatives, synthesis
DOI: 10.1134/S1068162010030167
1
INTRODUCTION
of enzymatic systems of mitochondrial electron transꢀ
port chains and disconnects the processes of respiraꢀ
tion and oxidative phosphorylation [12–14]. Thus, the
toxic effects of gossypol can be partially explained by
the inhibition of gossypolꢀmediated enzymatic sysꢀ
tems.
Gossypol, 2,2'ꢀbis(8ꢀformyl,1,6,7ꢀtrihydroxyl,5ꢀ
isopropyl,3ꢀmethylnaphtaline) (
tonseed pigment.
I), is a specific cotꢀ
O
O
Antitumor and antiviral properties displayed by
gossypol [15] allow for its consideration as a potential
drug. However, pharmacological studies have shown
some disadvantages preventing its use as an effective
drug, in particular, marked toxicity at optimal theraꢀ
peutic doses, cumulating properties, insolubility in
water, and pain at the injection sites [16–18]. The
preparation of gossypol derivatives could reduce the
side effects. Therefore, many efforts were taken to
modify its structure and study the structural specific
features and physiological activities of the synthesized
compounds.
CH OH
OH HC
HO
OH
8
5
1
4
8'
1'
4'
9
9'
7
6
2
3
2'
3'
7'
6'
10
10'
5'
HO
CH3 H3C
OH
CH
CH
H3C CH3
H3C
CH3
Gossypol (I)
The poisoning of nonruminant farm animals and
birds observed over the course of longꢀterm feeding
with cotton cake and cottonseed meal is the basis for
numerous studies of the physiological activities of gosꢀ
sypol [1–4]. It was shown that gossypol can bind to
iron and give a low soluble and poorly absorbed comꢀ
plex compound, which may result in disorder in the
iron circulation in the organism followed by an imbalꢀ
ance in the functioning of ironꢀdependent enzymatic
systems [5–8].
Gossypol derivatives were obtained by coupling
with the corresponding aliphatic, aromatic, and hetꢀ
erocyclic amines; sulfanyl amide agents; and some
compounds containing reactive methylene groups
[19–24]. In addition, gossypol esters and ethers were
synthesized [25, 26].
For derivatives of compound (I), the structure–
activity relationship was most reliably found for
immunomodulating activity [27]. The comparative
analysis of gossypol derivatives differing in the substiꢀ
tution degree of the hydroxyl groups demonstrated
that gossypol methyl ethers were less active than gosꢀ
sypol. The substitution of hydroxyl groups decreased
the activity nearly proportionally to the substitution
degree. The absence of aldehyde groups also supported
It was found in vivo and in vitro that gossypol
inhibited the activity of Na and KꢀATPase [9, 10] and
decreased the activity of the metabolic system in an
organism, especially during longꢀterm administration
[11]. At high doses, gossypol also reduces the activity
1
Corresponding author; phone: (99871) 260ꢀ3758; eꢀmail: tilyaꢀ
baevzaid@mail.ru.
390

SYNTHESIS, STRUCTURES, AND ACUTE TOXICITY
391
O
R
CH OH
CH OH
HO
HO
+H R
2
–H O
2
HO
HO
2
2
(A)
R
O
O
CH OH
HO HC
CH OH
HO
HO
OH
OH
HO
HO
+H R
2
–H O
2
2
(B)
O
O
H
H
N
N
CH3
N
R: =NH (II); =NC6H5 (III);
(
IV);
(V);
O
N
O
N
CH3
C6H5
Fig. 1. General scheme of the formation of gossypol amino derivatives.
a decrease in activity, whereas the transformation of preliminary cooled diluted solution of starting (I).
gossypol into quinone resulted in low activity and conꢀ When selecting the reaction conditions, we took into
siderably increased toxicity. It is noteworthy that the consideration that the formation of Schiff bases is
presence of unsubstituted hydroxyl groups and the known to be highly exothermic [32]. The relatively low
nature of the substituents at the aldehyde groups were solubility of the target products in chloroform at low
also essential [28].
temperatures enabled their isolation by precipitation
followed by filtration and recrystallization.
Due to the symmetry of the starting compound, for
a long time only symmetrical derivatives were available.
However, at present there are a lot of data on the higher
activity of nonsymmetrical gossypol derivatives as comꢀ
pared with the symmetrical counterparts [29–31].
This method resulted in the preparation of monoꢀ
derivatives of gossypol (
various types.
I) from amino compounds of
A spectral criterion of the completeness of the
monoderivative formation was the presence in the
1H NMR spectra of resonances of aldehyde protons at
11–11.3 ppm and ketimine protons at 9.4–10.4 ppm
at a 1 : 1 ratio.
The goal of the present work was the synthesis of
nonsymmetrical gossypol derivatives modified at the
aldehyde groups and prepared by reactions with
ammonia, aniline, 4ꢀaminoantipirine, and barbituric
acid and the study of the acute toxicities in white mice
with gossypol and the corresponding symmetrical
bisanalogues as reference compounds.
The quinoid structure of the synthesized nonsymꢀ
metrical monoimines of compound (I) (or more
exactly, of their aminoꢀsubstituted fragment) was corꢀ
roborated by NMR spectroscopy data (see the Experꢀ
imental section) based on the appearing doublet at
10.1–10.9 ppm (Fig. 2) resulting from the spin–spin
interaction of methine and amine protons inherent for
quinoidꢀlike forms [28]. Absorption peaks at 460–470
RESULTS AND DISCUSSION
The general scheme of the preparation of gossypol
amino derivatives (IIA)–(VA) and (IIB)–(VB) is given
in Fig. 1.
The optimal conditions for the formation of gossyꢀ nm in the UV spectra of compounds (IIIB) and (IVB
)
pol monoderivatives were found using highꢀdilution (see the Experimental section) also supported the
technologies: a cooled amine solution was added to a quinoid structure of compounds (IIIB) and (IVB) [28].
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 36
No. 3
2010

392
TILYABAEV et al.
R
H
N
O
O
N
O
H
HO HC
H
CH OH
HO
H
N
O
HO
HO
HO
O
O
HO
HO
OH
OH
Fig. 2. Quinoid structure of nonsymmetrical gossypol
amino derivatives.
Fig. 3. The lactol structure of the nonsymmetrical product
of the gossypol reaction with barbituric acid.
It is noteworthy that the aldehyde form remained absence of one of the substituent NH protons
(Fig. 3)). The presence in the IR spectrum of an
intact in all of the synthesized nonsymmetrical gossyꢀ
pol derivatives bearing unsubstituted aldehyde groups,
except the compounds that could only be dissolved in
deuterated DMSO. In these cases, we observed the
formation of lactol tautomeric forms, as was found for
absorption band at 1670 cm–1 characteristic of C=C
bonds whose
π electrons were conjugated with free
oxygen electron pairs [37] also supported the assumed
structure for derivative (VB).
gossypol [33]. In the UV spectrum of product (VB
)
The data on the acute toxicities of the synthesized
gossypol derivatives are shown in the table.
obtained by the reaction of gossypol with barbituric
acid in ethanol, in which the gossypol aldehyde group
was transformed into a lactol one [34] as it was
observed in DMSO, the absorption maximum at 376–
378 nm inherent for aldehyde groups [35] was absent.
At the same time, there was a maximum at 261 nm,
which is characteristic of a gossypol lactol tautomer
Five to ten minutes after the introduction in white
mice, the suppression and weakness of the pelvic limbs
were observed for 4–5 h. Autopsy studies demonꢀ
strated a lack of obvious disorders (flatulence and diarꢀ
rhea), peritoneal hemorrhage, and peritoneal liquid.
In dead animals with high doses of the tested comꢀ
pounds, their traces were found 1–4 days after dosing,
and most often in the liver, seminal glands, mesenterꢀ
ies, and stomach. In the surviving animals, the tested
compounds in capsulated forms were found in the
liver, seminal glands, mesenteries, and sites of the
injection 14 days after the administration.
1
[35, 36]. The analysis of the H NMR spectrum of
compound (VB) provided the assumption that the
intramolecular dehydration accompanying the reacꢀ
tion resulted in a heterocycle joining the gossypol
backbone with the substituent (the absence of the
C7'–OH resonance upfield (14.5–16.0 ppm) and the
Based on the data obtained, we can conclude that,
in general, gossypol monoderivatives (IIB)–(VB) disꢀ
played higher acute toxicity than the corresponding
bisderivatives (IIA)–(VA), which can probably be
explained by the presence of free aldehyde groups.
Due to the presence of two aldehyde groups, gossypol
Acute toxicity of gossypol and its derivatives
Tested compound
LD50, mg/kg*
(
(
(
(
(
(
(
(
(
I
)
154 (130–180)
1620 (1400–1800)
4400 (3400–5800)
1500 (1200–2000)
2240 (1000–2500)
1200 (900–1600)
3860 (3200–4600)
3160 (2000–5100)
257 (230–290)
(
I) displayed the highest acute toxicity.
IIA
IIIA
IVA
VA
IIB
IIIB
IVB
VB
)
It is interesting that compound (IVB) was less toxic
than (IVA).
)
)
For the understanding of the mechanism of physiꢀ
)
ological activity, as well as for an explanation of the
side effects, data on the distribution of the compound
in organelles and organ macromolecules are essential.
The increased gossypol affinity to microsome memꢀ
branes resulted in an adaptive increase in the activity
of oxidative enzymes, which in turn stimulated the
microsomal system of xenobiotic detoxication [38]. It
was also shown that gossypol oxidation (decarbonylaꢀ
tion) is one of the principal ways of detoxication upon
its elimination from the animal’s body.
)
)
)
)
* The dose range at which the death of the minimal (LD ) and
10
maximal (LD ) number of white mice was observed.
95
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 36
No. 3
2010

SYNTHESIS, STRUCTURES, AND ACUTE TOXICITY
393
As follows from the above data, the detoxication of substituent’s Ph), 3.5–3.96 (2 Н, m, С5–СН<), 2.18
gossypolꢀlike compounds in organisms of warmꢀ
blooded animals occurs via their oxidation.
(3 Н, s, С3–СН3), 2.12* (3Н, s, C3'–СН3), 1.59
(6 Н, d, isopropyl СН3), 1.52* (6 Н, d, isopropyl
СН3'). The C1–OH and –C1'–OH, as well as the
Based on the theory of hard and soft bases and acids
[39], we can regard derivative (IVC) as a softer acid C6–OH and –C6'–OH protons could not be identiꢀ
and, therefore, it must be oxidized under more drastic
conditions than a harder acid (IVA). This fact may
explain the lower toxicity of (IVB) than that of the corꢀ
responding bisderivative.
With the analysis of the data shown in the table, we
can also evaluate the effect of the substituent nature on
the acute toxicity. Aliphatic and heterocyclic substituꢀ
ents (compounds (IIC), (IVB), and (VB)) supported
its augmentation, whereas aromatic substituents
(compounds (IIIB)) exhibited the opposite effect.
fied separately because of proton exchange. Herein
and below, the resonances of the substituted fragments
are marked with an asterisk.
8ꢀFormylꢀ1,1',6,6',7ꢀpentahydroxylꢀ3,3'ꢀdimethylꢀ8
methynꢀ[4''ꢀiminoꢀ(1''ꢀphenylꢀ2'',3''ꢀdimethylpyrazolꢀ5''ꢀ
one]7'ꢀoxoꢀ5,5'ꢀdiisopropylꢀ2,2'ꢀbinaphthalene (IVB).
'ꢀ
A
solution of gossypol (104 mg, 0.2 mmol) and 4ꢀamiꢀ
noantipyrine (39 mg, 0.2 mmol) in chloroform (5 ml)
was kept for 3 days at ⎯15°С. The reaction course was
monitored by TLC (9 : 1 chloroform–ethyl acetate, Rf
of product (IVB) 0.5). The precipitate was filtered off
and recrystallized from acetone (mp 200–202°С) to
give 43% of compound (IVB). Found, %: С 69.89; Н
EXPERIMENTAL
Gossypol (I) was prepared at an experimental plant
5.72; N 5.83. C41H41N3O8. Calc., %:
N 5.97. After the filtrate was concentrated and purified
by column chromatography on silica gel (100/160 m)
in 9 : 1 (v/v) chloroform–ethyl acetate, it contained 30
and 27% of ( ) and (IVA), respectively. UV (CCl4), λmax
nm,
С 69.99; Н 5.83;
of the Institute of Bioorganic Chemistry, Uzbek Acadꢀ
emy of Sciences, from side products of cottonꢀoil proꢀ
duction. Chemical reagents and solvents were
obtained from Aldrich. Compounds (IIA)–(VA) and
μ
I
,
(
IIB) were synthesized as described in [32, 40–42].
(ε): 243 (13640), 280 (6160), 414 (3430), 462
The melting points were measured in a glass capilꢀ
(3520). IR (KBr), cm–1: 3550, 2360, 1630, 1590, 1170,
840. 1H NMR: (100 MHz, CDC13): 16.24* (1 Н, br s,
–NH), 15.25 (1 Н, s, С7–OН), 11.12 (1 Н, s,
lary. TLC was carried out on Silufol UVꢀ254 plates
with the development in an iodine chamber.
The UV spectra were registered on a Specord specꢀ
trophotometer.
⎯
СНО), 10.98* (1 Н, br s, =CH–N), 7.73–7.75*
(5 Н, m, substituent Ph), 7.71 (1 Н, s, Н4), 7.62*
(1 Н, s, Н4'), 3.84(1 Н, m, –С5ꢀisopropyl CH), 3.11*
(3 Н, s, N–CH3 substituent), 2.45* (3 Н, s, CꢀCH3
substituent), 2.16 (3 Н, s, С3–CH3), 2.11* (3 Н, s,
С3–CH3'), 1.59 (6 Н, d, isopropyl СН3), 1.52* (6 Н,
d, isopropyl СН3'). The OHꢀ1, OHꢀ1' and OHꢀ6,
OHꢀ6' protons could not be identified separately
because of the proton exchange.
The IR spectra were recorded on an IRꢀ10 spectroꢀ
photometer in the region of 3700–750 cm–1 in KBr
tablets.
1
The H NMR spectra (CDCl3 and DMSOꢀd6
)
were registered on a Tesla BS 567ꢀA spectrometer with
a working frequency of 100 MHz and tetramethylsiꢀ
lane as an internal standard.
8ꢀFormylꢀ1,1,6,6',7ꢀpentahydroxylꢀ3,3'ꢀdimethylꢀ8'ꢀ
methyniminobenzeneꢀ7'ꢀoxoꢀ5,5'ꢀdiisopropylꢀ2,2'ꢀbinaphꢀ
8ꢀFormylꢀ1,1',6,6',7ꢀpentahydroxylꢀ3,3'ꢀdimethylꢀ8
methynꢀ[pyrimidineꢀ1'',3'',5''ꢀtrione]7'ꢀoxoꢀ5,5'ꢀdiisoꢀ
'ꢀ
thalene (IIIB). Solutions of compound (I) (104 mg, propylꢀ2,2'ꢀbinaphthalene (VB). Dry gossypol (
I)
0.2 mmol) in chloroform (3 ml) and aniline (20
μl, (104 mg, 0.2 mmol) was added to a solution of barbituꢀ
0.2 mmol) in chloroform (1 ml) were kept for 1 day at ric acid (26 mg, 0.2 mmol) in ethanol (50 ml) and the
–15°C and then mixed and kept for several days at the mixture was kept at room temperature for 1 h. The
same temperature. The reaction was monitored by reaction course was monitored by TLC (ethyl acetate,
TLC (elution with chloroform,
IIIB). The precipitate was filtered and recrystallized ing 35% (
from acetone to give 65% (IIIB); mp 238–240°C. matographed on a silica gel column (100/160
R
f 0.3 for compound Rf of product (VA) 0.89). In 1 h, the mixture containꢀ
) and 35% ( ) was evaporated and chroꢀ
m) in
5.82; N 2.28. C36H35N1O7. ethyl acetate to give 30% (VB). Found, %: С 66.84;
5.90; N 2.36. After concentrating Н 4.85; N 4.47. C34H30N2O9. Calc, %: С 66.89; Н
(
I
V
μ
Found, %:
Calc., %:
С
72.85;
72.71; Н
С
Н
followed by separation by column chromatography on 4.92; N 4.59. Melting point 220–223°С (ethyl aceꢀ
silica gel (100/160
filtrate contained 10 and 25% of compounds (
IIIA), respectively. UV (CCl4), λmax, nm,
(11570), 280 (5340), 411 (3850), 470 (2970). IR DMSOꢀ
(KBr), cm–1: 3560, 2350, 1620, 1540, 1240, 840. >С15=СН–), 7.89 (1 Н, s, Н4), 7.45* (1 Н, s, Н4'), 7.12
1Н NMR: (100 MHz, CDCl3): 15.28 (1
, s, С7–ОН), (1 Н, br s, >СН–Oꢀlactol). The individual attribution of
11.18 (1 , s, –СНО), 10.13 (1 H, d, =CH N), 7.79 hydroxyl groups with resonances at 10.3, 9.2, 8.6, 7.8,
(1H, 1, H4), 7.63* (1 Н, s, Н4'), 7.83–7.88* (5 Н, m, and 7.0 ppm (broad singlets) was difficult. The singlets of
μm, elution with chloroform), the tate). UV (C2H5OH), λmax, nm, (ε): 229 (14370), 261
I
) and (13740), 485 (2780). IR (KBr), cm–1: 3680, 2870,
1
(
(
ε): 242 1670, 1610, 1525, 1220, 860. Н NMR (100 MHz,
d6): 11.31* (1 Н, br s, NH), 10.58* (1 Н, br s,
Н
Н
–
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 36
No. 3
2010

394
TILYABAEV et al.
16. Sadykov, A.S. and Aripov, U.A., Some Results of
Studies of Gossypol and Its Derivatives ad Immunodeꢀ
pressive Drugs, in Mat. II simp. po fenol’nym
soedineniyam (Proc. II Symp. on Phenolic Comꢀ
pounds), Tashkent: Fan, 1974.
methyl groups from the two molecule halves only insigꢀ
nificantly differed and were located at the standard specꢀ
tral regions [33, 43].
Acute toxicity was determined in white mice with
1 g of body weight using the Prozorovskii method
20
17. Zakirov, U.B., Ganieva, R.G., and Ishmukhamedov, N.A.,
On Pharmacological Properties of GSN, in Mat. II simp. po
fenol’nym soedineniyam (Proc. II Symp. on Phenolic Comꢀ
pounds), Tashkent: Fan, 1974, pp. 38–42.
[44]. The tested compounds were administered intraꢀ
peritoneally at doses of 150–5000 mg/kg. The experiꢀ
ments were observed for 14 days.
18. Kamilov, I.K., Nasirov, S.A., and Abdumalikova, N.V.,
Pharmacology and Toxicology of Gossypol, in Mat.
I simp. po fenol’nym soedineniyam (Proc. I Symp. on Pheꢀ
nolic Compounds), Tashkent: Fan, 1971, pp. 16–18.
ACKNOWLEDGMENTS
The work was supported by the Foundation for
Support of Fundamental Research, Academy of Sciꢀ
ences of the Uzbekistan Republic, project no. FAꢀF3ꢀ
Tꢀ141.
19. Nguyen Kim Phi Phung, Nguyen Ngoc Suong, and
Pham Dinh Hung, Tap Chi Hoa Hoc., 1997, vol. 35,
pp. 83–87.
20. Ziyaev, Kh.L., Kamaev, F.G., Baram, N.I., Biktimirov, L.,
and Ismailov, A.I., Chem. Nat. Comp., 1998, vol. 33,
pp. 545–547.
REFERENCES
1. Boatner, Ch.H., in Pigments of Cottonseed, Bailey, A.E.,
Ed., New York: Interscience Publ. Inc., 1948, pp. 213–
363.
21. Przybylski, P., Wlodarz, M., Brzezinski, B., and Bartl, F.,
J. Mol. Struct., 2004, vol. 691, pp. 227–234.
2. Smith, H.A., Am. J. Pathol., 1957, vol. 33, pp. 353–365.
22. Przybylski, P., Jasinski, K., Brzezinski, B., and Bartl, F.,
J. Mol. Struct., 2002, vol. 611, pp. 193–201.
3. Phelps, R.A., World’s Poultry Sci. J., 1966, vol. 22,
pp. 86–112.
23. Przybylski, P., Bejcar, G., Schroeder, G., and Brzezinꢀ
4. Eagle, E., Toxicants Occurring Naturally in Foods, Pubꢀ
lication 1154, National Acad. Sci., Nat. Res. Council,
Washington, D.C., 1968, pp. 242–249.
5. Berardi, L.L and Goldblatt, L.A, in Toxic Constituents
of Plant FoodꢀStuffs, 2 nd ed., Liener, J.E., Ed., New
York: Academic, 1980, pp. 183–237.
ski, B., J. Mol. Struct., 2003, vol. 654, pp. 245–252.
24. Przybylski, P., J. Mol. Struct., 2003, vol. 654, pp. 167–
176.
25. Morris, R.C. and Adams, R.J., J. Am. Chem. Soc., 1937,
vol. 59, p. 1731.
26. Murty, K.S. and Seshadri, T.R., Proc. Indian Acad. Sci.
,
6. Braham, J.E., Jarquin, R., Bressani, R., and Elias, L.,
1942, vol. 16, p. 146.
J. Nutr., 1967, vol. 93, pp. 241–248.
27. Ismailova, G.A., Analysis of the StructuralꢀFunctional
Relationship of Gossypol Derivatives and Their Effect
on Different Components of Immunogenesis, Cand.
Sci. (Med.) Dissertation, Almaty: Nauch.ꢀIssled. Inst.
Epidemiol., Microbiol. Infekts. Bol., Minzdrav Kaz.
SSR, 1986.
7. Herman, D.L. and Smith, F.H., J. Nutr., 1973, vol. 103,
pp. 882–889.
8. Scutches, Ch.L., Herman, D.L., and Smith, F.H.,
J. Nutr., 1974, vol. 104, pp. 415–422.
9. Sokolova, S.F., Mirsalikhova, N.M., Sakhibov, A.D.,
and Kuznetsov, A.M., in Sb. Voprosy transplantologii i
immunosupressii (Problems of Transplantology and
Immunosuppression: Collected Papers), Tashkent: Izd.
Tashkent. Gos. Med. Inst., 1983, pp. 79–83.
10. Sokolova, S.F., in Voprosy transplantologii i immunokoꢀ
rrigiruyushchei terapii (Problems of Transplantology
and ImmuneꢀCorrection Therapy), Tashkent: Izd.
Tashkent. Gos. Med. Inst., 1986, pp. 55–57.
11. Karabanovich, A.K., Sologub, G.R., Khakimov, Z.Z.,
et al., in IV Vsesoyuznyi simp. po fenol’nym soedineniyam.
Tez. dokl (Abstr. IV AllꢀUnion Symp. on Phenolic Comꢀ
pounds), Tashkent: Fan, 1982, pp. 22–23.
28. Baram, N.I., Ismailov, A.I., Biktemirov, L., Paizieva, R.Z.,
and Ziyaev, Kh.L., in Problemy i perspektivy razvitiya
khimii prirodnykh i fiziologicheski aktivnykh veshchestv
(Problems and Prospects of Development of Chemistry
of Natural an d Physiologically Active Compounds),
Tashkent: Fan, 1988, pp. 78–99.
29. Guo Zhengming, Wan Feng, Gu Zhiping, Wu Guopei,
and Peng Sixum, Yaoxue Xuebao, 1987, vol. 22,
pp. 597–602.
30. Xue Hoizhong, Guo Zhengming, Kong Aihua, and Wu
Guopci, Chin. Chem. Lett., 1992, vol. 3, pp. 165–166.
31. Dodou, R., Anderson, R.J., Lough, W.J.,
Small, D.A.P., Shelley, M.D., and Groundwater, P.W.,
Bioorg. Med. Chem., 2005, vol. 13, pp. 4228–4237.
12. Meksongsee, L.A., Clawson, A.J., and Smith, F.H.,
J. Agr. Food Chem., 1970, vol. 18, pp. 917–919.
13. AbouꢀDonia, M.B. and Dieckert, J.W., Life Sci., 1974,
32. Talipov, S.A. and Ibragimov, B.T., J. Incl. Phen. Mol.
Recogn. Chem., 1997, vol. 29, pp. 33–39.
vol. 14, pp. 1955–1963.
14. Turakulov,
Ya.Kh.,
Tashmukhamedov,
B.A.,
33. Kamaev, F.G., Baram, N.I., Ismailov, A.I.,
Leont’ev, V.B., and Sadykov, A.S., Izv. Akad. Nauk
SSSR, Ser. Khim., 1979, no. 6, p. 1003.
Gagel’gans, A.I., et al., Prospects of the Use of Gossyꢀ
pol and Its Derivatives in Medicine, in Mat. I simp. po
fenol’nym soedineniyam (Proc. I Symp. on Phenolic
Compounds), Tashkent: Fan, 1971, pp. 19–22.
34. Bronislaw, M., Schroeder, G., Kozubek, H., and
Brzezinski, B., J. Chem. Soc., Perkin Trans., 1991,
vol. 29, pp. 1359–1362.
15. Kalliopi Dodou, Expert Opin. Investig. Drugs, 2005,
vol. 14, pp. 1419–1434.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 36
No. 3
2010

SYNTHESIS, STRUCTURES, AND ACUTE TOXICITY
395
35. Glushenkova, A.I., Nazarova, I.P., Ul’chenko, N.T., 40. Adams, R., Price N.N., Dial W.R, J. Am. Chem. Soc.,
and Kristallovich, E.L., Khim. Prirod. Soed., 1989,
1938, vol. 60, pp. 2158–2160.
no. 5, p. 712.
41. Baram, N.I., Ziyaev, Kh.L., Khodzhiniyazov, B., and
Ismailov, A.I., Khim. Prirod. Soed., 1999, no. 1,
pp. 38–41.
36. Gusakova, S.D., Yunusova, S.G., Chernenko, T.V.,
Nazarova, I.P., and Glushenkova, A.I., Khim. Prirod.
Soed., 1986, no. 6, p. 677.
37. Katritskii, A.R. and Embler, A.P., Fizicheskie Metody v
Khimii Geterotsiklicheskikh Soedinenii (Physical Methꢀ
ods in Chemistry of Heterocyclic Compounds), Mosꢀ
cow: Khimiya, 1966.
38. Sumin, V.I., Study of Pharmacokinetics of Physiologiꢀ
cally Active Gossypol Derivatives, Cand. Sci. (Biol.)
Dissertation, Tashkent: Inst. Bioorg. Khim. im. Akad.
A.S. Sadykova AN RUz, 1990, pp. 10–35.
42. Sadykov, A.S., Aripov, U.A., Ismailov, A.I.,
Biktimirov, L.B., Baram, N.I., Khashimov, I.Kh., Arusꢀ
tamov, D.L., Abdullakhodjaeva, M.S., Urazmetova,
M.S., and Karimova, R.I., USSR Patent No. 545634,
1977.
43. Ziyaev, Kh.L., Baram, N.I., Kamaev, F.G., Biktimirov, L.,
Dzhurabekova, S.B., and Ismailov, A.I., Khim. Prirod.
Soed., 1998, no. 1, p. 52.
39. Pearson, R.G., J. Am. Chem. Soc., 1963, vol. 85, 44. Prozorovskii, K.V., Farmakol. Toksikol., 1983, no. 6,
pp. 3533–3539.
pp. 91–94.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 36
No. 3
2010