Polymeric derivatives of dipterocarpol, a dammarane triterpenoid

Article abstract of DOI:10.1134/S107042720604029X

Polymeric derivatives of dammarane triterpenoids with both labile and strong (covalent) polymer-triterpenoid bonds were prepared from N-vinylpyrrolidone copolymers. Pleiades Publishing, Inc., 2006.

Full text of DOI:10.1134/S107042720604029X

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2006, Vol. 79, No. 4, pp. 654 659.
Pleiades Publishing, Inc., 2006.
Original Russian Text
No. 4, pp. 663 668.
A. D. Zorina, L. V. Balykina, O. V. Nazarova, A. A. Rebezov, 2006, published in Zhurnal Prikladnoi Khimii, 2006, Vol. 79,
MACROMOLECULAR CHEMISTRY
AND POLYMERIC MATERIALS
Polymeric Derivatives of Dipterocarpol,
a Dammarane Triterpenoid
A. D. Zorina, L. V. Balykina, O. V. Nazarova, and A. A. Rebezov
St. Petersburg State University, St. Petersburg, Russia
Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, Russia
Received December 26, 2005
Abstract Polymeric derivatives of dammarane triterpenoids with both labile and strong (covalent) poly-
mer triterpenoid bonds were prepared from N-vinylpyrrolidone copolymers.
DOI: 10.1134/S107042720604029X
Treatment of virus diseases requires development
of effective nontoxic antiviral preparations. Synthesis
of polymeric derivatives of low-molecular-weight
biologically active substances (BASs) opens prospects
for development of improved medicinals of reduced
toxicity, enhanced efficiency, and prolonged effect.
carpol) I. It can be prepared in amounts required for
the studies from Dipterocarpus alatus latex [7].
We prepared dammarane derivatives containing at
C-17 an open chain (VII), a -lactone ring (III), and
a tetrahydrofuran ring (IV). Diol VII was prepared by
reduction of dipterocarpol with sodium borohydride in
ethanol. To prepare compounds III and IV, diptero-
carpol was oxidized with chromic anhydride in acetic
acid to lactone II. Reduction of II with sodium boro-
hydride in ethanol yielded hydroxy lactone III, and
reduction with sodium borohydride in the presence of
BF3 OEt2 in THF yielded epoxydammaranol IV.
From compounds III, IV, and VII (Scheme 1) con-
taining the 3 -hydroxy group, we prepared by reflux-
ing with phthalic anhydride phthalic acid monoesters
V, VI, and VIII, respectively (Scheme 1). Through
the free carboxy group, these compounds were bonded
to an amino group of the polymer.
Polymers based on N-vinylpyrrolidone (VP) are
among the most widely used polymeric carriers [1, 2].
VP copolymers containing amino groups show prom-
ise as BAS carriers. Alkylation with various alkyl
halides of VP copolymers with primary and tertiary
amines allows preparation of polymers containing,
along with the ionic ammonium group, alkyl substitu-
ents providing hydrophobic interaction in aqueous
solutions [3]. Preparation of water-soluble derivatives
(salts) of polyene antibiotics Levorin and Nystatin on
the basis of such copolymers was reported in [4].
Previous studies revealed more pronounced anti-
viral properties of polymeric derivatives of certain tri-
terpene acids compared to the nonmodified acids [5].
To prepare polymeric derivatives of triterpenoids
of the dammarane series with a labile BAS polymer
bond (BAPs), we used a copolymer of VP with di-
methylaminoethyl methacrylate (DMAEM) and with
its derivative quaternized with dodecyl iodide
(DMAEM C12H25I) [8]. Polymeric salts of phthalic
acid monoesters were prepared by Scheme 2.
The goal of this study was to develop procedures
for preparing from VP copolymers polymeric deriva-
tives of triterpenoids of the dammarane series differ-
ing in the type and lability of the polymer triterpenoid
bond.
As solvent we used methanol in which all the re-
actants (triterpenoid hydrogen phthalates and the poly-
mer) and products (polymeric salts) are soluble. After
the synthesis completion, methanol was gradually
replaced by water [4]. As a result, we obtained poly-
meric derivatives which, in contrast to the starting
Among dammarane triterpenoids, the highest anti-
viral activity is exhibited by alnincanone, 24-methyl-
20S,24R-epoxydammaran-3-one [6]; however, its
content in plant sources is insufficient for more com-
prehensive biological studies. As a model compound
we chose 20(S)-hydroxydammar-24-en-3-one (diptero-
654

POLYMERIC DERIVATIVES OF DIPTEROCARPOL, A DAMMARANE TRITERPENOID
655
Scheme 1.
triterpenoid hydrogen phthalates, are soluble in water.
The UV spectra of all the derivatives contain absorp-
tion bands of the corresponding triterpenoid hydrogen
The products were separated by gel permeation
chromatography (GPC) on a column packed with
Sephadex LH-20 gel (eluent ethanol). The absorption
of the fractions taken was measured at 274 nm (the
starting polymer is virtually transparent in this range).
The chromatograms of all the polymeric salts obtained
phthalates V, VI, and VIII (
= 274 nm), which
allowed determination of the BAS content in the poly-
max
meric products. The results are given in Table 1.
It is known that polyvinylpyrrolidone (PVP) forms
complexes with many substances [1, 2]. We attempted
to prepare PVP derivatives of triterpenoid hydrogen
phthalates by the procedure similar to that used for
preparing salts of VP DMAEM DMAEM C12H25I
copolymer. We failed to obtain water-soluble prod-
ucts. Addition of water to a solution of the reactants
in methanol resulted in precipitation of triterpenoid
hydrogen phthalates. This fact confirms that, to obtain
a water-soluble product, the starting copolymer should
contain ionic groups.
Table 1. Polymeric salts of hydrogen phthalates of
dipterocarpol derivatives*
[R ]
,
Hydrogen
phthalate
Run no.
1
l mol 1 cm
wt %
mol %
1
2
3
VIII
V
VI
1600
1600
1300
10.2
9.1
11.6
2.3
2.2
2.9
*
The salts are water-soluble.
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656
ZORINA et al.
R = V, VI, VII.
Scheme 2.
R = V, VI, VII.
Scheme 3.
exhibit peak I in the same region as for the unmodi-
fied BAS (Fig. 1). There is also a weak peak II in
the region of small retention volumes corresponding
to polymer-containing fractions (for comparison,
we show a chromatogram of a copolymer of VP with
N-hydroxyphthalimide ester of acrylic acid). The UV
spectra of fractions I and II are similar to the spectra
of the low-molecular-weight BAS and starting poly-
mer, respectively.
To prepare polymeric derivatives of hydrogen
phthalates V, VI, and VIII in which the BAS is linked
to the polymer by a strong covalent bond, we used
a copolymer of VP with allylamine (AlAm) [9].
The reactions of triterpene hydrogen phthalates
with this copolymer were performed in CH2Cl2 in
the presence of N, N -dicyclohexylcarbodiimide (DCC),
as shown in Scheme 3.
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POLYMERIC DERIVATIVES OF DIPTEROCARPOL, A DAMMARANE TRITERPENOID
657
The reaction should yield derivatives in which
BAS is linked to the polymeric carrier by an amide
bond. The characteristics of the reaction products are
given in Table 2. Their composition, similarly to the
polymeric salts, was determined by UV spectroscopy,
Table 2. Polymeric derivatives of hydrogen phthalates
of dammarane triterpenoids with an amide bond BAS
polymer
[R ]
Degree of
conver-
Run Hydrogen
no. phthalate
Solubility
in water
as the absorption band at
= 274 nm was ob-
max
wt % mol % sion, %
served in the spectra of all the products. As seen from
Table 2, in all the cases, as in the case of the poly-
meric salts, the derivatives containing 12 wt % triter-
penoid hydrogen phthalate are water-soluble (run nos.
5 7). At a high BAS content, as in the case of betu-
linic and betulonic acid derivatives [5], the solubility
in water is lost (run no. 4).
4
5
6
7
VIII
VIII
VI
19.6
8.6
11.6
10.2
4.1
1.7
2.6
2.2
75
62
91
80
Insoluble
Soluble
Soluble
Soluble
V
The chromatograms of covalent derivatives of tri-
terpenoid hydrogen phthalates (Fig. 2) differ from
those of polymeric salts (Fig. 1). As seen from Fig. 2,
for the covalent derivatives, with the same gel (LH-
20) and eluent (ethanol), peak I is weak, and peak II,
on the contrary, strong. The UV spectra of the frac-
tions corresponding to peak II, as those of the initial
1
data [7]: mp 184 186 C). IR spectrum, cm : 1765
(C=O in -lactone), 1695 (C=O).
25,26,27-Trinordammaran-3 -ol-20(S),24-olide
III. Dipterocarpol lactone II (2 g) was refluxed with
250 mg of NaBH4 in 85 ml of isopropyl alcohol for
24 h, after which the solution was diluted with water
and acidified to pH < 2. The precipitate was filtered
off, washed with water, dried, and recrystallized from
ethyl acetate. Yield of reduced lactone III 1.5 g
BASs, contain a band with
= 274 nm. Similar
max
chromatograms are obtained with Sephadex G-75 gel
and water as eluent. This fact confirms that, in con-
trast to the derivatives obtained in run nos. 1 3, in the
products from run nos. 4 7 the BAS is strongly bound
to the polymeric carrier, because its chromatographic
behavior is similar to that of the carrier.
EXPERIMENTAL
20(S)-Hydroxydammar-24-en-3-one I. Diptero-
carpol I was eluted with hexane ethyl acetate (15 : 1)
in the course of chromatographic separation (silica
gel, 5/40 m) of an ethyl acetate solution of Diptero-
carpus alatus latex; mp 133 135 C [7]. IR spectrum,
Fig. 1. Chromatograms (LH-20, eluent ethanol): (1) dam-
mar-24-ene-3 ,20(S)-diol hydrogen phthalate VIII, (2) co-
polymer of VP with N-hydroxyphthalimide ester of acrylic
acid, and (3) polymeric salt of dammar-24-ene-3 ,20(S)-
diol hydrogen phthalate VIII and VP DMAEM DMAEM
1
cm : 3480, 1690. Yield 67%.
25,26,27-Trinordammaran-3-on-20(S),24-olide
II. Dipterocarpol I (10 g) was dissolved in 50 ml
of benzene and 30 ml of acetic acid; 4 g of CrO3 and
3 ml of H2O were added, The mixture was cooled
with ice and allowed to stand for 12 h at room tem-
perature, after which it was diluted with water.
The precipitate was filtered off and washed with wa-
ter, 5% sodium carbonate solution, and again water
to neutral reaction. The dry precipitate was chro-
matographed on a column packed with silica gel.
C
H I copolymer (run no. 1).
12 25
Fractions containing dipterocarpol lactone II were
combined, and the solvent was evaporated. The re-
sidue was crystallized from ethyl acetate. Yield of
dipterocarpol lactone II (25,26,27-trinordammaran-
3-on-20(S),24-olide) 7.9 g, mp 180 182 C (published
Fig. 2. Chromatogram (LH-20, eluent ethanol) of the de-
rivative of dammar-24-ene-20(S),3 -diol hydrogen phthalate
VIII and VP AlAm copolymer (run no. 5).
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658
ZORINA et al.
1
(75%), mp 199 201 C (published data [7]: mp 203
204 C). IR spectrum, cm : 3450 (OH), 1765 (C=O in
25 C in 0.1 M CH3COONa 0.13 dl g , molecular
1
weight M = 21000, by the following procedures.
-lactone).
Example 1. VP DMAEM DMAEM C12H25I co-
polymer (0.35 g) was dissolved in 30 ml of methanol,
and 0.044 g of dammar-24-ene-3 ,20(S)-diol hydro-
gen phthalate VIII was added. The mixture was stirred
for 24 h at room temperature. The polymeric salt was
isolated by gradual replacement of methanol as solv-
ent by water (stepwise addition of water with distil-
lation of methanol) [4]. The polymer was isolated
from the resulting aqueous solution by freeze drying.
Yield 0.38 g (96%) (run no. 1).
Dammar-24-ene-20(S),3 -diol VII. Dipterocarpol
I [20(S)-hydroxydammar-24-en-3-one] was reduced
with NaBH4 under the same conditions as compound
II. Diol VII was obtained in 40% yield; mp 132
134 C (published data [10]: mp 131 133 C). 13C
NMR spectrum, , ppm: 78.4 (C-3 OH).
25,26,27-Trinor-20(S),24-epoxydammaran-3 -ol
IV. A solution of 5 g of dipterocarpol lactone II in
100 ml of THF and 10 ml of BF3 OEt2 were added
over a period of 3 h at 15 C to 1.28 g of sodium
borohydride in 50 ml of THF. The mixture was al-
lowed to stand for 2 h at 15 C, after which it was
refluxed on a water bath for 5 h. Then the mixture
was cooled, diluted with a fivefold volume of water,
and acidified with 2 N HCl to pH < 2. The precipitate
was filtered off, washed with water, and dried. The
residue (4.7 g) was chromatographed on a column
packed with 150 g of silica gel (70/230 m). Elution
with hexane 5% ethyl acetate gave 2.9 g (65%) of IV,
mp 182 183 C (published data [7]: mp 180 182 C).
Under similar conditions we prepared the polymer-
ic salts of hydrogen phthalates V [yield 61% (0.24 g)
(run no. 2)] and VI [yield 94% (0.37 g) (run no. 3)].
Polymeric derivatives of triterpenoids with a poly-
mer BAS covalent bond were prepared from the VP
(94.5 mol %) AlAm (5.5 mol %) copolymer, [ ] at
1
25 C in 0.1 M CH3COONa 0.12 dl g , M = 18000.
Example 2. A solution of 0.23 g of VP AlAm
copolymer, 0.075 g of VIII, and 0.025 g of DCC in
4.5 ml of CH2Cl2 was kept for 2 h at 18 C and then
for 72 h at 5 C. The molar ratio of the reactants was
1 : 1 : 1. Then the polymer was precipitated into di-
ethyl ether, and the precipitate was separated on a
glass frit and vacuum-dried to constant weight. The
low-molecular-weight impurities were separated by
gel permeation chromatography on a column packed
with Sephadex LH-20 gel (h = 44 cm, d = 1.5 cm),
eluent ethanol. The high-molecular-weight fraction
was collected, and ethanol was distilled off on a rotary
evaporator.
1
IR spectrum, cm : 3450 (OH stretching vibrations)
[7]. 1H NMR spectrum, , ppm: CH3 (0.79 s, 0.89 s,
1.05 s, 0.9 s, 0.69 s, 0.79 s); 3.09 t; 3.6 m.
Hydrogen phthalates of compounds III, IV, and
VII. Hydroxy derivative III, IV, or VII (0.01 mol)
and phthalic anhydride (0.02 mol) were refluxed in
pyridine for 48 h, after which the mixture was diluted
with a fourfold volume of water and acidified with
10% HCl to pH < 2. The white precipitate was filtered
off, washed with water to neutral reaction, and dried;
the residue was recrystallized from petroleum ether
ethyl acetate.
Run no. 5: polymeric derivative of VIII, yield 89%
(0.31 g); run no. 6: polymeric derivative of VI, yield
69% (0.24 g); run no. 7: polymeric derivative of V,
yield 64% (0.22 g).
Dammar-24-ene-20(S),3 -diol hydrogen phthal-
ate VIII: mp 208 210 C. 1H NMR spectrum,
,
ppm: 4.8 ( -H at C-3) and 7.5 7.9 (4H).
CONCLUSIONS
25,26,27-Trinor-20(S),24-epoxydammaran-3 -ol
hydrogen phthalate VI: mp 219 221 C. H NMR
spectrum, , ppm: 4.75 ( -H at C-3) and 7.6 7.9 (4H).
1
(1) Previously unknown 25,26,27-trinordammaran-
3 -ol-20(S),24-olide hydrogen phthalate V, 25,26,27-
trinor-20(S ), 24-epoxydammaran-3 -ol hydrogen
phthalate VI, and dammar-24-ene-20(S),3 -diol hy-
drogen phthalate VIII were prepared.
25,26,27-Trinordammaran-3 -ol-20(S),24-olide
1
V: mp 258 260 C. H NMR spectrum, , ppm: 4.75
( -H at C-3) and 7.6 7.9 (4H).
(2) Procedures were developed for preparing poly-
meric water-soluble derivatives of V, VI, and VIII
with N-vinylpyrrolidone copolymers, with both labile
and strong covalent bonding of the polymer with
the triterpenoid.
Synthesis of polymeric derivatives of triterpe-
noids. Polymeric salts of triterpenoids were prepared
from the VP (87.8 mol %) DMAEM (9.2 mol %)
DMAEM C12H25I (3.0 mol %) copolymer, [ ] at
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POLYMERIC DERIVATIVES OF DIPTEROCARPOL, A DAMMARANE TRITERPENOID
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