Synthesis of ionic biologically active conjugates from trolox and α-tocopherol succinates

Article abstract of DOI:10.1007/s10600-016-1850-x

Six ionic conjugates with nitroxyl radical amino-TEMPO and diethanolamine as the amines were synthesized from trolox and α-tocopherol succinates. The water solubility of the synthesized ammonium salts was determined. It was shown that formation of the trolox succinate salts increased the water solubility whereas this phenomenon was not observed for α-tocopherol succinates.

Full text of DOI:10.1007/s10600-016-1850-x

DOI 10.1007/s10600-016-1850-x
Chemistry of Natural Compounds, Vol. 52, No. 6, November, 2016
SYNTHESIS OF IONIC BIOLOGICALLY ACTIVE CONJUGATES
FROM TROLOX AND ꢀ-TOCOPHEROL SUCCINATES
Yu. V. Yushkova, S. V. Morozov,1,2
E. I. Chernyak, and I. A. Grigorꢁev
1*
1
1,3
Six ionic conjugates with nitroxyl radical amino-TEMPO and diethanolamine as the amines were synthesized
from trolox and ꢀ-tocopherol succinates. The water solubility of the synthesized ammonium salts was
determined. It was shown that formation of the trolox succinate salts increased the water solubility whereas
this phenomenon was not observed for ꢀ-tocopherol succinates.
Keywords: trolox, ꢀ-tocopherol, succinates, diethanolamine, nitroxyl radical amino-TEMPO, ammonium salts, ionic
conjugates, water solubility.
Currently, 60% of marketed drugs are highly soluble in H O whereas 80% of new drugs in various research and
2
development stages are poorly soluble in H O. This reduces their bioavailability, prevents them from entering the pharmaceutical
2
market, and necessitates the development of methods for increasing the water solubility of promising pharmacologically
active compounds [1].
Several approaches for increasing the water solubility of compounds are known, e.g., mechanochemical activation;
production of nanocomposites, inclusion complexes with cyclodextrins, and complexes with metals and metal carbonates;
introduction of hydrophilic fragments into the molecule, etc. Preparation of salts of acidic or basic organic compounds is an
effective pathway to increasing their water solubility.
A series of covalent spin-labeled derivatives of trolox and ꢀ-tocopherol were synthesized by us earlier [2, 3]. These
are antioxidants with a chromane motif that are now widely used for targeted chemical transformations in order to synthesize
highly promising pharmacologically active compounds [4, 5]. We also prepared homo- and heterodimers of trolox with
various types of binding (covalent, ionic, and ionic-covalent) and showed that the water solubility of the symmetric ionic
trolox homodimer was 130 times greater than that of trolox [6].
Ionic conjugates of trolox and ꢀ-tocopherol succinates were synthesized and their water solubilities were determined
during modifications of trolox and ꢀ-tocopherol that were aimed at producing new pharmacologically active compounds.
The amines for synthesizing the ionic biologically active conjugates of trolox and ꢀ-tocopherol succinates were the
nitroxyl radical amino-TEMPO, which is widely used to prepare spin-labeled biologically active conjugates, and diethanolamine,
which is infinitely soluble in water.
Trolox (1) reacted with succinic anhydride in CH Cl in the presence of Et N and dimethylaminopyridine (DMAP)
2
2
3
to produce trolox succinate 2 [7], reaction of which with solutions of amines a and b in THF in a 1:2 ratio at 20–25°C gave
ammonium salts of trolox monosuccinate 3a and 3b (Scheme 1).
1
) N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, 9
Prosp. Akad. Lavrentꢁeva, Novosibirsk, 630090, e-mail: yushkova@nioch.nsc.ru; 2) Novosibirsk State University, 2 Pirogova
St., Novosibirsk, 630090, e-mail: moroz@nioch.nsc.ru; 3) E. N. Meshalkin Novosibirsk Scientific Research Institute of
Circulation Pathology, 15 Rechkunovskaya St., Novosibirsk, 630055, e-mail: grig@nioch.nsc.ru. Translated from Khimiya
Prirodnykh Soedinenii, No. 6, November–December, 2016, pp. 872–876. Original article submitted April 25, 2016.
0
009-3130/16/5206-1015 ©2016 Springer Science+Business Media New York
1015

O
O
+
_
O
5
4
HO
O
O
O
RNH
3
O
O
HO
+
4a
8a
3
_
O
+
R
2
R
1
NH
2
7
OH
O
OH
NH
O
NH
3
R
O
O
O
2
+
NH
8
2
R
1
R
2
1
2
3a, b
NH
2
2
R :
NHR
1
R
2
:
HO
OH
N
H
N
O
.
a
b
Scheme 1
–
1
IR spectra of conjugates 3a and 3b retained ester C=O stretching bands at 1738 and 1745 cm . The carboxylic C=O
–
1
stretching band of trolox succinate at 1717 cm disappeared. Instead of it, bands of asymmetric and symmetric carboxylate
–
1
–1
anion stretching vibrations at 1620–1641 cm and 1396–1400 cm , respectively, appeared in addition to bending vibrational
–
1
bands (ꢂN–H) for the quaternary N atom at 1556–1574 cm [8]. This argued in favor of ionic structures 3a and 3b. The
hyperfine coupling (HFC) constant a in the EPR spectrum of spin-labeled conjugate 3a was 16.0 G, which agreed with the
N
HFC constant for piperidine radicals [9].
PMR and 13C NMR spectra of 3b exhibited all characteristic resonances of succinyl, trolox, and diethanolamine
fragments. The phenol methyls of trolox were located at 1.96–2.19 ppm in the PMR spectrum; the pyran 2-methyl group, at
1
.58 ppm. Resonances for succinyl CH groups had chemical shifts of 2.59–2.68 ppm and 2.87–2.92 ppm; of diethanolamine
2
CH groups, 3.04–3.08 ppm and 3.74–3.78 ppm.
2
13C NMR spectra showed resonances (ppm) for carbonyl and two carboxylate C atoms at 174.06–181.36; six aromatic
C atoms at 119.25–151.67; tertiary C-2 at 80.13; three trolox phenol methyl C atoms at 12.19–13.15; and ethanolamine
resonances at 50.47 and 57.92. The carboxylate C atoms (179.62 and 181.36) underwent weak-field shifts of 3.90 and
4
.34 ppm relative to those of the carboxylic acids of trolox succinate (2) (175.72 and 177.02). This was characteristic of
carboxylic acid C atoms after salt formation [10]. Thus, the obtained spectral data confirmed the structures 3a and 3b.
Alcohol 4 was obtained via reduction of the trolox carboxylic acid by LiAlH in THF as before [11]. Reaction of it
4
with succinic anhydride in a 1:2.5 ratio in CH Cl in the presence of Et N and DMAP produced the disuccinate derivative of
2
2
3
2
-hydroxymethyl trolox (5), treatment of which with amines a and b in THF in a 1:2 ratio at 20–25°C synthesized ammonium
salts 6a and 6b (Scheme 2).
O
HO
O
HO
O
O
HO
OH
OH
OH
O
O
O
1
O
O
5
O
4
O
+
_
O
5
4
RNH
+
3
O
O
_
O
+
4a
8a
3
NH
3
R
R
2
R
1
NH
2
7
O
O
+
O
2
NH R R
8
2
1
2
O
6
a, b
Scheme 2
–
1
The IR spectrum of 5 showed characteristic carboxylic C=O stretching bands at 1713 cm and ester C=O stretching
bands at 1730 and 1747 cm . The PMR spectrum of 5 contained resonances for the phenol methyls with chemical shifts
–
1
(
4
ppm) at 1.94–2.04; 2-CH methyl at 1.25; succinyl CH groups at 2.57–2.68, 2.77–2.80, and 2.88–2.91; and 2-CH at
.14–4.23. The C NMR spectrum of 5 exhibited characteristic resonances (ppm) for two carbonyl and two carboxylic
3
2
2
1
3
C atoms at 173.24–175.91, six aromatic C atoms at 118.64–149.23, C-2 at 75.17, and phenol methyls at 11.89–13.05.
–
1
IR spectra of conjugates 6a and 6b retained ester C=O stretching bands at 1738 and 1740 cm . The band at
1
713 cm–1 for carboxylic C=O stretching vibrations of 5 disappeared. Instead of it, bands of asymmetric and symmetric
–1
carboxylate stretching appeared at 1619–1637 and 1396–1412 cm , respectively, in addition to bending vibrational bands
(
ꢂN–H) of the quaternary N atom at 1570–1572 cm–1 [8]. This argued in favor of ionic structures 6a and 6b. The HFC
1
3
constant in the EPR spectrum of spin-labeled conjugate 6a was 16.0 G, like in conjugate 3a. PMR and C NMR spectra of
salt 6b showed all characteristic resonances for succinyl, trolox, and diethanolamine.
1
016

The PMR spectrum had the trolox phenol methyl resonances at 1.98–2.07 ppm; 2-Me of the pyran ring, at 1.30;
succinyl CH fragments, at 2.46–2.88; diethanolamine CH groups, at 3.09–3.14 and 3.76–3.82; and 2-CH , at 4.07–4.18.
2
2
2
1
3
The C NMR spectrum showed resonances for two carbonyl and two carboxylate C atoms at 173.89–179.41 ppm;
six aromatic C atoms at 118.67–149.90; tertiary C-2 at 75.19; three trolox phenol methyls at 11.90–13.13; and diethanolamine,
at 50.49 and 57.98. The resonances for the carboxylate C atoms (179.26 and 179.41 ppm) underwent weak-field shifts of 3.50
and 3.51 ppm relative to the carboxylic C atoms of 2-hydroxymethyl trolox disuccinate 5 (175.75 and 175.91 ppm). This was
characteristic of carboxylic acid C atoms after forming salts [10]. Thus, the spectral results confirmed the structures 6a and 6b.
Conjugates 9a and 9b were prepared by adding solutions of amines a and b to a solution of ꢀ-tocopherol succinate 8
in THF in a 1:1 ratio at 20–25°C (Scheme 3).
O
O
+
RNH
+
_
O
4
5
HO
O
O
3
3
HO
4
a
7
8a
3
O
R R
2 1
NH
2
O
3
2
O
O
8
7
8
9a, b
Scheme 3
IR spectra of salts 9a and 9b retained ester C=O stretching bands at 1749 and 1751 cm . Carboxylic C=O stretching
–
1
–
1
band of ꢀ-tocopherol succinate at 1715 cm disappeared. Instead of it, bands of asymmetric and symmetric carboxylate-
–1
anion stretching vibrations appeared at 1620–1631 and 1412 cm , respectively, in addition to quaternary N bending vibrations
–
1
(
ꢂN–H) at 1568–1570 cm [8]. This argued in favor of ionic structures 9a and 9b. The HFC constant in the EPR spectrum of
1
3
spin-labeled conjugate 9a was 16.1 G, like for conjugates 3a and 6a. PMR and C NMR spectra of 9b showed all characteristic
resonances for succinyl, ꢀ-tocopherol, and diethanolamine.
The PMR spectrum had ꢀ-tocopherol phenol methyl resonances at 1.89–2.00 ppm; ꢀ-tocopherol side-chain alkyl
methyls, 0.80–0.85; pyran 2-Me, 1.19; succinyl CH groups, 2.51–2.57 and 2.77–2.82; and diethanolamine CH groups as
2
2
two triplets at 2.72 and 3.51 with J = 5.5 Hz.
The 13C NMR spectrum exhibited resonances for carbonyl and carboxylate C atoms at 171.81 and 175.97 ppm,
respectively; six aromatic C atoms at 117.13–148.97; tertiary C-2 at 74.75; and three ꢀ-tocopherol phenol methyls at
11.18–12.25. The carboxylate C atom resonance (175.97) was observed in the spectrum with the same characteristic weak-
field shift by 1.86 ppm relative to that of ꢀ-tocopherol carboxylic acid (174.11) [10]. Thus, the spectral results confirmed the
structures 9a and 9b.
Water solubilities of 1, 3a, 3b, 6a, 6b, 9a, and 9b were determined by the literature method [12]. The water solubilities
of trolox succinate salts 3a (1.1 g/L) and 3b (26 g/L) increased by 10–260 times whereas those of 2-hydroxymethyl trolox
disuccinate salts 6a (0.8 g/L) and 6b (9 g/L) rose by 8–90 times compared with trolox (0.1 g/L). The solubilities of salts 3b and
6
b were 24 and 11 times greater than those of salts 3a and 6a because diethanolamine is infinitely soluble in H O. However,
2
the solubilities of salts 9a and 9b were the same as that of ꢀ-tocopherol (<0.1 g/L). This may have been related to the high
lipophilicity of the ꢀ-tocopherol 2-alkyl group. According to pharmacopoeial classification, ꢀ-tocopherol and salts 9a and 9b
were insoluble in H O.
2
Thus, new ionic conjugates of trolox succinates that were much more soluble in H O than starting trolox were
2
prepared. However, formation of the ammonium salts of ꢀ-tocopherol succinate did not increase their solubilities compared
with starting ꢀ-tocopherol.
EXPERIMENTAL
NMR spectra of CD OD, DMSO-d , and CDCl solutions of 3a, 3b, 6a, 6b, 9a, and 9b were recorded on Bruker
3
6
3
AV-300, AV-400, and DRX-500 spectrometers. IR spectra were recorded from KBr pellets on a Vector-22 instrument. Elemental
CHN-analyses were performed on a EURO EA 3000 Elemental Analyzer. Melting points were measured on a Mettler Toledo
FP90 Central Processor apparatus. Trolox (Acros Organics), D,L-ꢀ-tocopherol (Alfa Aesar), and succinic anhydride (Aldrich)
were purchased. The radical 4-amino-TEMPO (a) was synthesized at the Chemical Pilot Facility, NIOCh, SB, RAS. Trolox
succinate (2) and ꢀ-tocopherol succinate (8) were prepared by reacting trolox and ꢀ-tocopherol with succinic anhydride in
CH Cl in the presence of Et N and DMAP by the literature method [7]. Their spectral characteristics agreed fully with those
2
2
3
in the literature. 2-Hydroxymethyl trolox 4 was prepared by reducing trolox (1) with LiAlH in THF as before [11]. Its
4
spectral characteristics agreed fully with those in the literature.
1
017

General Method for Preparing Ammonium Salts 3a, 3b, 6a, 6b, 9a, 9b. Trolox 2-hydroxymethyl mono- or
disuccinate or ꢀ-tocopherol succinate (17.5–26.5 mg, ~0.05 mmol) in THF (EtOAc) (0.5 mL) was treated with a solution of
the appropriate amine a or b (~0.1 mmol for 2 and 5; 0.05 mmol for 8) in THF (EtOAc) (0.3 mL). The mixtures were
evaporated after 16–20 h. The viscous residue was triturated with Et O to form a powder or viscous liquid that was filtered
2
off, rinsed with EtOAc, and dried to constant weight.
1
-Oxyl-2,2,6,6-tetramethylpiperidine-4-ammonium 6-(3-Carboxylatopropanoyloxy)-2,5,7,8-tetramethyl-
–1
chromane-2-carboxylate (3a). Orange powder, yield 34.3 mg (99%), mp 95.4°C (dec.). C H N O . IR spectrum (ꢃ, cm ):
396 and 1641 (COO ), 1556 (ꢂN–H), 1738 (ester COO). EPR spectrum: a = 16.0 G.
36 60 4 9
–
1
N
bis(2-Hydroxyethyl)ammonium 6-(3-Carboxylatopropanoyloxy)-2,5,7,8-tetramethylchromane-2-carboxylate
–
1
–
(
1
3b). Viscous white liquid, yield 26.6 mg (95%). C H N O . IR spectrum (ꢃ, cm ): 1400 and 1620 (COÎ ), 1574 (ꢂN–H),
24 44 2 11
1
745 (ester COO). Í NMR spectrum (400 MHz, CD OD, ꢂ, ppm): 1.58 (3Í, s, ÑÍ -2), 1.96 (3Í, s), 2.03 (3Í, s), 2.19 (3Í, s)
3 3
–
ÑÍ -5, 7, 8, 1.71–1.79 (1Í, m, H-3), 2.43–2.52 (1Í, m, Í-3), 2.59–2.68 (4Í, m) and 2.87–2.92 (2Í, m) – Í-4 and
3
1
3
succinyl CH ; 3.04–3.08 (8Í, m), 3.74–3.78 (8Í, m) – diethanolamine CH . C NMR spectrum (75 MHz, CD OD, ꢂ, ppm):
2
2
3
1
2.19, 12.24, 13.15 (ÑÍ -5, 7, 8), 22.49, 26.02, 32.01, 31.21, 32.77 (Ñ-3, 4, ÑÍ -2, succinyl CH ), 50.47, 57.92 (diethanolamine
3
3
2
CH ); 80.13 (Ñ-2), 119.25, 123.70, 126.12, 127.75 (Ñ-5, 7, 8, 4à); 141.98, 151.67 (Ñ-6, 8à); 174.06 – carbonyl C atom;
2
1
79.62, 181.36 – carboxylate C atoms.
-{[6-(3-Carboxylatopropanoyloxy)-2,5,7,8-tetramethylchroman-2-yl]methoxy}-4-oxobutanoicAcid (5). Alcohol
(54 mg, 0.23 mmol), succinic anhydride (68 mg, 0.68 mmol), DMAP (13 mg, 0.1 mmol), and Et N (32 ꢄL) in CH Cl (1 mL)
4
4
3
2
2
was stirred for 20–24 h at room temperature, washed with HCl solution (5%), dried over MgSO , and evaporated. Viscous
4
+
light-brown liquid, yield 76.8 mg (77%). Mass spectrum: found m/z 459.159 [M + Na] . C H O Na, calcd m/z: 459.163
2
2 28 9
+
–1
1
[
M + Na] . IR spectrum (ꢃ, cm ): 1713 (COÎH), 1730 and 1747 (ester COO). Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm)
3
1
.25 (3Í, s, ÑÍ -2), 1.94, 1.98, 2.04 (each 3Í, s, ÑÍ -5, 7, 8), 1.71–1.79 (2Í, m, Í-3), 2.57–2.68 (6Í, m) – succinyl CH , 2.77–
3 3 2
13
2.80 (2Í, m, Í-4) and 2.88–2.91 (2Í, m) – succinyl CH , 4.14–4.23 (2Í, m, ÑÍ -2). C NMR spectrum (100 MHz, CD OD,
2
2
3
ꢂ, ppm): 11.89, 12.17, 13.05 (ÑÍ -5, 7, 8), 20.98, 22.22, 29.41, 29.70, 29.74, 29.76, 30.05 (Ñ-3, 4, ÑÍ -2, succinyl CH ),
3
3
2
6
9.63 (ÑÍ -2), 75.17 (Ñ-2), 118.64, 124.00, 126.46, 128.25 (Ñ-5, 7, 8, 4à), 142.34, 149.93 (Ñ-6, 8à), 173.24, 173.87 – carbonyl
2
C atoms, 175.75, 175.91 – carboxylate C atoms.
-Oxyl-2,2,6,6-tetramethylpiperidine-4-ammonium 4-{[6-(3-Carboxylatopropanoyloxy)-2,5,7,8-
tetramethylchroman-2-yl]methoxy}-4-oxobutanoate (6a). Orange powder, yield 35.8 mg (92%), mp 106.6–108.4°C.
1
–1
–
C H N O . IR spectrum (ꢃ, cm ): 1396 and 1637 (COÎ ), 1572 (ꢂN–H), 1740 (ester COO). EPR spectrum: à = 16.0 G.
40
66
4
11
N
bis(2-Hydroxyethyl)ammonium 4-{[6-(3-Carboxylatopropanoyloxy)-2,5,7,8-tetramethylchroman-2-
–
1
yl]methoxy}-4-oxobutanoate (6b). Viscous white liquid, yield 30.1 mg (93%). C H N O . IR spectrum (ꢃ, cm ): 1412
3
0 50 2 13
–
1
and 1619 (COÎ ), 1570 (ꢂN–H), 1738 (ester COO). Í NMR spectrum (500 MHz, CD OD, ꢂ, ppm, J/Hz): 1.30 (3Í, s,
3
ÑÍ -2), 1.98, 2.00, 2.07 (each 3Í, s, ÑÍ -5, 7, 8), 1.78–1.89 (1Í, m, ÑÍ -3), 2.46–2.53 (3Í, m), 2.60 (4Í, t, J = 6.5), 2.66
3
3
2
(
2Í, t, J = 6.8), 2.88 (2Í, t, J = 6.9) – Í-3, Í-4 and succinyl CH , 3.09–3.14 (8Í, m), 3.76–3.82 (8Í, m) – diethanolamine
2
1
3
CH , 4.07–4.18 (2Í, m, ÑÍ -2). C NMR spectrum (125 MHz, CD OD, ꢂ, ppm): 11.90, 12.25, 13.13 (ÑÍ -5, 7, 8), 20.99,
2
2
3
3
2
2.30, 29.46, 31.20, 31.41, 32.60 (Ñ-3, 4, ÑÍ -2, succinyl CH ), 50.49, 57.98 (diethanolamine CH ), 69.39 (ÑÍ -2), 75.19
3 2 2 2
(
1
Ñ-2), 118.67, 123.91, 126.52, 128.26 (Ñ-5, 7, 8, 4à), 142.43, 149.90 (Ñ-6, 8à), 173.89, 174.67 – carbonyl C atoms, 179.26,
79.41 – carboxylate C atoms.
-Oxyl-2,2,6,6-tetramethylpiperidine-4-ammonium 4-Oxo-4-[2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)
1
–
1
chroman-6-yloxy]butanoate (9a). Viscous orange liquid, yield 32.6 mg (93%). C H N O . IR spectrum (ꢃ, cm ): 1412
and 1631 (COÎ ), 1568 (ꢂN–H), 1749 (ester COO). EPR spectrum: à = 16.1 G.
4
2 73 2 6
–
N
(
2-Hydroxyethyl)ammonium 4-Oxo-4-[2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-
–1
yloxy]butanoate (9b). Viscous yellow liquid, yield 31.2 mg (98%). C H NO . IR spectrum (ꢃ, cm ): 1412 and 1620
COÎ ), 1570 (ꢂN–H), 1751 (ester COO). Í NMR spectrum (400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 0.80–0.85 (12H, m) – alkyl
3
7
65
7
–
1
(
6
side-chain methyls, 0.99–1.57 (21Í, m) – alkyl side-chain methylenes and methines, 1.19 (3Í, s, ÑÍ -2), 1.89 (3Í, s), 1.91
3
(
3Í, s), 2.00 (3Í, s) – ÑÍ -5, 7, 8, 1.70–1.79 (2Í, m, Í-3), 2.51–2.57 (4Í, m), 2.77–2.82 (2Í, m) – Í-4 and succinyl CH
3
2
1
3
2
1
3
1
.72 (4Í, t, J = 5.5), 3.51 (4Í, t, J = 5.5) – diethanolamine CH2. C NMR spectrum (75 MHz, CDCl , ꢂ, ppm): 11.18, 11.40,
2.25 (ÑÍ -5, 7, 8), 19.01–19.22, 20.15, 20.59, 22.01, 22.10, 23.97, 24.37, 27.54, 29.40, 29.73, 30.71, 32.18–32.41,
6.79–37.20 (Ñ-3, 4, ÑÍ -2, succinyl CH and alkyl side-chain C atoms), 38.95, 56.70 (diethanolamine CH ), 74.75 (Ñ-2),
17.13, 122.57, 124.62, 126.31 (Ñ-5, 7, 8, 4à), 140.14, 148.97 (Ñ-6, 8à), 171.81 – carbonyl C atom, 175.97 – carboxylate C atom.
3
3
3
2
2
1
018

The solubilities of 1, 3a, 3b, 6a, 6b, 9a, and 9b were determined as usual [12]. Weighed portions of 1, 3a, 3b, 6a, 6b,
a, and 9b (0.5–10 mg) were treated with distilled H O (0.1 mL) and shaken for 10 min. The addition of H O was repeated
9
2
2
until the compound dissolved completely or a solubility of <0.1 g/L was reached.
ACKNOWLEDGMENT
The work was sponsored by RFBR Grant No. 16-34-00465.
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49, 4684 (2006).
1
RF State Pharmacopoeia, XIIth Ed., Moscow, 2007, p. 92.
1
019