Use of the mannich reaction to synthesize spin-labeled derivatives of the natural flavonoid dihydroquercetin

Article abstract of DOI:10.1007/s10600-014-0927-7

Mono-substituted spin-labeled compounds were synthesized from Mannich reactions of dihydroquercetin with 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, 3-amino-2,2,5,5-tetramethylpyrrolidine-1-oxyl, and 3-aminomethyl-2,2,5,5- tetramethylpyrrolidine-1-oxyl.

Full text of DOI:10.1007/s10600-014-0927-7

Chemistry of Natural Compounds, Vol. 50, No. 2, May, 2014 [Russian original No. 2, March–April, 2014]
USE OF THE MANNICH REACTION TO SYNTHESIZE SPIN-LABELED
DERIVATIVES OF THE NATURAL FLAVONOID DIHYDROQUERCETIN
*
N. V. Kosheleva, E. I. Chernyak, Yu. F. Polienko,
S. V. Morozov, and I. A. Grigorꢀev
Mono-substituted spin-labeled compounds were synthesized from Mannich reactions of dihydroquercetin
with 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, 3-amino-2,2,5,5-tetramethylpyrrolidine-1-oxyl, and
3-aminomethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl. According to preliminary data, the compounds
possessed antioxidant activity and selective cytotoxicity against various tumor cells and were promising for
biomedical tests including magnetic resonance tomography.
Keywords: dihydroquercetin, nitroxyl radicals, spin-labeled compounds, Mannich reaction.
Flavonoids represent a large group of natural biologically active compounds [1], chemical modification of which in
order to prepare new pharmacologically active compounds is a critical problem for organic and medicinal chemistry. It is well
known that introducing modifiers into biologically active compounds can cause new properties to appear and existing ones to
intensify [2, 3]. Methods for preparing acylated, methoxylated, brominated, and alkylphosphonate flavonoid derivatives [4,
5] and for transforming the flavonoid pyran ring [6] were reported. Several aminomethyl flavonoid derivatives were obtained
via a Mannich reaction with primary and secondary amines [7–10].
A promising pathway for modifying biologically active compounds is the introduction of nitroxyl radicals that produces
new spin-labeled hybrid polyfunctional compounds with enhanced and/or modified biological activity and decreased general
and elevated selective toxicity [11–13]. A known example is the introduction of an aminonitroxyl moiety into the natural
isoflavone rotenone in order to produce a series of paramagnetic derivatives that exhibited anticancer activity [14].
We used the natural flavonoid dihydroquercetin (DQ) isolated from Larix sibirica wood as starting material. It
possesses powerful antioxidant, hepatoprotective, anti-inflammatory, and antihistamine properties [15]. DQ is known to bind
toxins and free radicals, normalize cell-membrane structures and functions [16], and inhibit the development of tumor cells
without suppressing the division of healthy cells [17]. The broad spectrum of biological activity and low toxicity of DQ [15]
allow it to be considered a lead compound for structural modification in order to synthesize new hybrid polyfunctional
pharmacologically active compounds.
5'
OH
OH
OH
B
1
8
7
HO
O
HO
RHN
O
1'
3' OH
8a
4a
NH R
A
C
2
3
OH
OH
H CO
2
O5H O4
9
OH
O
1
2 - 4
R =
N
O
N
O
N
O
2
3
4
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, RussianAcademy of Sciences, 630090,
Novosibirsk, Prosp. Akad. Lavrentꢀeva, 9, fax: +7 (383) 330 97 52, e-mail: kosheleva@nioch.nsc.ru. Translated from Khimiya
Prirodnykh Soedinenii, No. 2, March–April, 2014, pp. 231–235. Original article submitted September 16, 2013.
©
0009-3130/14/5002-0261 2014 Springer Science+Business Media New York
261

Mannich aminomethylation of DQ and its close structural analogs with an equimolar ratio of reagents is known to
afford 6-mono-substituted derivatives; with a two-fold excess of amine and formaldehyde, 6- and 8-di-substituted derivatives.
Spin-labeled 6-mono-substituted derivatives 2–4 were prepared via a Mannich reaction in the presence of formalin of equimolar
amounts of DQ (1) and 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO); 3-amino-2,2,5,5-
tetramethylpyrrolidine-1-oxyl (3-amino-PROXYL); and 3-aminomethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (3-aminomethyl-
PROXYL) [7–10].
The hyperfine coupling (HFC) constants a in EPR spectra of 2–4 were 16.1, 15.1, and 15.2 G. This corresponded
N
exactly to the HFC constants for piperidine- and pyrrolidine-type radicals [18–20]. The position of the absorption maximum
–1
in UV spectra of 2–4 agreed with that for DQ and was 290 1 nm. IR spectra retained the band at 1643 cm that was
characteristic of the DQ C=O group [21]. This indicated that the flavonoid backbone was preserved. HPLC/MS in positive-
ion mode gave m/z 488.213, 474.200, and 488.218 for the molecular ions of the synthesized compounds corresponding to
proposed structures 2–4. It should be noted that 2–4 fragmented in the same manner that was characterized by cleavage of the
C(9)–N bond and detection of characteristic benzyl-type fragment ions with m/z 317.066. Thus, the spectral characteristics
obtained by UV and IR spectroscopy and mass spectrometry were consistent with proposed structures 2–4.
Spin-labeled 2 and 4 were reduced to the corresponding N-hydroxy derivatives 2a and 4a using HCl–EtOH [22] in
order to confirm the structures of the obtained DQ aminonitroxyl derivatives. Compound 3 could not be reduced in this
system. N-Hydroxy-derivative 3a was prepared via reduction of 3 by Zn in MeOH in the presence of NH Cl [18, 20].
4
OH
HO
O
O
OH
OH
H
OH
N
R
2a - 4a
10
3''
R =
5''
3''
1''
1''
N
5''
N
N
OH
2a
OH
3a
OH
4a
Resonances in NMR spectra of 2a–4a were assigned using spectral characteristics of DQ derivatives obtained via a
Mannich reaction with t-butylamine, cyclohexylamine, benzylamine, diethylamine, morpholine, and piperidine [7–10].
Resonances in PMR spectra of the DQ backbone and the C-9 position in 2a–4a were similar to those for the previously
prepared DQ aminomethyl derivatives [7–10]. Chemical shifts in PMR spectra of the hydroxypiperidine and hydroxypyrrolidine
moieties in 2a–4a were similar to the analogous resonances for derivatives of trolox [18], cytisine [19], and betulonic acid [20]
that contained these same moieties. Thus, piperidine methyl proton resonances for 2a were located at 1.3–1.5 ppm; methylene
multiplets, at 2.2–2.4 ppm. The methyl proton resonances in the pyrrolidine moieties of 3a and 4a appeared at 1.2–1.6 ppm;
methylene multiplets, 2.0–3.2 ppm. The methine proton multiplets for 3a and 4a were found at 4.0 and 2.5 ppm, respectively.
Spectra of 2a and 4a showed resonances for OH groups in the 5- and 7-positions of ring A and the 3ꢀ- and 4ꢀ-positions of ring
B with chemical shifts 12.6 and 11.5 and in the range 8.8–9.0 ppm, respectively. This agreed completely with the literature
3
data for DQ [23] and its 6-aminomethyl-substituted derivatives [7]. The resonance of the OH group on the sp -hydribized C
atom was not observed in spectra of 2a and 4a. According to the literature, this hydroxyl cannot always be detected for DQ
[24] and its derivatives [7, 8].
13
13
The C NMR spectra of 2a and 4a agreed fully with their structures. C NMR spectra of 2a and 4a had characteristic
DQ backbone resonances that were similar to those for the corresponding resonances of DQ aminomethyl derivatives [7–9].
Chemical shifts of piperidine and pyrrolidine resonances were similar to those of analogous resonances of hydroxypiperidine
and hydroxypyrrolidine derivatives of trolox, cytisine, and betulonic acid [18–20]. Compound 3a turned out to be extremely
13
unstable. Therefore, its C NMR spectrum could not be recorded.
262

Preliminary tests showed that synthesized compounds 2–4 exhibited greater antioxidant activity than starting DQ,
ꢁ
possessed selective cytotoxicity against various tumor cells, retained the spin label in vivo in test animals for >2 h, and was
non-toxic. These aspects will be discussed separately.
EXPERIMENTAL
IR spectra were recorded in KBr pellets on a Vector-22 instrument; UV spectra, during HPLC analyses. NMR spectra
were taken from DMSO-d , MeOD-d , and D O solutions on Bruker AV-400 spectrometers (operating frequencies
6
4
2
1
13
400.1 MHz for H and 100.8, for C). Solvent resonances of DMSO-d , MeOD-d , and D O were used as internal standards.
6
4
2
EPR spectra of paramagnetic samples were recorded on a Bruker ESP-300 radiospectrometer equipped with a double cavity.
The UHF-radiation power was 265 mW; modulation frequency, 100 Hz; modulation amplitude, 0.1 G (0.01 mT).
The course of reactions was monitored by TLC [Silufol UV-254 plates, CHCl –MeOH (3:1) or EtOAc–MeOH–H O
3
2
(100:17:13) eluent] and HPLC.
HPLC-UV analysis was carried out on an Agilent 1100 chromatograph with a CCD detector using a Zorbax XDB-C8
column (4.6 ꢂ 150 mm), mobile phase MeOH–CF COOH (0.1%) gradient from 10 to 90% MeOH over 30 min. HPLC-MS
3
analysis used anAgilent 1200 liquid chromatograph with a micrOTOF-Q hybrid quadrupole-TOF mass spectrometer (Bruker),
a Zorbax XDB-C8 column (2.1 ꢂ 50 mm), and mobile phase MeOH–HCOOH (2%) gradient from 20 to 100% MeOH over
20 min. Masses were detected using atmospheric pressure ionization and electrospray drying (API-ES). Negative and positive
ions were scanned in the range m/z 100–1200 with N drying gas.
2
Radicals 4-amino-TEMPO, 3-amino-PROXYL, and 3-aminomethyl-PROXYL were synthesized at the Pilot Chemical
Plant, NIOC, SB, RAS. DQ (96–97% pure) was purchased (Sibirskii Kedr Co.).
General Method for Preparing Spin-labeled DQ Derivatives (2–4) [7–9]. A solution of DQ (1, 200 mg,
–4
6.6 ꢂ 10 mol) in i-PrOH–C H (2.5 mL, 1:1, v/v) was treated dropwise over 1 min with solutions of the radicals (4-amino-
6
6
–4
TEMPO, 3-amino-PROXYL, 3-aminomethyl-PROXYL, 6.6 ꢂꢃ10 mol) in i-PrOH–C H (2.5 mL), stirred at ~20°C for 1.5 h,
6
6
–3
treated dropwise over 1–1.5 min with stirring at 20–22°C with a solution of formalin (26%, 0.2 mL, 1.6 ꢂꢃ10 mol), stirred for
1–1.5 h (TLC monitoring), evaporated in a rotary evaporator at ~40°C, and held in vacuo (2–3 mm Hg) for 1–2 h until the
weight was constant. Compounds 2 and 4 were obtained after multiple work ups with CH Cl –Et O (5:1); compound 3,
2
2
2
CH Cl .
2
2
2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-6-[(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)aminomethyl]chroman-
+
4-one (2). Amorphous orange powder, yield 83%. Mass spectrum: found m/z 488.213 [Ì + H] , calcd for C H N O ,
488.215 [Ì + H] . R 0.48 (EtOAc–MeOH–H O 100:17:13). HPLC: retention time 4.2 min. UV spectrum (ÌåÎÍ, ꢄ , nm)
(log ꢅ): 290 (3.93). HFCC, ꢆ (G) 16.1. IR spectrum (KBr, , ñm ): 3420, 2972, 2930, 2856, 1643, 1581, 1522, 1450, 1366,
25 32
2 8
+
f
2
max
–1
N
1279, 1244, 1205, 1163, 1115, 980, 866, 815, 775.
2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-6-[(1-oxyl-2,2,5,5-tetramethylpyrrolidin-3-yl)aminomethyl]chroman-
+
4-one (3). Amorphous yellow powder, yield 88%. Mass spectrum: found m/z 474.200 [Ì + H] , calcd for C H N O ,
24 30
2 8
+
474.210 [Ì + H] . R 0.48 (CHCl –MeOH 3:1). HPLC: retention time 13.2 min. UV spectrum (ÌåÎÍ, ꢄ , nm) (log ꢅ): 290
(4.24). HFCC, ꢆ (G) 15.1. IR spectrum (KBr, , cm ): 3422, 2976, 2934, 1643, 1580, 1522, 1450, 1368, 1279, 1205, 1161,
f
3
max
–1
N
1161, 1115, 1096, 980, 868, 812, 775.
2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-6-[(1-oxyl-2,2,5,5-tetramethylpyrrolidin-3-
ylmethyl)aminomethyl]chroman-4-one (4). Amorphous yellow powder, yield 86%. Mass spectrum: found m/z 488.218
+
+
[Ì + H] , calcd for C H N O , 488.215 [Ì + H] . R 0.52 (CHCl –MeOH 3:1). HPLC: retention time 13.4 min.
25 32
2
8
f
3
–1
UV spectrum (ÌåÎÍ, ꢄ , nm) (log ꢅ): 290 (4.00). HFCC, ꢆ (G) 15.2. IR spectrum (KBr, , cm ): 3418, 2972, 2928, 3855,
max
N
1643, 1580, 1522, 1452, 1366, 1281, 1205, 1157, 1111, 980, 872, 816, 775.
2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-6-[(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-
–5
yl)aminomethyl]chroman-4-one (2a) [22]. Compound 2 (13 mg, 2.7 ꢂꢃ10 mol) was dissolved in EtOH (1.3 mL), saturated
with HCl (pH 2), stirred for 20 min at 25°C, evaporated in a rotary evaporator at 40–45°C, dried in vacuo to constant weight,
and dissolved in DMSO-d (0.5 mL). PMR spectrum (400 MHz, DMSO-d , ꢇ, ppm, J/Hz): a) piperidine moiety (CH-4ꢈ
6
6
methine resonances were overlapped by the solvent resonance): 1.33 (6H, s) and 1.53 (6H, s), methyl resonances; 2.29 (2H, d,
J = 12.4) and 2.38 (2H, d, J = 12.4), methylene resonances (CH -3ꢈ, CH -5ꢈ); b) 4.03 (2H, br.m), methylene resonance
2
2
ꢁ
We thank Cand. Chem. Sci., Docent of NGPU, N. V. Kandalintseva and Dr. Biol. Sci., Prof. V. B. Loktev, GNTs of Virusology
and Biotechnology for preliminary data on the antioxidant and cytotoxic activity of 2–4
263

(CH -9); c) DQ moiety: 4.54 (1Í, d, J = 10.8, Í-2), 5.05 (1Í, d, J = 10.8, Í-3), 6.22 (1Í, s, Í-8), 6.75 (2Í, s, Í-5ꢀ, 6ꢀ), 6.89
2
13
(1Í, s, Í-2ꢀ), 8.97 (2Í, br.s) – (3ꢀ-OH, 4ꢀ-OH), 11.50 (1Í, br.s, 7-OH), 12.60 (1Í, s, 5-OH). C NMR spectrum (100 MHz,
DMSO-d , ꢇ, ppm): a) piperidine moiety (C-3ꢈ and C-5ꢈ CH resonances were overlapped by the solvent resonance): 19.80,
6
2
27.08, methyls; 47.72 (C-4ꢈ), 66.77 (C-2ꢈ, 6ꢈ); b) 56.00, methylene (C-9); c) DQ moiety: 71.38 (C-3), 83.12 (C-2),
3
sp -hydridized C atoms of ring C; 94.61 (Ñ-8), 98.84 (Ñ-4à), 100.02 (Ñ-6), 115.30 (Ñ-2ꢀ, 5ꢀ), 119.24 (Ñ-6ꢀ), 127.64 (Ñ-1ꢀ), 145.00
2
(Ñ-3ꢀ), 145.83 (Ñ-4ꢀ), 162.11 (Ñ-8à), 162.58 (Ñ-5), 165.72 (Ñ-7), 198.10 (Ñ-4) , sp -hybridized C atoms.
2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-6-[(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-
–5
yl)aminomethyl]chroman-4-one (3a) [18-20]. Reduction of 3. A solution of 3 (12.5 mg, 2.6 ꢂꢃ10 mol) in MeOH (0.9 mL)
was treated with activated Zn (76 mg) and NH Cl (7.6 mg) and stirred at ~25°C for 10 min. A voluminous precipitate formed
4
during the course of the reaction. It was separated from the solution and dried in vacuo to constant weight. The resulting solid
was treated with MeOD-d (0.5 mL). The solution was filtered under Ar into an ampul for recording NMR spectra.
4
PMR spectrum (400 MHz, MeOD-d , ꢇ, ppm, J/Hz): a) pyrrolidine moiety: 1.52 (3H, s), 1.59 (3H, s), 1.64 (3H, s), 1.65
4
(3H, s), methyl resonances; 2.32 (1H, m) and 2.87 (1H, m), CH –C4ꢈ methylene resonance; 3.99 (1H, t, J = 9.5), CH-3ꢈ
2
methine resonance; b) 4.35 (2H, m), CH -9 methylene resonance; c) DQ moiety: 4.62 (1Í, d, J = 11.5, ÑÍ-2), 5.02 (1Í, d,
2
J = 11.6, ÑÍ-3), 6.12 (1Í, s, ÑÍ-8), 6.86 (2Í, s, ÑÍ-5ꢀ, 6ꢀ), 6.09 (1Í, s, ÑÍ-2ꢀ).
2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-6-[(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-
–5
ylmethyl)aminomethyl]chroman-4-one (4a) [22]. Reduction of 4. Compound 4 (10 mg, 2.1 ꢂꢃ10 mol) was dissolved in
EtOH (1 mL), saturated with HCl (pH 2), stirred for 40 min at ~25°C, dried in vacuo to constant weight, and dissolved in
DMSO-d (0.5 mL). PMR spectrum (400 MHz, DMSO-d , ꢇ, ppm): a) pyrrolidine moiety: 1.12 (3H, s), 1.33 (3H, s), 1.49
6
6
(3H, s), 1.52 (3H, s), methyl resonances; 1.98 (1H, br.m), 2.33 (1H, br.m), 2.54 (1H, br.m), CH -4ꢈ and CH-3ꢈ methylene and
2
methine resonances; b) 2.92 (1H, m) and 3.15 (1H, m), CH -10 methylene resonance; c) 4.00 (2H, m), CH -9 methylene
2
2
resonance; d) DQ moiety: 4.54 (1Í, d, J = 10.9, ÑÍ-2), 5.04 (1Í, d, J = 10.9, ÑÍ-3), 6.19 (1Í, s, ÑÍ-8), 6.75 (2Í, s, ÑÍ-5ꢀ,
ÑÍ-6ꢀ), 6.89 (1Í, s, ÑÍ-2ꢀ), 8.85 (1Í, br.s), 8.89 (1Í, br.s) – (Ñ3ꢀ-OH, C4ꢀ-OH); 11.54 (1Í, br.s, C7-OH), 12.58 (1Í, s,
13
C5-OH). C NMR spectrum (100 MHz, D O, ꢇ, ppm): a) pyrrolidine moiety: 21.96, 22.92, 28.33, 29.68, methyl resonances;
2
41.67, 42.32 (C-4ꢈ, C-3ꢈ), 74.15, 76.39 (C-2ꢈ, C-5ꢈ); b) 48.34 and 59.63, C-10 and C-9 methylene; c) DQ moiety: 73.83
3
(C-3), 85.39 (C-2), sp -hybridized C atoms of ring C; 97.16 (Ñ-8), 100.45 (Ñ-4à), 102.83 (Ñ-6), 117.6, 118.44 (Ñ-2ꢀ, Ñ-5ꢀ),
123.03 (Ñ-6ꢀ), 130.12 (Ñ-1ꢀ), 146.42 (Ñ-3ꢀ), 147.47 (Ñ-4ꢀ), 163.96 (Ñ-8à), 165.38 (Ñ-5), 167.22 (Ñ-7), 199.51 (Ñ-4),
2
sp -hybridized C atoms.
ACKNOWLEDGMENT
The work was supported financially by RFBR Grant No. 12-03-00718a and the Moscow Administration Program
(Contract No. 16/12-Gen-M). Spectral characteristics of the synthesized compounds were obtained at the Chemical Service,
CCU, SB, RAS.
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