Novel potent inhibitors of lipid peroxidation with protective effects against reperfusion arrhythmias

Article abstract of DOI:10.1021/jm010962w

A series of new compounds that contain lipoic acid and trolox connected through spacers were synthesized and examined for their antioxidant activity and their protective effects against reperfusion arrhythmias in isolated heart preparations. All compounds

Full text of DOI:10.1021/jm010962w

4300
J . Med. Chem. 2001, 44, 4300-4303
Novel P oten t In h ibitor s of Lip id P er oxid a tion w ith P r otective Effects a ga in st
Rep er fu sion Ar r h yth m ia s
Maria Koufaki,*,† Theodora Calogeropoulou,† Anastasia Detsi,† Aristidis Roditis,† Angeliki P. Kourounakis,‡
Panagiota Papazafiri,§ Karyofyllis Tsiakitzis,‡ Catherine Gaitanaki,§ Isidoros Beis,§ and Panos N. Kourounakis‡
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vasileos Constantinou Avenue,
11635 Athens, Greece, Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki,
54006 Thessaloniki, Greece, and Department of Animal & Human Physiology, School of Biology, University of Athens,
Panepistimiopolis, 15784 Athens, Greece
Received J une 21, 2001
A series of new compounds that contain lipoic acid and trolox connected through spacers were
synthesized and examined for their antioxidant activity and their protective effects against
reperfusion arrhythmias in isolated heart preparations. All compounds tested are strong
inhibitors of lipid peroxidation in rat liver microsomal membranes induced by ferrous ions
and ascorbate. N-(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carbonyl)-N′-
(1,2-dithiolane-3-pentanoyl)-1,2-phenylenediamine (13) exhibits anti-lipid peroxidation activity
at the nanomolar range. N-(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-
carbonyl)-N′-(1,2-dithiolane-3-pentanoyl)ethylenediamine (10) and 13 totally suppressed rep-
erfusion arrhythmias.
In tr od u ction
mentation of tocopherol and R-lipoic acid decreased lipid
peroxidation during in vivo ischemia-reperfusion in
young adult rats. However, the combination did not
influence cardiac performance.8
Reactive oxygen species (ROS) are believed to be
involved in several pathological conditions. Endogenous
antioxidant defenses are inadequate in many of these
disorders. Oxidative damage and disease progression
may be retarded by administering natural antioxidants
(enzymes and vitamins) or synthetic agents.1
Tocopherol (vitamin E) is the most important and
widely studied natural, lipid-soluble, chain-breaking
antioxidant. Recent studies provide evidence of protec-
tive effects of vitamin E against atherosclerosis2 and
reperfusion injury.3
Lipoic acid is an antioxidant that is found endog-
enously as lipoamide in five proteins in eukaryotes
where it is covalently bound to a lysyl residue. Exog-
enously supplied lipoic acid is taken up readily by a
variety of cells and tissues where it is reduced rapidly
to dihydrolipoic acid (DHLA).4,5
On the basis of the promising synergistic results of
the combined use of lipoic acid and vitamin E in the
protection of the hypoxic reoxygenated heart,6-8 we set
out to synthesize hybrids of these two compounds and
to study their cardioprotective activity. We opted to use
trolox amides since this type of compounds exhibit
improved results in the ischemia-reperfusion model.9
The aim of this study is to probe the necessary struc-
tural requirements of the linkers for the best cardio-
protective results. The issue of stereochemistry is not
addressed in the new compounds since its does not seem
to influence the antioxidant activity either of trolox
amides10 or of lipoic acid.11
Ch em istr y
There is a growing interest in these natural antioxi-
dants as a protective strategy against myocardial is-
chemia-reperfusion damage. Thu¨rich et al.6 compared
the cardioprotective effects of DHLA and vitamin E
during the reoxygenation of hypoxic hearts. The results
showed that the mechanism of action of these two
antioxidants is different, and thus a combined treatment
of lipoic acid and tocopherol could result in improved
mitochondrial function. In other studies in which ro-
dents were fed a high vitamin E diet and DHLA was
added to the myocardial perfusion medium, it was
reported that the combination improved cardiac perfor-
mance and reduced myocardial lipid peroxidation.7
Recently, Coombes et al. showed that dietary supple-
The synthesis of the novel compounds is shown in
Schemes 1-3. The aminoamides 1 and 2 were synthe-
sized by heating trolox methyl ester with ethylenedi-
amine or hexamethylenediamine, respectively.12 Acti-
vation of trolox with 1,1′-carbonyldiimidazole (CDI) and
subsequent coupling to piperazine or aromatic diamines
afforded 3-8. N-(1,2-Dithiolane-3-pentanoyl)-1,2-phen-
ylenediamine (9) was prepared from lipoic acid and
o-phenylenediamine after activation with CDI. The
synthesis of the final diamides 10-17 involves the
reaction of the aminoamides 1-8 with lipoic acid
chloride in THF/H2O. Lipoic acid chloride was prepared
following the procedure described by Wagner et al.13
with minor modifications. Reduction of 10 and 13 using
NaBH4 gave the DHLA analogues 18 and 19, respec-
tively. Finally, the carbocyclic analogue of diamide 10,
compound 22, was synthesized via the corresponding
acid 21 as shown in Scheme 3.
* Corresponding author tel: +301 7273818; fax: +301 7273831;
e-mail: mkoufa@eie.gr.
† National Hellenic Research Foundation.
‡ Aristotelian University of Thessaloniki.
§ University of Athens.
10.1021/jm010962w CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/31/2001

Brief Articles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4301
Sch em e 1a
a
Reagents and conditions: (i) lipoic acid cloride, THF/H2O, room temperature.
Sch em e 2a
Ta ble 1. Inhibition of In Vitro Peroxidation (LP) of Rat
Hepatic Microsomal Membrane Lipidsa
compd
LP IC50 (µM)
DPPH IC50 (mM)
ClogP
lipoic
trolox
1
6
9
10
11
12
13
14
15
16
17
18
19
22
>1000
>0.4
0.045
0.057
0.034
>0.4
0.044
nd
0.050
0.053
nd
0.033
0.020
0.055
0.028
0.066
0.158
2.39
3.19
2.50
3.37
2.51
4.96
5.67
5.90
5.99
6.20
6.20
8.13
8.50
4.18
5.20
5.96
24.8 ( 1.0
2.49 ( 0.14
1.63 ( 0.32
61.0 ( 4.5
0.34 ( 0.05
1.04 ( 0.03
0.35 ( 0.05
0.06 ( 0.01
0.62 ( 0.05
0.53 ( 0.04
2.58 ( 0.49
1.22 ( 0.29
0.29 ( 0.10
0.69 ( 0.02
0.73 ( 0.05
a
Reagents and conditions: (i) NaBH4, MeOH, room tempera-
ture.
Sch em e 3a
a
Results are expressed as mean ( SEM, n ) 3. Interaction of
compounds with 0.2 mM of the stable free radical DPPH. nd, not
determined. Calculated lipophilicity of compounds is expressed as
ClogP values.
a
Reagents and conditions: (i) KNSi2(CH3)6, THF, room tem-
perature; (ii) H2, 10% Pd/C, 10 psi, (iii) CDI, THF, 1.
aminoamides 1 and 6 also exhibit better antioxidant
activity on lipid peroxidation than trolox, as expected.
However, the final trolox-lipoic acid diamides 10 and
15 are stronger inhibitors than the corresponding
intermediate aminoamides. It seems that the presence
of lipoic acid results in increased activity, which is
dependent on the nature of the spacer (IC50 ranged from
0.06 to 2.58 µM). Despite the fact that lipoic acid is
inactive on iron-induced lipid peroxidation, its amino-
amide analogue 9, bearing 1,2-phenylenediamine, was
found to be a weak inhibitor (IC50 ) 61 µM).
Diamide 18, which is the DHLA analogue of 10, has
similar activity in the lipid peroxidation bioassay (IC50
) 0.29 µM vs 0.34 µM) while the DHLA analogue of 13
is less active (IC50 ) 0.70 µM vs 0.06 µM). On the basis
of these data and the fact that the DHLA analogues are
less stable, there does not seem to be an obvious
advantage in using the reduced analogues as potential
therapeutic agents, at least for this class of compounds.
Although in many cases there is a correlation between
antioxidant activity and lipophilicity, this is not ap-
plicable for these compounds. However, we can deduce
an optimum ClogP range of 4.18-6.20 for these series
Resu lts a n d Discu ssion
The interaction of the new compounds at 30 min with
0.2 mM stable free radical DPPH expressed as IC50
values is shown in Table 1. All the analogues tested
possess similar IC50 values ranging from 0.02 to 0.07
mM. Lipoic acid and the aminoamide 9 are inactive
while diamide 22, which does not contain lipoic acid,
exhibits an IC50 of 0.158 mM.
The activity of the new analogues on the in vitro
peroxidation of rat hepatic microsomal membrane lipids
is expressed as the concentration of compound that
inhibited lipid peroxidation by 50% after 45 min of
incubation (IC50 values) and is shown in Table 1. All
compounds tested exhibited very potent antioxidant
activities. The most active of the series is the o-
phenylenediamine-substituted analogue 13 with 400-
fold higher antioxidant activity as compared to trolox.
The activity of all other compounds tested was 10-125-
fold higher than that of trolox.
Amide or amine analogues of trolox have been re-
ported to inhibit microsomal lipid peroxidation with IC50
values ranging from 1 to 10 µM.10,14 Our intermediate

4302 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Brief Articles
Ta ble 2. Effects of Selected Compounds on In Vitro
Myocardial Electrical Activity and Accumulation of MDA
Derivatives
fusion arrhythmias, 22 induced a decrease of arrhyth-
mias (6.98 ( 3.12, p < 0.001 as compared to the control),
and the arrhythmias observed were due to both prema-
ture beats and nonsustained ventricular fibrillations.
The lack of correlation between the protective effects
of the new compounds against myocardial lipid peroxi-
dation and suppression of the arrhythmias has been
previously observed.15 Concerning our compounds, the
observed cardioprotective activity is probably due in
part to their antioxidant potency. In addition, we
measure total MDA production, and we cannot distin-
guish between local MDA production differences.
In conclusion, we have synthesized new trolox-lipoic
acid hybrids that possess potent anti-lipid peroxidation
activity on rat liver microsomal membranes and exhibit
protective effects against reperfusion damage on isolated
heart preparations. The IC50 values against microsomal
lipid peroxidation ranged from 0.06 to 2.58 µM. All the
compounds tested were equipotent in reducing total
MDA production during reoxygenation of the heart
tissue. Trolox amides 6 and 22, even though they
possessed good antioxidant activity, did not reduce
reperfusion arrhythmias effectively. Trolox-lipoic acid
hybrids 10 and 13 that were very potent antioxidants
in microsomal lipid peroxidation totally suppressed
arrhythmias during reoxygenation. Since the ischemia-
reperfusion injury is of multifactorial nature, identifica-
tion of specific events contributing to myocardial dam-
age in relation to the class of compounds described
herein is necessary for the design of more effective
cardioprotective agents.
compd (5 µM)
arrhythmia score
MDA
none
lipoic acid
15 ( 3.4
6.3 ( 2.1a
3.15 ( 1.7a
0
16 ( 4.1
0
10.25 ( 2.34
10.98 ( 4.1
6.98 ( 3.12a
2.11 ( 0.3
1.03 ( 0.02b
1.07 ( 0.05b
1.10 ( 0.1b
1.19 ( 0.09b
0.99 ( 0.06b
1.13 ( 0.08b
1.27 ( 0.06c
trolox
10
12
13
9
6
22
c
1.41 ( 0.15
a
b
p < 0.001 vs control. p < 0.001 vs control. c p < 0.05 vs
control; n ) 2-4.
of compounds for improved antioxidant capacity. Higher
or lower values result in decreased activity as shown
in Table 1.
The most active of the final diamides (10, 12, and 13)
as well as the intermediate aminoamide analogue of
trolox 6 and the aminoamide analogue of lipoic acid 9
were evaluated for their antiarrhythmic and antioxidant
activity on isolated heart preparations using the Krebs
perfused Langerdorff model (Table 2). The tissue MDA
levels reflect the antioxidant capacity of the analogues
under study. As shown in Table 2, the MDA content in
hearts perfused in the absence of test compounds is 2.11
( 0.3 µmol/g of tissue. All the compounds tested induced
a statistically significant decrease of MDA content (p
< 0.001 or 0.05) approximately to the same extent,
including trolox and lipoic acid.
Arrhythmia scores were calculated for the first 15 min
of reperfusion. The arrhythmic score of controls was 15
( 3.4 and was mainly due to premature beats and
nonsustained ventricular fibrillation. The experiments
were performed using a 5 µM concentration for each
compound. Both lipoic acid and trolox reduced the
arrhythmias induced by reoxygenation during reperfu-
sion (6.3 ( 2.1 and 3.15 ( 1.7, respectively; p < 0.001).
The arrhythmias observed in the presence of these
compounds were due to premature beats and were not
accompanied by ventricular fibrillations. It should be
noted, however, that bradycardia was observed in the
presence of both compounds. In hearts treated with the
test compounds, a total suppression of arrhythmias was
observed in the presence of 10 and 13, whereas 12, 9,
and 6 did not reduce the arrhythmia score. 10, 12, and
13 are trolox-lipoic acid hybrids and exhibit similar
microsomal and myocardial anti-lipid peroxidation ac-
tivity and lipophilicity. The striking difference in anti-
arrhythmic activity of these compounds could be attrib-
uted to the presence of the secondary diamine in
analogue 12 whereas 10 and 13 are primary amine
analogues. However, further investigations are required
to clarify this point.
To evaluate the influence of lipoic acid on the anti-
arrhythmic activity of the new compounds, we synthe-
sized 22 in which the dithiolane ring is replaced by a
cyclopentane ring. The carbocyclic analogue 22 was
slightly less potent than the corresponding lipoic acid
analogue 10 in inhibiting in vitro microsomal lipid
peroxidation (IC50 ) 0.73 µM vs 0.34 µM, p < 0.005)
and reacts less with the DPPH radical (IC50 ) 0.158 mM
vs 0.044 mM). In contrast to the corresponding lipoic
acid analogue 10, which totally suppressed the reper-
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Am in o-
a m id es 1 a n d 2. A mixture of trolox methyl ester (500 mg,
1.9 mmol) and 5 mL of the appropriate diamine was heated
at 110 °C for 4 h. The reaction mixture was diluted with CHCl3
and washed with saturated aqueous NaHCO3. The organic
layer was dried (Na2SO4), and the solvent was evaporated in
vacuo.
N-(3,4-Dih ydr o-6-h ydr oxy-2,5,7,8-tetr am eth yl-2H-1-ben -
zop yr a n -2-ca r bon yl)eth ylen ed ia m in e (1). Trituration with
Et2O to afford a white solid (350 mg, 78%), mp 164-165 °C.
1H NMR (δ): 6.76 (bs, 1H), 3.40-3.15 (m, 2H), 2.70-2.55 (m,
4H), 2.40-2.30 (m, 1H), 2.16 (s, 3H), 2.14 (s, 3H), 2.06 (s, 3H),
1.90-1.80 (m, 1H), 1.51 (s, 3H). Anal. (C16H24N2O3) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Am in o-
a m id es 3-8. A solution of trolox (500 mg, 2 mmol) and 1,1′-
carbonyldiimidazole (350 mg, 2.2 mmol) in 25 mL of anhydrous
THF was stirred at ambient temperature under nitrogen for
1 h. The appropriate diamine (4 mmol) was added to the
solution, and stirring was continued overnight. The reaction
mixture was diluted with H2O and extracted with EtOAc. The
organic extracts were combined, washed with brine, and dried
(Na2SO4), and the solvent was evaporated in vacuo.
N-(3,4-Dih ydr o-6-h ydr oxy-2,5,7,8-tetr am eth yl-2H-1-ben -
zop yr a n -2-ca r bon yl)-1,2-p h en ylen ed ia m in e (4). Purified
by flash column chromatography using CH2Cl2-MeOH (98:2)
as an eluent. Yield 490 mg (72%), yellowish solid, mp 150-
1
153 °C. H NMR (δ): 8.02 (s, 1H), 7.33 (m, 1H), 6.98 (m, 1H),
6.80-6.68 (m, 2H), 4.34 (s, 1H), 2.64 (t, J ) 5.5 Hz, 2H), 2.56-
2.49 (m, 1H), 2.24 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H), 1.95-1.90
(m, 1H), 1.66 (s, 3H).
N -(1,2-D it h io la n e -3-p e n t a n o y l)-1,2-p h e n y le n e d i-
a m in e (9). Prepared from lipoic acid and 1,2-phenylenedi-
amine as described in the general procedure above. Purified
by flash column chromatography using petroleum ether-
acetone (70:30) as an eluent. Yield 75%, yellow solid, mp 74-
1
76 °C. H NMR (δ): 7.15-6.56 (m, 5H), 3.85 (bs, 2H), 3.70-

Brief Articles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4303
3.55 (m, 1H), 3.20-3.05 (m, 2H), 2.48-2.30 (m, 3H), 1.95-
1.50 (m, 7H). Anal. (C14H20N2OS2) C, H, N.
peroxidation, interaction of test compounds with DPPH, ClogP,
isolated heart preparation, and MDA measurements, with
corresponding references. This material is available free of
charge via the Internet at http://pubs.acs.org.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Di-
a m id es 10-17. To a mixture of THF (3 mL) and H2O (2 mL)
were sequentially added the appropriate aminoamide (0.3
mmol), lipoic acid chloride (135 mg, 0.6 mmol), and NaHCO3
(100 mg, 1.2 mmol); the mixture was stirred at ambient
temperature for 2 h. The reaction mixture was diluted with
H2O and extracted with EtOAc. The organic extracts were
combined, washed with saturated aqueous NaCl, and dried
(Na2SO4), and the solvent was evaporated in vacuo.
N-(3,4-Dih ydr o-6-h ydr oxy-2,5,7,8-tetr am eth yl-2H-1-ben -
zop yr a n -2-ca r bon yl)-N′-(1,2-d ith iola n e-3-p en ta n oyl)-1,2-
p h en ylen ed ia m in e (13). Purified by flash column chroma-
tography using petroleum ether-acetone (70:30) as an eluent.
Yield 65 mg (41%), yellowish solid, mp 80-82 °C. 1H NMR
(δ): 8.52 (s, 1H), 8.02 (s, 1H), 7.58-7.55 (m, 1H), 7.21-7.13
(m, 3H), 4.53 (s, 1H), 3.53-3.50 (m, 1H), 3.19-3.08 (m, 2H),
2.73-2.55 (m, 2H), 2.43-2.28 (m, 3H), 2.23 (s, 3H), 2.18 (s,
3H), 2.09 (s, 3H), 2.00-1.80 (m, 3H), 1.70-1.60 (m, 4H), 1.62
(s, 3H), 1.47-1.35 (m, 2H). 13C NMR (δ): 174.1, 171.6, 145.9,
143.9, 130.9, 129.3, 126.7, 125.9, 125.6, 125.1, 122.2, 121.8,
119.1, 117.6, 78.4, 56.3, 40.2, 38.5, 36.7, 34.6, 29.6, 29.2, 28.9,
25.3, 24.3, 24.2, 20.5, 12.4, 12.1, 11.4. Anal. (C28H36N2O4S2)
C, H, N.
N-(3,4-Dih ydr o-6-h ydr oxy-2,5,7,8-tetr am eth yl-2H-1-ben -
zop yr a n -2-ca r bon yl)-N′-(6,8-d im er ca p t ooct a n oyl)et h yl-
en ed ia m in e (18). NaBH4 (90 mg, 0.8 mmol) was added to a
solution of 10 (120 mg, 0.2 mmol) in MeOH (3 mL) at 0 °C,
and the mixture was stirred at ambient temperature for 4 h.
Yield 120 mg (100%) yellowish oil. 1H NMR (δ): 6.74 (bs, 1H),
5.81 (bs, 1H), 4.50 (s, 1H), 3.45-3.25 (m, 4H), 2.95-2.90 (m,
1H), 2.70-2.55 (m, 4H), 2.40-2.30 (m, 1H), 2.17(s, 6H), 2.08
(s, 3H), 2.07 (m, 1H), 1.85-1.70 (m, 2H), 1.65-1.50 (m, 4H),
1.51 (s, 3H), 1.45-1.35 (m, 2H). 13C NMR δ 175.8, 173.4, 145.8,
144.1, 122, 121.9, 119.2, 117.8, 78.2, 42.7, 40.1, 39.3, 39.1, 38.7,
36.2, 29.6, 26.6, 25.2, 24.4, 22.3, 20.6, 12.4, 12.1, 11.5. Anal.
(C24H38N2O4S2) C, H, N.
Refer en ces
(1) Maxwell, S. R. J . Prospects for the use of antioxidant therapies.
Drugs 1995, 49, 345-361.
(2) Stephens, N. G.; Parsons, A.; Schofield, P. M.; Kelly, F.;
Cheeseman, K.; Mitchinson, M. J .; Brown, M. J . Randomised
controlled trial of vitamin E in patients with coronary disease:
Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996,
347, 781-786.
(3) Venditti, P.; Masullo, P.; Agnisola, C.; Di Meo, S. Effect of
vitamin E on the response to ischemia-reperfusion of Langen-
dorff heart preparations from hyperthyroid rats. Life Sci. 2000,
66, 697-708.
(4) Biewenga, G. P.; Haenen, G. R. M. M.; Bast, A. The pharmacol-
ogy of the antioxidant lipoic acid. Gen. Pharmacol. 1997, 29,
315-331.
(5) Packer, L.; Witt, E. H.; Tritschler, H. J . R-Lipoic acid as a
biological antioxidant. Free Radical Biol. Med. 1995, 19, 227-
250.
(6) Thu¨rich, T.; Bereiter-Hahn, J .; Schneider, M.; Zimmer, G.
Cardioprotective effects of dihydrolipoic acid and tocopherol in
right heart hypertrophy during oxidative stress. Arzneim.-
Forsch./ Drug Res. 1998, 48, 13-21.
(7) Haramaki, N.; Assadnazari, H.; Zimmer, G.; Schepkin, V.;
Packer, L. The influence of vitamin E and dihydrolipoic acid on
cardiac energy and glutathione status under hypoxia-reoxygen-
ation. Biochem. Mol. Biol. Int. 1995, 37, 591-597.
(8) Coombes, J . S.; Powers, S. K.; Demirel, J .; J essup, H. K.; Vincent,
K. L.; Hamilton, K. L.; Naito, H.; Shanely, R. A.; Sen, C. K.;
Packer, L.; J i L. L. Effect of combined supplementation with
vitamin E and alpha-lipoic acid on myocardial performance
during in vivo ischaemia-reperfusion. Acta Physiol. Scand. 2000,
169, 261-269.
(9) Campo, G. M.; Squadrito, F.; Campo, S.; Altavilla, D.; Avenoso,
A.; Ferlito, M.; Squadrito, G.; Caputi, A. P. Antioxidant activity
of U-83836E, a second generation lazaroid, during myocardial
ischemia reperfusion injury. Free Radical Res. 1997, 27, 577-
590.
(10) J acobsen, E. J .; VanDoornik, F. J .; Ayer, D. E.; Belonga, K. L.;
Braughler, J . M.; Hall, E. D.; Houser, D. J . 2-(Aminoethyl)-
chromans that inhibit iron-dependent lipid peroxidation and
protect against Central Nervous System trauma and ischemia.
J . Med. Chem. 1992, 35, 4464-4472.
(11) Tirosh, O.; Sen, C. K.; Roy, S.; Kobayashi, M. S.; Packer, L.
Neuroprotective effects of R-lipoic acid and its positively charged
amide analogue. Free Radical Biol. Med. 1999, 26, 1418-1426.
(12) Chou, W.-C.; Tan, C.-W.; Chen, S.-F.; Ku, H. One-pot neat
reactions of carboxylic esters and alkylenediamines for efficient
preparation of N-acylalkylenediamines. J . Org. Chem. 1998, 63,
10015-10017.
(13) Wagner, A. F.; Walton, E.; Boxer, G. E.; Pruss, M. P.; Holly, F.
W.; Folkers, K. Properties and derivatives of lipoic acid. J . Am.
Chem. Soc. 1956, 78, 5079-5081.
N-(3,4-Dih ydr o-6-h ydr oxy-2,5,7,8-tetr am eth yl-2H-1-ben -
zop yr a n -2-ca r bon yl)-N′-(cyclop en tyl-5-p en ta n oyl)eth yl-
en ed ia m in e (22). Prepared from 1 (175 mg, 0.6 mmol) and
21 (100 mg, 0.6 mmol) as described for 3-8. Yield 50 mg (20%),
1
gummy solid. H NMR (δ): 6.77 (bs, 1H), 5.85 (bs, 1H), 3.40-
3.30 (m, 4H), 2.70-2.50 (m, 3H), 2.40-2.30 (m, 1H), 2.17 (s,
6H), 2.08 (s, 3H), 2.1-2.01 (m, 1H), 1.90-1.76 (m, 1H), 1.75-
1.24 (m, 19H). Anal. (C26H40N2O4) C, H, N.
Ack n ow led gm en t. This work is supported in part
by the GSRT, program PENED 99ED 181. A.P.K.
acknowledges support from the EC financed program
QLK6-CT-1999-51170.
(14) Vajragupta, O.; Toasaksiri, S.; Boonyarat, C.; Woongkrajang, Y.;
Peungvicha, P.; Watanabe, H.; Boonchoong, P. Chroman amide
and nicotinyl amide derivatives: Inhibition of lipid peroxidation
and protection against head trauma. Free Radical Res. 2000,
32, 145-155.
(15) Lebeau, J .; Neviere R.; Cotelle, N. Beneficial effects of different
flavanoids, on functional recovery after ischemia and reperfusion
in isolated rat heart. Bioorg. Med. Chem. Lett. 2001, 11, 23-27.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures for the synthesis of compounds 2, 5-8, 10-
12, 14-17, and 19-21, analytical data for all compounds
presented in Table 1, and experimental details for in vitro lipid
J M010962W