Antiradical activity of β-ionyl compounds

Article abstract of DOI:10.2174/157017810791130603

Antioxidant potential of some β-ionyl compounds has been assessed by examining their ability to protect methyl linoleate from aerial and 2,2'-azobisisobutyronitrile-induced radical-mediated oxidation. It is observed that the π electron density of β-ionyl structure is an important factor in the antiradical activity of these compounds.

Full text of DOI:10.2174/157017810791130603

338
Letters in Organic Chemistry, 2010, 7, 338-342
Antiradical Activity of ꢀ-Ionyl Compounds
Anil K. Singh* and Solomon B. Libsu
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai – 400 076, India
Received December 29, 2008: Revised March 01, 2010: Accepted March 02, 2010
Abstract: Antioxidant potential of some ꢀ-ionyl compounds has been assessed by examining their ability to protect
methyl linoleate from aerial and 2,2’-azobisisobutyronitrile-induced radical-mediated oxidation. It is observed that the ꢁ-
electron density of ꢀ-ionyl structure is an important factor in the antiradical activity of these compounds.
Keywords: ꢀ-Ionone, retinoids, antiradical, antioxidants, radioprotectants, peroxidation, methyl linoleate, AIBN.
INTRODUCTION
In view of the variety of biological activities of ꢀ–ionyl
compounds and the potent antioxidant and radioprotectant
properties of retinoids, it was thought desirable to examine
the antiradical properties of compounds based on ꢀ–ionyl
structure. Herein we report antiradical properties of
compounds 1-6 (Fig. 1) and show the significance of
electronic factors in the antiradical behaviour of these
compounds. The observed antiradical properties make some
of these compounds potential antoxidants/radioprotectants.
Oxygen-derived free radicals or reactive oxygen species
(ROS) like superoxide anion and hydroxyl radicals are
strong oxidants and are known to induce oxidative damage
to various biomolecules in living systems, thereby causing
numerous health hazards in humans [1]. The in vivo natural
antioxidants as well as a variety of other naturally occurring
and synthetic compounds have been found to quench ROS
and counter their deleterious effects [2-5]. Carotenoids and
retinoids [6,7], which play key roles in a number of
important physiologic functions like cell maintenance and
differentiation, reproduction, embryonic development,
regulation of immune system, prevention of infection and the
inception or progress of skin cancer cells, etc. are also
known to possess potent antioxidant activity [8-22]. The
ability of carotenoids and retinoids to intercept deleterious
10
1: X = H, Y = O
2: X = OH, Y = O
3: X = OCOCH2NHC(NH)NH2, Y = O
4: X = H, Y = NNH2
7
1
Y
2
4
5: X = OH, Y: = NNH2
X
6: X = H, Y = NNHSO2C6H4p-CH3
ROS
including
peroxyl
radicals
by
adduct-
Fig. (1). Structures of ꢀ-ionyl compounds.
formation/electron transfer mechanisms also makes them
potential radioprotectants [3, 5, 13, 16, 18, 20-22].
MATERIALS AND METHODS
ꢀ-Ionone (1, Fig. 1), a naturally occurring short-chain
homolog of retinoids, is widely used in the fragrance and
flavour industries as well as in the synthesis of retinoids and
several other substances possessing desirable biological
properties. The structural features 1 shares with vitamin A
compounds and many carotenoids has led to its utility as a
model of these compounds for theoretical investigations
[23,24] and synthetic transformations [25,26]. Many
compounds based on the ꢀ–ionyl structure possessing useful
properties have been obtained from either natural sources
[27-32] or as a result of chemical synthesis [33-40]. For
instance, in search for compounds with microbicidal activity,
synthesis of ꢀ–ionyl structure with heterocyclic moiety has
been considered [33]. Similarly, analogues of antimalarial
agent Licochalcone A have been synthesized using 1 [34,
35]. Likewise the quest for compounds having
antileishmanial activity has led to the synthesis of ꢀ-ionyl
S,N- and N,N-acetals [36].
ꢀ-Ionone was from Indian Perfumers Ltd. Mumbai and it
was purified by column chromatography (silica gel, 3% ethyl
acetate in petroleum ether) prior to its use. Methyl linoleate
from Aldrich Chem. Co. USA was used as received.
Acetonitrile,
n-hexane
(both
UV-grade),
2,2’-
azobisisobutyronitrile (AIBN) and all other reagents and
chemicals used in this work were procured from suppliers in
Mumbai, India. AR-grade organic solvents were dried and
freshly distilled prior to use. Petroleum ether of boiling range
60-70 0C and ethyl acetate, purchased from the local
suppliers were dried over calcium chloride and distilled
before use. Thin-layer chromatography (TLC) was
performed on silica gel (GF254) plates prepared by coating
thin films of silica gel slurry prepared in ethyl acetate on
glass plates. Column chromatography was performed on
silica gel of 100-200 mesh. Melting points were recorded on
a Veego melting point apparatus and are uncorrected.
Electronic absorption spectra were recorded on JASCO V-
570 UV/VIS/NIR spectrophotometer. Fourier transform
infrared (FTIR) spectra were measured on Nicolet Impact-
1
400 series spectrophotometer. H- and 13C- NMR spectra
*Address correspondence to this author at the Department of Chemistry,
Indian Institute of Technology Bombay, Powai, Mumbai – 400 076, India;
Tel: (+91) (022) 2576 7167; Fax: (+91) (022) 2576 7152;
E-mail: Retinal@chem.iitb.ac.in
were recorded on a Varian VXR 400 MHz FTNMR
spectrometer using tetramethylsilane (TMS) as internal
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

ꢀ-Ionyls as Antiradical Compounds
Letters in Organic Chemistry, 2010, Vol. 7, No. 4
339
standard and CDCl3 as solvent. Mass spectra were obtained
compound (0.04 mM) but lacked the methyl linoleate.
Similarly, for AIBN-catalyzed oxidations, the sample cuvette
contained methyl linoleate (0.25 mM), AIBN (0.15 mM) and
a ꢄ-ionyl compound (0.06 mM) or ꢅ-tocopherol (vitamin E,
VE, 0.006 mM) while the reference cuvette lacked the
methyl linoleate but contained AIBN (0.15 mM) and an
antioxidant of similar concentration as that in the sample
cuvette. The concentration of conjugated diene lipid
hydroperoxides resulting from the oxidation of methyl
linoleate was calculated from the absorbance at 233 nm
recorded at regular time intervals during the incubation
period using absorption coefficient value of 2.52 ꢆ 104 M-1.
cm-1 [14,15, 45-47]. At least two runs of antioxidant studies
were conducted for each of the compounds examined.
employing
a
Micromass Q-TOF (YA-105) mass
spectrometer.
Synthesis
Compounds 2-4 were synthesised as described earlier
[41, 42]. Hydrazones 5 and 6 were prepared by the reaction
of respective ketones 1 and 2 with hydrazine monohydrate
and p-toluenesulphonic acid hydrazide respectively, by
following procedures similar to the procedures described
earlier [41, 43]. In a typical experiment, the carbonyl
compound (1.0 mmol) taken in dry ethanol (5 mL) was drop
wise added to a refluxing mixture of hydrazine monohydrate
or p-toluenesulphonic acid hydrazide (3.0 mmol) in ethanol
(10 mL). The mixture was refluxed for 3 hr, poured into a
beaker containing 15 mL water and then extracted with
dichloromethane. The pure hydrazone product 5 or 6 was
obtained by recrystallisation from methanol in 70 – 75 %
yield. Compound 5: Orange sticky solid; UV/VIS (MeOH)
ꢀmax nm (ꢁ/ dm3 mol-1cm-1): 296 nm (13310); IR (CHCl3)
ꢂmax cm-1: 3293, 3018, 2962, 2933, 2858, 1660, 1621, 1576,
RESULTS AND DISCUSSION
Typical results obtained when autoxidation of 0.25 mM
methyl linoleate is performed in the absence (blank curve)
and presence of 0.04 mM of 1, 2, 3, 4, and 6 are compiled in
Fig. (2). A rapid rise in the concentration of conjugated diene
hydroperoxides resulting from the aerial oxidation of methyl
linoleate in the presence of 1, 3, or 4 sets in only after a finite
time lag relative to the corresponding reactions in their
absence (blank curve). On the other hand, the change in the
concentration of conjugated dienes resulting from
autoxidation of methyl linoleate in the absence of any added
compound is similar to that observed when the oxidation is
conducted in the presence of keto-alcohol 2. It thus appears
that 2 neither suppresses nor promotes the un-catalyzed
oxidation of methyl linoleate. However, the concentration of
conjugated diene hydroperoxides increases from the outset
when the autoxidation is conducted in the presence of trans-
ꢄ-ionone p-tosylhydrazone (6), suggesting pro-oxidant
activity for this compound.
1
1518, 1448, 1365, 1216, 1074, 1024, 974, 928; H NMR
(400 MHz): ꢃ 1.04 (3 H, s, C1-Me), 1.08 (3 H, s, C1-Me),
1.42-1.70 (4 H, m, C2-H and C3-H), 1.86 (3 H, s, C5-Me),
2.06 (3 H, s, C10-H), 4.00 (1 H, m, C4-H), 6.35 (1H, d, J =
16.40 Hz, C8-H), 6.64 (1 H, d, J = 16.40 Hz, C7-H); 13C
NMR (100 MHz): ꢃ 12.91, 18.62, 27.50, 27.60, 28.97, 34.68,
34.72, 69.87, 131.70, 133.66, 134.78, 140.45, 159.81; MS:
m/z (%) 221 (36, M+ - H). Compound 6: Pale yellow solid,
0
0
0
m.p. 143-145 C; Lit. 94-96 C [43] [27], 169-171 C [44]
[28]; UV/VIS (MeOH) ꢀmax nm (ꢁ/ dm3 mol-1cm-1): 281 nm
(11200); IR (KBr) ꢂmax cm-1: 3485, 3020, 2929, 1654, 1336,
1
1215, 1165, 1019, 927, 669; HNMR (400 MHz): ꢃ 0.98 (6
H, s, C1-Me2), 1.44 (2 H, m, C2-H), 1.59 (2 H, m, C3-H),
1.65 (3 H, s, C5-Me), 1.92 (3 H, s, C10-H), 2.00 (2 H, C4-
H), 2.42 (3 H, s, Ar-Me), 6.10 (1 H, d, J = 16.80 Hz, C8-H),
6.47 (1 H, d, J = 16.80 Hz, C7-H), 7.35 (2 H, d, J = 8.40 Hz,
Ar-H), 7.87 (2 H, d, J = 8.40 Hz, Ar-H); 13CNMR (100
MHz): ꢃ 11.53, 19.18, 21.80, 28.94, 33.15, 34.23, 39.60,
128.18, 128.29, 128.42, 129.67, 130.07, 13.42, 133.63,
135.60, 136.60, 144.13, 154.46; MS: m/z (%) 361.21 (100,
M+ + H).
Antiradical Assays
The antiradical behaviour of these compounds was
determined by examining their ability to protect methyl
linoleate from aerial and AIBN-induced oxidation at 370C.
The oxidation reactions in quartz cuvettes were performed
according to the literature method [8, 14] and freshly
prepared solutions of methyl linoleate and AIBN in n-hexane
and acetonitrile were used for the antiradical assays.
Compounds whose antiradical activities were to be examined
were taken in either UV-grade n-hexane (1, 3, and 4) or
acetonitrile (2, 5, and 6). Electronic absorption spectra were
recorded at regular intervals during the oxidation reaction.
Fig. (2). Effect of compounds 1, 2, 3, 4 and 6 (0.04 mM ) on the
autoxidation of methyl linoleate (0.25 mM). (CD: conjugated
diene).
Similarly, AIBN-initiated oxidation of methyl linoleate in
the presence of 0.06 mM of compound 3, 4, or 5 experiences
a sudden rise in the concentrations of conjugated diene
hydroperoxides only after a finite time lag relative to the
corresponding reactions performed in their absence (blank
curve) (Fig. 3). Not unexpectedly, the catalyzed oxidation of
For autoxidation reaction, freshly prepared solution of
methyl linoleate (0.25 mM) in n-hexane and a ꢄ-ionyl
compound (1, 2, 3, 4, and 6; 0.04 mM) were placed in the
UV cuvette while the reference contained a ꢄ-ionyl

340 Letters in Organic Chemistry, 2010, Vol. 7, No. 4
Singh and Libsu
methyl linoleate is maximally delayed in the presence of VE
(Fig. 4). Fig. (3) also suggests that compound 1 exerts little
or no effect on the catalyzed oxidation of methyl linoleate.
The inability of tosylhydrazone 6 to shield methyl linoleate
from autoxidation is also carried to the catalyzed oxidation, a
feature shared by 2 also (Fig. 4). Compound 1 is seen to
significantly defer the onset of conjugated diene
hydroperoxides formation due to autoxidation of methyl
linoleate. However, the antiradical activity of 1 seemed to be
modulated slightly in AIBN-initiated oxidation of methyl
linoleate (Fig. 3). The related compounds 3, 4, and 5 are able
to delay the commencement of catalyzed oxidation of methyl
linoleate (Fig. 3) at least in the early stages.
compounds better electron donors than ꢁ-ionone, 1. This is
particularly so with compound 4. It may be noted that
selective thermal epoxidation by molecular oxygen at the
ring double bond of ꢁ-carotene has been ascribed to higher
electron density at the terminal double bond of a conjugated
system [9]. Recently, we have found that photo-irradiation of
compound 4 results in the epoxidation of the ring double
bond [41], the site of highest electron density in the
molecule. This claim is further corroborated by the
observation that an oxidation potential of 0.85 V recorded
for compound 4 is significantly less than that of compound 1
(1.4 V) suggesting better capability of the former to donate
electrons. Compound 5 likewise has an oxidation potential of
1.1 V suggesting that it is better oxidizable and, hence, better
able to protect the lipid from oxidation. It has also been
recently found that as a result of a single electron transfer, a
radical cation of compound 1 is formed during its photolysis
in the presence of electron acceptors [48].
The behaviour of compound 6 stands in sharp contrast to
that of compounds 4 or 5 in that both the catalyzed- and
aerial oxidations of methyl linoleate proceed without any
noticeable induction time in its presence. This observation
may be traceable to mesomeric electron withdrawal by the
sulphone group in compound 6. On the other hand,
introduction of hydroxyl group into the ꢁ-ionyl structure as
in compound 2 appears to modulate the ability of the parent
structure 1 to act as an antiradical. The results in Fig. (2 and
4) suggest that compound 2 seemingly has little or no effect
on either the autoxidation or AIBN-catalyzed oxidation of
methyl linoleate. The oxidation potential recorded for
compound 2 (1.5 V) is greater than that of either the
compound 4 (0.85 V) or the compound 5 (1.1 V) showing its
poor electron donating capacity relative to the latter two
compounds. This effect of the hydroxyl function is
apparently overshadowed by the hydrazone moiety in
compound 5 whose ability to deter the catalyzed oxidation of
the lipid is comparable to that of compound 4.
Fig. (3). Effect of compounds 1, 3, 4, and 5 (0.06 mM ) on the
oxidation of methyl linoleate (0.25 mM) triggered by AIBN (0.15
mM).
Thus, the polarity of position 4 in ꢁ-ionyl structure can
play important role in the antiradical/antioxidant activity of
these compounds. It has been reported that the 4-oxo group
in the trimethylcyclohexenyl ring enhances the antioxidant
activity of ꢁ-carotene toward peroxy radical dependent lipid
peroxidation [12]. However, it has been also reported that
polar moieties like hydroxyl and oxo groups on the terminal
rings modulate the free radical scavenging ability of
carotenoids [19]. It remains to be verified whether the course
of antioxidant actions of ꢁ-ionyl compounds involves, by
analogy with carotenoids and retinoids, formation of
resonance stabilized free radical adduct [13, 16] or electron
transfer to the chain carrying peroxyl radical [18, 22].
However, in light of the ability of compound 1 to donate a
single electron on photolysis in the presence of electron
acceptors giving rise to the corresponding radical cation [48]
and the lower oxidation potential of compounds 4 and 5
relative to that of compound 1, the mode of antiradical action
of these compounds may be presumed to involve electron
transfer to the chain-carrying peroxyl group thereby
inactivating it. This mechanism is shown in Fig. (5) for
compound 4, which can transfer an electron to a peroxyl
radical giving rise to the corresponding radical cation 4a.
Such a mechanism is in line with the inability of compound
Fig. (4). Effect of compounds 2 and 6 (0.06 mM) and ꢀ-tocopherol
(VE, 0.006 mM) on the oxidation of methyl linoleate (0.25 mM)
triggered by AIBN (0.15 mM).
The induction time observed for the catalyzed oxidation
of methyl linoleate in the presence of compounds 3, 4, or 5 is
a reflection of their ability to inactivate the chain-carrying
peroxyl radicals, which would otherwise trigger the onset of
oxidation reaction earlier. The sudden rise in the
concentration of conjugated diene hydrperoxides observed in
these cases is consequent to the depletion of these
compounds from the reaction mixture.
The enhanced antiradical capabilities of compounds 3, 4,
and 5 relative to compounds 1 and 2 can be attributed to their
guanidine and hydrazone moieties. It can be said that the
guanidine and tosylhydrazone functionalities make these

ꢀ-Ionyls as Antiradical Compounds
Letters in Organic Chemistry, 2010, Vol. 7, No. 4
341
NH2
NH2
.
ROO
+ ROO
N
N
4a
Fig. (5). Plausible electron transfer mechanism for antioxidant action of electron rich ꢀ-ionyl compounds.
4
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In conclusion, it is found that while compounds 1, 3 and
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ACKNOWLEDGEMENTS
Financial supports from BRNS [No. 2002/37/1/
BRNS/1032], Government of India and Research Fellowship
to SBL from the Government of the Federal Democratic
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