Arch. Pharm. Chem. Life Sci.

2014, 347, 1–6 1

Full Paper
Synthesis and Biological Evaluation of Glucosyl Curcuminoids

Adari Bhaskar Rao1, Ernala Prasad1, Seelam S. Deepthi1, and Imtiaz A. Ansari1,2

1
Medicinal Chemistry and Pharmacology Division, CSIR – Indian Institute of Chemical Technology, Tarnaka,
Hyderabad, India
2
Department of Chemistry, King Khalid University, Abha, Saudi Arabia

Medicinal plants proved to be a rich source in exploring a variety of lead structures in the development
of new drugs. The natural curcuminoids have gained considerable attention in recent years for
their multiple beneficial pharmacological and biological activities. Clinical application of these
curcuminoids is often impaired due to their poor water solubility, resulting in low in vivo bioavailability
of the active compound in humans. The objective of the present study is to synthesize glucosyl
conjugates of curcumin 1 and tetrahydrocurcumin 4 and to evaluate their biological activities.
The study highlights the synthesis of curcumin-b-di-glucoside 3 (yield 71%) and tetrahydrocurcumin-b-
di-glucoside 6 (yield 64%) in good yields in a biphasic reaction medium using a phase transfer catalyst
under simple and ecofriendly conditions. Both the glucosyl curcuminoids showed enhanced
antioxidant, tyrosinase enzyme inhibitory, antimicrobial and potent cytotoxic activity. The improved
biological activity may be due to the increased solubility of the glucosyl conjugated compounds
compared to the native curcuminoids; this was further confirmed by partition coefficient studies. Thus,
the synthesized glucosyl curcumin may serve as promising future therapeutic molecule in the
management of cancer, whereas glucosyl tetrahydrocurcumin can be a useful ingredient in
achromatic food and in cosmetic applications.

Keywords: Antioxidant / Cosmetic / Hyperpigmentation / Tetrahydrocurcumin / Tyrosinase

Received: May 15, 2014; Revised: July 8, 2014; Accepted: July 9, 2014

DOI 10.1002/ardp.201400195

Introduction dying industry. In addition, curcuminoids possess antiin-

Natural compounds derived from plants, animals, and
microorganisms proved to be an excellent source for
therapeutic agents. Phytochemicals once served the human-
kind as the source of new drug development, today these
natural products or their analogs still represent as preventive
and therapeutic agents against a wide range of human
diseases [1, 2]. Curcuminoids are naturally occurring
hydrophobic polyphenolic compounds isolated from the
rhizomes of Curcuma longa Linn. (Zingiberaceae) [3]. Curcumin
is a predominant compound, which has attracted a lot of
attention due to its wide applications in traditional
medications, food coloration, cosmetic utility, and fabric
Correspondence: Dr. Adari Bhaskar Rao, Medicinal Chemistry and
Pharmacology Division, CSIR – Indian Institute of Chemical Technology,
Tarnaka, Hyderabad 500 007, AP, India.
E-mail: adarirao2002@yahoo.co.in
Fax: þ91 40 27193189
flammatory, antioxidant, antiangiogenic, anticancer, and
many more therapeutic activities [4, 5]. Tetrahydrocurcumin
is one of the colorless hydrogenated metabolites of the
curcumin that demonstrates broad physiological and
pharmacological activities similar to that of native curcumin
[6]. Despite wide range of food processing and pharmacologi-
cal activities, the major barrier for clinical applications of
these curcuminoids is their poor solubility in water, thus
limiting the bioavailability and in vivo therapeutic concen-
tration of the compound in the humans. In addition, a
relative short gastric emptying time results in an incomplete
release of curcuminoids from the dosage and to the site of
absorption, leading to a diminished efficacy of the com-
pound [7, 8]. Attempts were made to enhance the bioavail-
ability of curcuminoids through structural modifications of
the molecule and/or through new formulations (nano-
particles, adjuvants, nanoparticles and liposomes) but have
not gained much attention due to various limitations in their

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2 A. Bhaskar Rao et al. Arch. Pharm. Chem. Life Sci. 2014, 347, 1–6

methodologies [9, 10]. It is well known that the glycosylation
of hydrophobic phytochemicals has improved the bioavail-
ability and biological activity of the compounds [11, 12]. In
the present study, it is planned to synthesize glucosyl-
conjugated curcuminoids and to evaluate their biological
activity.
Results and discussion
Chemistry
Synthesis of glucosyl curcuminoids
Synthesis of curcumin-4,4-b-di-D-glucoside(glucosyl-curcumin)
3 and tetrahydrocurcumin-4,4-b-di-glucoside (glucosyl-THC) 6
was achieved in higher yields, in a simple economical process
[13]. The glucosyl conjugation reaction was facilitated by a
phase transfer catalyst (tetrabutylammonium bromide), that
promotes better mass transfer of reactants between two
immiscible liquid phases, resulting in high product forma-
tion with selectivity. The progress of the reaction was
monitored through HPLC and the single product peak was
obtained at the end of the optimum reaction period. The
structures of the glucosyl-conjugated curcuminoids were
confirmed by spectral analysis. From 1H NMR studies, it was
confirmed that the configurations of the anomeric carbons
were defined as b for all the glucose molecules therefore the
conjugated glucosylations of the two curcuminoids show b-
configuration. The SN2 nucleophilic substitution at the
anomeric C-1 position of the activated sugar moiety resulted
in the formation of curcumin-di-b-glucoside (glucosyl-curcu-
min) 3 and a colorless product tetrahydrocurcumin-di-b-
glucoside (glucosyl-THC) 6 (Scheme 1).
Curcumin-4,4-b-di-glucoside (3)
Yellow colored solid, yield 71%. 1H NMR (DMSO-d6): 3.1–3.4 (m,
8H), 3.6 (m, 3H), 3.77 (s, 6H, OCH3), 4.31 (br, s, 1H), 4.5 (t, 2H,
J ¼ 5.5Hz), 4.93 (d, 2H, J ¼ 7 Hz), 4.98 (d, 2H, J ¼ 5 Hz), 5.06 (br, s,
2H), 5.25 (d, 2H, J ¼ 4 Hz), 6.04 (s, 1H), 6.81(d, 2H, J ¼ 16 Hz),
7.05 (d, 2H, J ¼ 8.5 Hz), 7.18 (d, 2H, J ¼ 8 Hz), 7.32 (s, 2H), 7.52 (d,
2H, J ¼ 16 Hz); ESI-MS (m/z): 715 (MþNa)þ.
Tetrahydrocurcumin-4,4-b-di-glucoside (6)
Half white colored solid, yield: 64%; m.p. ¼ 184°C, TLC
rf ¼ 0.27 (DCM/MeOH, 9.5:0.5), UV (EtOH) lmax 258, 220 nm.
IR(KBr): nmax 3453, 3017, 2927, 2854, 1753, 1605, 1514, 1370,
1229, 1037, 757 cm1; 1H NMR (DMSO-d6 and D2O): 6.86–6.59
(m, 6H, –CH2); 5.64–5.50 (m, 2H), 5.16 (t, J ¼ 9.8 Hz, 2H), 4.37–
4.26 (m, 6H), 4.17–4.10 (m, 4H), 3.87 (s, 6H), 2.86–2.70 (m, 8H);
13
C NMR (DMSO): 193.1, 146.3, 143.9, 132.5, 120.7, 114.3,
110.9, 99.7, 79.1, 76.8, 76.1, 72.6, 70.3, 61.9, 55.8, 40.3, 31.2. LC
MS (m/z): 719.13 (MþNa)þ.
Natural curcuminoids are yellow colored compounds
resulting in staining of the skin and dress materials during
topical application. Tetrahydrocurcumin is a colorless metab-
olite of curcumin that exhibits pharmacological and biologi-
cal activities similar to that other curcuminoids. It is planned
to synthesize the conjugated glucosyl-curcumin and glucosyl-
tetrahydrocurcumin compounds to increase hydrophilicity of
these molecules and improve their biological activity.

O Br
AcO
KOH
O O AcO OAc O O
MeO OMe OAc TBAB CH 3 ONa MeO OMe
2
HO OH 45°C/2 h O O
1
OH OH
O O

OH
3 OH
OH OH OH OH

O Br
AcO
KOH
O O AcO OAc O O
MeO OMe OAc TBAB CH3 ONa MeO OMe
5
HO 4 OH 45°C/2 h O O

OH OH
O O

OH OH
OH OH
6
OH OH

Scheme 1. Synthesis of curcumin-4,4-b-di-glucoside 3 and tetrahydrocurcumin-4,4-b-di-glucoside 6.

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2014, 347, 1–6
Figure 1. Partition coefficient (log P o/w) of potent compounds.
Partition coefficient
From the results (Fig. 1), it was observed the glucosyl
conjugated curcuminoids 3 and 6 show much lower lip-
ophilicity compared to compounds 1 and 4, and thus these
glucosyl-curcuminoids were more water soluble and show
better bioavailability and pharmacological activities.
Biological results
The radical scavenging and tyrosinase inhibition activities
The test compounds curcumin 1, glucosyl-curcumin 3, THC 4,
and glucosyl-THC 6 show potent antioxidant activity by
inhibiting oxidation of the added 2,2-diphenyl-1-picrylhydra-
zyl (DPPH) (Fig. 2). The results revealed that the glucosyl
conjugated curcuminoids show promising antioxidant activ-
ity when compared to non-conjugated curcuminoids studied.
The IC50 value of glucosyl-curcumin was 20.25 mM and for
glucosyl-THC it was 18.25 mM. The improved free radical
scavenging activity is maybe due to increased water solubility
of glucosylated hydrophilic curcuminoid compounds. The
Figure 2. IC50 values of curcuminoids on DPPH radical scavenging and tyrosinase inhibition activity.
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Glucosyl Curcuminoids 3
free radical scavenging activity of the curcuminoids studied
may be attributed mainly due to the compound’s pharma-
cophore, which contains phenolic hydroxyl group and
b-diketone structure. The chemoprotective nature of the
natural polyphenolic compound curcumin (diferuloylme-
thane) against oxidative stress-mediated disorders is through
the anti-oxidative functioning [14].
Natural products are known to inhibit tyrosinase enzyme
activity that participates in melanin formation thereby
lightening the skin tone [15]. The natural curcuminoids are
of particular interest both in skin medications and in
cosmetics as these molecules show a potent tyrosinase
inhibition activity. The glucosylated curcumin show enhanced
tyrosinase inhibition activity with IC50 52.12 mM for glucosyl-
curcumin 3, whereas for glucosyl-THC 6 it was IC50: 48.12 mM,
nearly comparable to conventional tyrosinase inhibitors.
Antimicrobial activity
The curcuminoids 1, 3, 4, and 6 tested show broad
antimicrobial and antifungal activity against following
bacterial strains Escherichia coli, Pseudomonas aeruginosa,
Klebsiella pneumoniae, Bacillus subtilis, and Staphylococcus aureus
and against two fungal strains Aspergillus fumigatus and
Candida albicans. From the results, it was inferred that both the
glucosyl-conjugated curcumin 3 and glucosyl-THC 6 have
shown enhanced antimicrobial activity, with lower MIC
values when compared to curcumin 1 and THC 4 (Fig. 3).
Curcumin has not shown antimicrobial activity against
B. subtilis whereas both curcuminoids have no activity against
the fungal strain A. fumigatus. The glucosyl-curcumin and
glucosyl-THC exhibited potential anti-microbial activity as
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4 A. Bhaskar Rao et al.
confirmed by low MIC values, this may be due to the increased
aqueous solubility of these hydrophilic curcuminoids.
Cytotoxicity
The cytotoxicity of the four curcuminoids curcumin 1, THC 4,
curcumin-b-di-glucoside 3, and THC-b-di-glucoside 6 were
studied in selected human cancer cell lines (HT-29 colon
cancer, A549 lung cancer, MCF-7 breast cancer) by MTT assay.
From the results, it was observed that all the tested
curcuminoids have shown cytotoxic activity on the four cell
lines and compounds 4 and 6 exhibited marked activity on
colon cancer cell line (HT-29). The IC50 value on colon cancer
Figure 4. Evaluation of cytotoxicity (IC50 mM) of curcuminoids on different cancer cell lines by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl
tetrazolium bromide) assay method.
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–6
Figure 3. Antimicrobial activity of curcumin,
THC, glucosyl-THC (MIC mmol/L).
cells for curcumin 1 was 66.94 mM, THC 4 it was 77.17 mM
whereas for curcumin-b-di-glucoside 3 and for THC-b-di-
glucoside 6 IC50 values were 41.56 mM and 32.13 mM. Thus, it
was confirmed from the results that on glucosidation of the
curcuminoids the inhibition of colon cancer cells (HT-29)
activity was increased by twofolds when compared with free
curcuminoids (Fig. 4). The conjugated curcumin has also
showed a noticeable inhibition activity on breast cancer cells
(MCF-7), whereas no significant activity was found in liver
cancer cells (A549). Curcuminoids possess a wide spectrum of
antitumor properties but, due to its poor bioavailability the
curcuminoids are not yet been clinically used routinely in
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Arch. Pharm. Chem. Life Sci. 2014, 347, 1–6
anticancer chemotherapy [16–18]. Glycosylation of hydropho-
bic curcuminoids increases solubility of the compound and
thus improving the anticancer activity as confirmed by their
lower IC50 values.
Natural products are known to possess potent anticancer
activity and are also used topically against widespread skin
diseases and cosmetics. Curcuminoids attracted considerable
attention in the recent years due to their broad pharmaco-
logical activities. The poor circulating bioavailability of these
curcuminoids attributed due to low water solubility thus
impairing the compounds biological activity. The synthesized
glucosyl-conjugated compounds curcumin-b-di-glucoside 3
and tetrahydrocurcumin-b-di-glucoside 6 have shown potent
antioxidant and cytotoxic activities when compared to native
curcuminoids. The results obtained clearly substantiate the
beneficial effects of glucosyl-curcumin as a potent anticancer
agent and colorless glucosyl-THC shows superior antioxidant
and inhibit tyrosinase activity thereby helping in lightening
the skin tone. Therefore, the conjugated THC acts as useful
ingredients in anti-ageing and other cosmetic topical
formulations designed to maintain general skin health [19].
Conclusion
The study confirms a novel synthesis of curcumin-b-di-glucoside
3 and tetrahydrocurcumin-b-di-glucoside 6 in good yields and
selectivity (b-form) in simple and eco-friendly reaction
conditions. The results confirm the increased hydrophilicity
and biological activity of glucosyl conjugated curcuminoids
when compared to their native un-conjugated curcuminoids;
this was further confirmed by partition coefficient studies. The
data also reveal the compounds glucosyl-curcumin and
glucosyl-THC showing enhanced antioxidant, antimicrobial,
and tyrosinase inhibition activities, when compared to non-
conjugated curcuminoids studied. In summary, the glucosyl-
curcumin shows potent antioxidant and cytotoxic activity, and
thus the molecule may be of therapeutic importance against
several types of cancer diseases. Whereas, the non-staining
glucosyl-conjugated THC molecule acts as a potent ingredient
in achromatic food and in cosmetic applications.
Thus, the study concludes both the synthesized conjugated
curcuminoids, help in improving the medical value of the
natural curcuminoids and hope that future clinical trials will
lead to the development of potent preventive and therapeutic
agent for skin photo aging and UV induced cancer diseases.
Experimental
Materials and methods
Chemicals and materials
Curcumin and THC were gift from Ashian Herbex Ltd.,
Hyderabad, India. DPPH, and bovine serum albumin (BSA),
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Glucosyl Curcuminoids 5
L-DOPA, tyrosinase T-3824, 25 KU were procured from Sigma
Chemical Co. (St. Louis, MO, USA). The cancer cell lines A549 (lung
cancer), MCF-7 (breast cancer) and HT-29 (colon cancer) used were
obtained from National Center for Cell Science (NCCS), Pune,
India. All the microbial strains and the Mueller Hinton broth,
Dulbeccos modified Eagles agar medium (DMEM) and other
media components used in these studies were procured from
Hi Media Ltd (Mumbai, India). All the reagents and solvents
(n-octanol) used in the experiments were of analytical grade and
were purchased from Merck (India).
Equipment
Spectrophotometric analyses were carried out using UV visible
spectrophotometer (Perkin Elmer). 1H and 13C NMR spectra for
the products were recorded on a 300, 500 MHz NMR spectrometer
(Bruker, Avance, Germany). Mass spectral analyses of compounds
were performed using MS (Waters Q-Tof Ultima, Manchester, UK)
in the ESI positive mode.
HPLC
The concentration of curcumin, THC, glucosyl-curcumin, and
glucosyl-THC were quantified through HPLC (Gilson LC), using
reverse phase analytical C18 column (150 mm  3.9 mm, 5 mm
particle size). The system was eluted isocratically using mobile
phase acetonitrile/water (85:15 v/v; pH adjusted to 3.0 with 0.01%
acetic acid) at a flow rate of 1 mL/min and the sample detection
was at 280 nm. The mobile phase was filtered through 0.5 mm
nylon membrane filter and the solvent was degassed ultrasoni-
cally before use. Salbutamol (0.2 mg/mL) was added to each test
sample as an internal standard. Peak area was used as a measure
to calculate the respective concentrations.
Chemistry
General procedure for the synthesis of glucosyl-
curcuminoids
The general method used for synthesis of glucosyl conjugated
compounds 3 and 6 are summarized in Scheme 1. A modified
procedure of Koenings–Knorr was followed in synthesis of
glucosyl-conjugated curcuminoids [20, 21]. The reaction was
initiated by adding aqueous solution of KOH (10.8 mmol) to 20 mL
of DCM solvent containing disallowed compounds 1 or 4
(2.71 mmol), followed by the addition of 2,3,4,6-tetra-O-acetyl-b-
D-glucopyranosyl bromide (5.41 mmol) and molecular sieves (4 A).
The reaction mixture was stirred for 3 h at 45°C under the
nitrogen atmosphere. On completion of the reaction, the
compounds curcumin-b-di-glucoside tetraacetate 2 or tetrahy-
drocurcumin-b-di-glucoside tetraacetate 5 were isolated and
these compounds were deacetylated by adding 2% sodium
methoxide in dichloromethane. The two products formed were
isolated and purified through column chromatography silica gel
(100–200 mesh). The purity of the final products was determined
by HPLC and the structures of the compounds obtained
curcumin-b-di-glucoside 3 or tetrahydrocurcumin-b-di-glucoside
6 were confirmed by NMR (1H, 13C), mass and LC–MS studies.
Partition coefficient (log P value)
The concentration of curcuminoids present in two-phase n-
octanol/water system was determined by HPLC [22]. The
curcuminoids 50 mM (curcumin, THC, glucosyl-curcumin, and
glucosyl-THC) were dissolved in known volumes of n-octanol (2, 4,
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6 A. Bhaskar Rao et al.
6, 8, and 10 mL)/water (O/W ratio) in a shake-flask and incubated
at 37°C for 2 h. Lipophilicity of the compound quantified by the
logarithm of the 1-octanol/water partition: log P ¼ log[Co/Cw],
where Co was the concentration of compound in the octanol
phase and Cw its concentration in the aqueous water phase, when
the system was at equilibrium. log P values presented were an
average of three measurements.
Biological assays
Antioxidant activity by DPPH free radical-scavenging
method
The hydrogen donating or free radical-scavenging activity of the
curcumin 1, glucosyl-curcumin 3, THC 4, and glucosyl-THC 6 was
evaluated by the reduction of DPPH as described in the
literature [23]. Trolox (0.1 mg/mL) was used as a standard
antioxidant agent [24]. The experiments were performed in
triplicates for each concentration and IC50 values (scavenge 50%
of the DPPH radicals) were determined by the interpolation of the
dose.
Tyrosinase enzyme inhibition assay
The tyrosinase enzyme inhibition assay was performed using L-
DOPA as the substrate as reported, with slight modifications [25,
26]. Kojic acid was used as the standard/reference inhibitor
compound to study tyrosinase enzyme activity. All the analyses
were performed in triplicates for each concentration and the IC50
values of tyrosinase inhibition activity were determined.
Antimicrobial assay
The antimicrobial activities of the curcumin 1, glucosyl-curcumin
3, THC 4, and glucosyl-THC 6 were carried out using the dilution
technique and minimum inhibitory concentrations (MIC) of the
compounds were determined. The following microbial strains S.
aureus (ATCC 29737), B. cereus ATCC 14603, E. coli (ATCC 10536), K.
pneumoniae (ATCC 13883), and P. aeruginosa (ATCC 25619), and the
fungi C. albicans (ATCC 53324) and A. fumigatus (ATCC 204305) were
evaluated for antimicrobial activity. Standard antibiotics genta-
mycin sulfate and fluconazole were used in the study for
comparison of antimicrobial activity of glucosyl-conjugated
curcuminoids [27].
In vitro cytotoxicity study
The cytotoxicity activity for the test compounds curcumin 1,
glucosyl-curcumin 3, THC 4, and glucosyl-tetrahydrocurcumin 6,
against human cancer cells were determined by MTT (3-(4,5-
dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide) assay.
The cell lines used in the study were MCF-7 breast cancer cells,
HT-29 colon cancer cells, and A549 lung cancer cells. The study
was initiated by plating 104 cells per well in 96-well plates, and
addition of DNR solutions with or without P85 (0.01%) to the cells
(100 mL/well). Cells were incubated with test compounds
dissolved in DMSO, for 4 days at 37°C and 5% carbon dioxide.
After the incubation period, the compound’s cytotoxic activity
was evaluated using the MTT assay at 570 nm [28]. All
experimental points were carried out in triplicate and IC50
values of the test compounds were determined.
The authors express sincere thanks to DST, New Delhi, India for
financial support for this project SR/SO/BB-54/2008; E.P. thanks DST,
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–6
New Delhi for award of fellowship; the authors also thank MD, Ashian
Herbix Ltd, Hyderabad for gift sample of curcuminoids.
The authors have declared no conflict of interest.
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