Synthesis, characterization, and antitumour studies of some curcuminoid analogues and their aluminum complexes

Article abstract of DOI:10.1080/00958972.2013.784281

Aluminum(III) complexes of three curcuminoid analogues [1,7-diphenyl-1,6- heptadiene-3,5-dione, HL¹; 1,7-bis(2-hydroxyphenyl)-1,6-heptadiene-3, 5-dione, HL²; and 1,7-bis(4-ethoxyphenyl)-1,6-heptadiene-3,5-dione, HL³] of [AlL₃] stoichiometry were synthesized and characterized by UV, IR, ¹H NMR, and mass spectral data The compounds were investigated for cytotoxic and antitumor activities The aluminum chelates are remarkably active compared to free curcuminoid analogues The aluminum complex of HL² with hydroxyl in the phenyl ring was most active towards Ehrlich ascites carcinoma cells (concentration needed for 50% inhibition of 5 μg/mL) and cultured L929 cells (1 μg/mL produced 60 + 3% cell death) Increase in lifespan and reduction of solid tumor volume in mice were also largest for the aluminum complex of HL² The study reveals that the antitumor activities of curcuminoids are more enhanced by complexation with aluminum than with transition metal ions

Full text of DOI:10.1080/00958972.2013.784281

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Synthesis, characterization,
and antitumour studies of some
curcuminoid analogues and their
aluminum complexes
Valapatukutikadan Davis John a , Muhammed Basheer Ummathur b
& Krishnannair Krishnankutty c
a Department of Chemistry , Christ College , Irinjalakuda , India
b Department of Chemistry , KAHM Unity Women’s College ,
Manjeri , India
c Department of Chemistry , University of Calicut , Thenhipalam ,
India
Accepted author version posted online: 12 Mar 2013.Published
online: 19 Apr 2013.
To cite this article: Valapatukutikadan Davis John , Muhammed Basheer Ummathur & Krishnannair
Krishnankutty (2013) Synthesis, characterization, and antitumour studies of some curcuminoid
analogues and their aluminum complexes, Journal of Coordination Chemistry, 66:9, 1508-1518, DOI:
10.1080/00958972.2013.784281
To link to this article: http://dx.doi.org/10.1080/00958972.2013.784281
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Journal of Coordination Chemistry, 2013
Vol. 66, No. 9, 1508–1518, http://dx.doi.org/10.1080/00958972.2013.784281
Synthesis, characterization, and antitumour studies of some
curcuminoid analogues and their aluminum complexes
VALAPATUKUTIKADAN DAVIS JOHN†, MUHAMMED BASHEER UMMATHUR*‡
and KRISHNANNAIR KRISHNANKUTTY§
†Department of Chemistry, Christ College, Irinjalakuda, India
‡Department of Chemistry, KAHM Unity Women’s College, Manjeri, India
§Department of Chemistry, University of Calicut, Thenhipalam, India
(Received 2 October 2012; in final form 23 January 2013)
Aluminum(III) complexes of three curcuminoid analogues [1,7-diphenyl-1,6-heptadiene-3,5-dione,
HL1; 1,7-bis(2-hydroxyphenyl)-1,6-heptadiene-3,5-dione, HL2; and 1,7-bis(4-ethoxyphenyl)-1,6-
heptadiene-3,5-dione, HL3] of [AlL3] stoichiometry were synthesized and characterized by UV, IR,
1H NMR, and mass spectral data. The compounds were investigated for cytotoxic and antitumor
activities. The aluminum chelates are remarkably active compared to free curcuminoid analogues.
The aluminum complex of HL2 with hydroxyl in the phenyl ring was most active towards Ehrlich
ascites carcinoma cells (concentration needed for 50% inhibition of 5 μg/mL) and cultured L929
cells (1 μg/mL produced 60 + 3% cell death). Increase in lifespan and reduction of solid tumor
volume in mice were also largest for the aluminum complex of HL2. The study reveals that the
antitumor activities of curcuminoids are more enhanced by complexation with aluminum than with
transition metal ions.
Keywords: Curcuminoids; Aluminum complexes; Cytotoxic and antitumor activities; Spectral
studies
1. Introduction
Curcuminoids (1,7-diaryl-1,6-heptadiene-3,5-diones), extracted from the rhizomes of the
traditional Indian medicinal plant turmeric (Curcuma longa, Linn., Zingiberacea family),
have been reported to possess antiinflammatory, antioxidant, antiarthritic, and antitumor
activities [1–4]. Presence of phenolic group together with the conjugated β-diketone struc-
ture is responsible for their high biological activity and this led to further studies using
structurally related compounds [5–8]. Medicinal importance of many plant chemicals is
enhanced by complex formation with various metal ions [9]. Metal complexation of these
unsaturated 1,3-diketones led to dramatic changes in their biochemical properties including
antitumor activity [10, 11].
Heavy metals, as poisons, were not assumed to act as potential anticancer drugs because
of their toxicity. The earliest attempt to introduce metals in the drug development was the
*Corresponding author. Email: mbummathur@gmail.com
Ó 2013 Taylor & Francis

Aluminium curcuminoid complexes
1509
so-called Fowler’s solution, arsenotherapy [12]. Some similar compounds are still used
today, such as As2O3 [13]. The effect of a heavy metal on cancer is not only due to the
metal alone but also due to the structure and the type of compounds [14]. Historically,
metals and metal complexes have played a key role in the development of pharmacy and
modern chemotherapy. However, they still remain a tiny minority of all therapeutics on the
market today [15]. There are many known and documented heavy metal complexes that
carry photochemical, anticancer, or both activities [16].
Interest in aluminum has considerably increased due to its potential toxic effects [17–
20]. The effects of aluminum are highly dependent upon the chemical form as well as the
concentration in which this element enters the biological system.
Chelation therapy is the preferred medical treatment for reducing the toxic effects of
metals [21]. Thus toxic heavy metals can be removed from the body through complexation
with curcumin [22]. Recent studies have shown that curcumin has neuroprotective effects
against aluminum-induced cognitive dysfunction and oxidative damage in rats [23]. Even
though literature is extensive on metal complexes of β-diketones, very few reports exist on
aluminum β-diketonates [24, 25].
The antitumor activities of natural and synthetic curcuminoids are enhanced by
complexation with some transition metal ions [26–29], even though these metal ions them-
selves are toxic [30]; but reports are scanty on the antitumor studies of non-transition
metal complexes of synthetic curcuminoids [31].
As part of our studies on chemical and biochemical activities of synthetic curcuminoid
analogues and their metal complexes [26–29, 31–33], the present study reports the synthe-
sis, structural characterization, and antitumor activities of three new curcuminoid analogues
and their Al(III) complexes.
2. Experimental
2.1. Materials and methods
Carbon and hydrogen were determined by microanalyses (Heraeus Elemental analyzer) and
metal contents by AAS (Perkin Elmer 2380 spectrometer). Electronic spectra of the com-
pounds in methanol (10À4 mol/L) were recorded on a 1601 Shimadzu UV–vis. spectrophotom-
1
eter, IR spectra (KBr disks) on a 8101 Shimadzu FTIR spectrophotometer, H NMR spectra
(CDCl3 or DMSO-d6) on a Varian 300 NMR spectrometer, and mass spectra on a Jeol/SX-102
mass spectrometer (FAB using argon and meta-nitrobenzyl alcohol as the matrix). Molar
conductances of the complexes were determined in DMF (ꢀ10À3 mol/L) at room temperature.
Eagle’s minimum essential medium (MEM) and trypsin were obtained from Himedia
Laboratories Private Ltd. (Mumbai). Qualigen’s silicagel G and silicagel 60–120 mesh
were used for analytical TLC and column chromatography, respectively. Tributyl borate
was procured from Fluka. All other reagents were of analytical reagent grade.
Ehrlich ascites carcinoma (EAC) cells were obtained from the Cancer Research Institute,
Mumbai, India; Dalton’s Lymphoma ascites (DLA) cells from the Cancer Institute, Adyar,
India; and L929 cells from National facility for animal cell and tissue culture, Pune, India.
EAC and DLA were maintained as ascites tumors in Swiss albino mice. L929 cells were
maintained in culture using MEM containing 10% goat serum and antibiotics.
Swiss albino mice were purchased from the Veterinary College, Thrissur, Kerala, India.
They were fed with normal mouse chow (Lipton India) and water ad libitum.

1510
V.D. John et al.
2.2. Synthesis of curcuminoids
The curcuminoid analogues were prepared by condensation of aromatic aldehydes (benzal-
dehyde, salicylaldehyde and 4-ethoxybenzaldehyde) with acetylacetone-boric oxide com-
plex in ethylacetate in the presence of tri(sec-butyl)borate and n-butyl amine as reported
earlier [28,32,34].
To a stirred mixture of acetylacetone (0.005 mol, 0.5 g) and boric oxide (0.0035 mol,
0.25 g) in dry ethylacetate kept at ꢀ80 °C, the aromatic aldehyde (0.01 mol) was added
and stirring was continued for ꢀ1 h with the addition of n-butyl amine (0.1 mL dissolved
in 1 mL dry ethylacetate) dropwise. Stirring was continued for an additional 4 h and the
solution was set aside overnight. Hot (ꢀ60 °C) HCl (0.4 mol, 7 mL) was added and the
mixture was again stirred for 1 h. Two layers were separated and the organic layer was
extracted with ethylacetate. The combined extracts were evaporated and the residual paste
was stirred with HCl (50%, 10 mL) for ꢀ1 h. The solid product was collected, washed
with water, and dried in vacuum. TLC of the product revealed the presence of two
components and was quantitatively separated by column chromatography using silica gel
(60–120 mesh) as detailed below.
The solid product obtained was dissolved in a minimum quantity of ethylacetate and
placed over a column (2 Â 100 cm) densely packed with silica gel. The eluting solvent was
1 : 5 (v/v) acetone:chloroform. As the elution proceeded, two bands developed in the
column, a pale yellow lower band and orange red upper band. The eluates from the pale
yellow lower region and the junction between the two bands were discarded. The elution
was then repeated using a 1 : 2 (v/v) mixture of acetone and chloroform to recover the
orange red band retained in the upper portion of the column. The eluates were collected in
aliquots of 10 mL in separate tubes, checked by TLC; and the combined extracts on
removing the solvent in vacuum yielded 1,7-diarylheptanoids (50–70%). They were recrys-
tallized twice from hot benzene to get chromatographically (TLC) pure material.
2.3. Synthesis of aluminum complexes
A methanolic solution of aluminum nitrate Al(NO3)3·9H2O (25 mL, 0.01 mol) was added
with stirring to a solution of curcuminoid (25 mL, 0.03 mol) in methanol. The mixture was
refluxed gently for 1 h. After reducing the volume to half, the solution was cooled to room
temperature, the precipitated complex was filtered, washed with 1 : 1 methanol–water
mixture, and recrystallized from hot methanol.
2.4. Antitumor experiments
2.4.1. Determination of short-term in vitro cytotoxicity. EAC cells were used for
in vitro cytotoxic studies. The compounds were dissolved in minimum DMSO which does
not enhance cytotoxicity [35–37]. The tumor cells aspirated from the peritoneal cavity of
tumor-bearing mice were washed with PBS (phosphate buffered saline). The cell
suspension (1 Â106 cells in 0.1 mL) was added to tubes containing various concentrations
(1–50 μg/mL) of the compounds and volume was made up to 1 mL using PBS. The
mixture was incubated for 3 h at 37 °C and the percentage of dead cells was evaluated by
trypan blue dye exclusion method [29,38].

Aluminium curcuminoid complexes
1511
2.4.2. Determination of cytotoxicity of compounds in tissue culture. L929 cells were
used for tissue culture studies. The cells (5 Â 103 cells/well) were plated in tarzon’s 96 well
flat-bottomed titer plates and incubated at 37 °C in 5% CO2 atmosphere. After 24 h of
incubation, various concentrations (1–10 μg/mL) of compounds were added to the wells
and incubated for a further 48 h. After incubation, the cells were detached by trypsinization
(0.2%) and stained with crystal violet. The cytotoxicity was calculated by measuring the
optical density at 570 nm after eluting the dye from the cells [29].
2.4.3. Determination of tumor-reducing activity. Groups of Swiss albino mice (6 per
group) were injected intraperitonially (ip) with Ehrlich ascites tumor cells (1 Â106 cells/
animal). The animals were injected (ip) with test compounds (200 μmoles/kg body weight)
suspended in gum accasia and the injections were continued for 10 days. The mortality rate
of the mice was noted in each group and the percentage increase in lifespan (%ILS) of the
treated group was calculated using the formula %ILS = [100(TÀC)]/C, where T is the mean
survival time of the treated mice and C is that of the control expressed in days [29].
2.4.4. Determination of the effect of compounds on solid tumor development. The
effect of various compounds on solid tumor development was studied using Swiss albino
mice. Groups of mice (6 per group) were injected subcutaneously with DLA cells
(106 cells in 0.1 mL) on the right hind limbs. One group was kept as control and the other
groups were injected (ip) with test compounds (200 μmoles/kg body weight) and the injec-
tions were continued for 10 days. Tumor diameter was measured every third day for one
2
month and tumor volume was calculated using the formula V = 4/3πr1r2 , where r1 and r2
are the minor and major radii, respectively [38, 39].
3. Results and discussion
3.1. Structural characterization of curcuminoids (HL) and their aluminum complexes
The elemental analytical data of curcuminoids (table 1) suggest that the condensation
between acetylacetone and aromatic aldehydes has occurred in 1 : 2 ratio as in figure 1.
They formed stable and well-defined crystalline complexes with Al3+. The analytical data
of the complexes together with non-electrolytic nature in DMF (specific conductance
<10 ΩÀ1cmÀ1; 10À3 M solution) suggest [AlL3] stoichiometry (table 1). The observed
analytical and spectral data of the complexes are in conformity with figure 2.
Table 1. Physical and analytical data of curcuminoids and their Al(III) complexes.
Elemental analysis: found (calculated) %
Compound/molecular formula Color
Yield % m.p. °C
C
H
Al
HL1 C19H16O2
Pale yellow
60
50
70
70
60
65
118
120
138
244
272
280
82.66 (82.61) 5.78 (5.80)
74.31 (74.03) 5.35 (5.19)
75.83 (75.82) 6.81 (6.59)
80.12 (80.28) 5.22 (5.28) 3.13 (3.17)
72.02 (72.15) 4.72 (4.75) 2.84 (2.85)
74.24 (74.19) 6.14 (6.18) 2.39 (2.42)
–
–
–
HL2 C19H16O4
Dirty green
Reddish yellow
Deep yellow
Dark green
Dark red
HL3 C23H24O4
[Al(L1)3] C57H45AlO6
[Al(L2)3] C57H45AlO12
[Al(L3)3] C69H69AlO12

1512
V.D. John et al.
Figure 1. Structure of curcuminoid analogues (HL). (a) 1,7-diphenyl-1,6-heptadiene-3,5-dione (HL1); (b) 1,7-bis
(2-hydroxyphenyl)-1,6-heptadiene-3,5-dione (HL2); (c) 1,7-bis(4-ethoxyphenyl)-1,6-heptadiene-3,5-dione (HL3).
Figure 2. Structure of the alumnium complexes of curcuminoids.
R1
H
R2
[Al(L1)3]
[Al(L2)3]
[Al(L3)3]
H
H
OH
H
OCH2CH3
3.1.1. IR spectra. The IR spectra of curcuminoids show a strong band at ꢀ1625 cmÀ1
and a broad band at 2800–3500 cmÀ1 due to the stretching of the chelated carbonyl and
the intramolecularly hydrogen-bonded enol, respectively [28, 32, 40]. The absence of any
band assignable to a normal α,β-unsaturated carbonyl at 1640–1740 cmÀ1 indicates the
existence of the compounds entirely in the enolic form [40] (figure 1). In IR spectra of Al
(III) complexes, the band at ꢀ1625 cmÀ1 due to the stretch of carbonyl is absent and,
instead, a strong band assignable to the stretch of the coordinated carbonyl is at
ꢀ1590 cmÀ1. The broad band at 2800–3500 cmÀ1 disappeared, indicating the replacement
of enolic proton by metal during complexation [41]. However, the spectrum of the
complex of HL2 exhibited bands at 3200–3600 cmÀ1 due to OH stretch in the phenyl ring
[28]. This suggests that only the enol proton is replaced by Al3+ and the phenolic OH does
not coordinate. The prominent band at ꢀ970 cmÀ1 is typical of a trans –CH=CHÀ which
remained unaltered in the spectra of metal complexes. That carbonyl groups are involved
in bonding with the metal ion is further supported by the appearance of two medium
intensity bands at ꢀ420 and ꢀ470 cmÀ1 assignable to νAl-O [28, 41].

Aluminium curcuminoid complexes
1513
1
3.1.2. 1H NMR spectra. The H NMR spectra of curcuminoids displayed a characteris-
tic downfield singlet at ꢀd16 ppm due to intramolecularly hydrogen-bonded enolic proton
1
[28,32,42] (figure 1). The methine proton signal is at ꢀd5.8 ppm. In H NMR spectra of
the Al(III) complexes, the low field signal at d16 ppm of the ligand is absent, indicating its
replacement by the metal ion during complexation [28]. The methine proton shifted
appreciably to low field compared to the shift in the olefinic protons due to the aromatic
character of the C3O2Al ring system of the chelates by the highly conjugated groups
attached to the dicarbonyl. The alkenyl proton signals with a J value of ꢀ16 Hz suggest
the trans alkene double bond, as in the free ligands [28]. Aryl protons are at d7.2–8.3 ppm
as a complex multiplet. The integrated intensities of various signals agree well with
figure 2 of the complexes. That the phenolic OH is not involved in complex formation is
clearly indicated [28] in the spectrum of the complex of HL2 where the signal remains
unaltered.
3.1.3. Mass spectra. The FAB mass spectra of curcuminoids show intense molecular
ion P+/(P + 1)+ peaks. Peaks due to the elimination of O, OH, H2O, C3HO2, and ArCH-
CHCO species from the molecular ion are also characteristic of the spectra [28, 32]. In
their mass spectra, all the complexes showed relatively intense (P + 1)+ peaks correspond-
ing to [AlL3] stoichiometry. Peaks due to [AlL]+, [AlL2]+, L+, and fragments of L+ are
sometimes more intense. Peaks at m/z corresponding to [PÀnAr]+, where n = 1 to 6, are
also present in the spectra of metal chelates due to stepwise elimination of aryl groups
[10].
3.1.4. UV spectra. UV spectra of curcuminoids exhibit two absorption maxima at ꢀ380
and ꢀ260 nm assignable to various n→π⁄ and π→π⁄ transitions of the highly conjugated
molecule [28, 32]. The absorption maxima of the metal chelates bear close resemblance
with free ligands, indicating that no structural alteration of the ligand has occurred during
complexation. However, the values shifted slightly to longer wavelength (ꢀ10 nm), indicat-
Table 2. Spectral data of curcuminoids and their Al(III) complexes.
IR stretching bands
(cmÀ1
)
1H NMR spectral data (d, ppm)
Compound
Mass spectral data, m/z
CH=CH M– Enolic
C=O
trans
O
OH
Methine Alkenyl
Aryl
HL1
HL2
1612
1630
972
978
–
–
16.86
15.86
10.44⁄
16.08
5.9
5.9
6.5–7.5 7.6–8.2 276, 199, 173, 145, 131, 103, 102
6.5–7.5 7.4–8.1 308, 291, 273, 187, 147, 120, 108
HL3
1628
1580
1593
1595
970
975
970
972
–
5.8
6.3
6.4
6.4
6.5–7.6 6.9–7.5 365, 346, 217, 189, 175, 147, 146,
134, 121
6.6–7.8 7.2–8.0 853, 775, 698, 621, 544, 467, 390,
721, 590, 459, 276, 199, 173, 145
6.7–7.2 7.5–7.9 949, 855, 762, 669, 576, 483, 390,
807, 654, 360, 308, 215, 189, 161
6.6–7.6 7.4–8.3 1117, 995, 874, 753, 632, 511, 390,
941, 820, 578, 364, 243, 122
[Al(L1)3]
[Al(L2)3]
[Al(L3)3]
461
425
469
–
–
427 10.43⁄
468
419
–
⁄Phenolic proton.

1514
V.D. John et al.
ing the involvement of the carbonyl group in metal complexation [10]. Spectral details are
given in table 2.
3.2. Antitumor studies
3.2.1. Short-term in vitro cytotoxicity. The results of short-term in vitro cytotoxicity of
curcuminoids and their aluminum(III) complexes towards Ehrlich ascites cells shown in
table 3 indicate that metal chelation enhances cytotoxicity considerably. Among the
compounds subjected to short-term assay, the aluminum complex of HL2, with a hydroxyl
group in the phenyl ring, is most active and HL1, which possesses unsubstituted benzene
ring system, shows low activity (figure 3 and Supplementary material).
3.2.2. Cytotoxicity of compounds in tissue culture. The results of the cytotoxicity of
curcuminoids and their aluminum complexes towards cultured L929 cells given in table 4
also indicate that the aluminum chelates are more cytotoxic than the respective curcumi-
noids. Compound HL1 is the least active and aluminum complex of HL2 is the most active
(Supplementary material).
Table 3. Short-term in vitro cytotoxicity of compounds towards Ehrlich ascites cells.
% cell death at different concentrations
Compounds
1 lg/ml
5 lg/ml
10 lg/ml
25 lg/ml
50 lg/ml
HL1
14
26
23
21
34
31
30
46
44
44
57
53
35
64
50
57
79
77
55
78
70
65
100
100
71
94
85
82
100
100
HL2
HL3
[Al(L1)3]
[Al(L2)3]
[Al(L3)3]
Figure 3. In vitro cytotoxic activity of aluminum complexes of curcuminoids towards Ehrlich ascites cells.

Aluminium curcuminoid complexes
1515
Table 4. Cytotoxicity of compounds towards tissue-cultured L929 cells.
% cell death at different concentrations
Compounds
1 μg/mL
2.5 μg/mL
5 μg/mL
10 μg/mL
HL1
15.9 1.5
32.9 1.0
29.2 2.8
28.7 1.3
60.1 2.9
47.2 1.8
20.2 1.3
37.7 2.8
31.3 1.6
33.1 1.8
63.9 2.4
52.3 1.7
28.1 2.0
43.9 2.2
37.1 1.9
45.8 1.7
72.6 2.9
58.4 2.4
39.4 1.3
55.6 2.7
50.6 2.9
53.4 1.9
91.2 3.1
66.7 1.6
HL2
HL3
[Al(L1)3]
[Al(L2)3]
[Al(L3)3]
3.2.3. Effect of compounds on ascites tumor reduction. All the compounds when
administered ip produced significant increase (p < 0.001 from normal) in the lifespan of
mice bearing ascites tumors (table 5). Aluminum(III) complexes produced a considerable
increase in lifespan of tumor-bearing mice compared with curcuminoids. The percentage
increase in lifespan (%ILS) of tumor-bearing mice was found minimum for HL1 and
maximum for aluminum complex of HL2 (figure 4 and Supplementary material). The
results reveal that antitumor activities of curcuminoids are enhanced more by complexation
with aluminum than with transition metal ions [26–29].
Table 5. Effect of compounds on Ascites tumor reduction.
Compound
No. of animals with tumor
No. of days survived
Increase in life span (%)
Control
HL1
6/6
6/6
6/6
6/6
6/6
6/6
6/6
17.3 1.1
22.4 1.9
30.1 1.5
29.2 2.7
26.5 1.8
35.1 1.7
31.5 1.4
29.5⁄
74.0⁄
68.8⁄
53.2⁄
102.9⁄
82.0⁄
HL2
HL3
[Al(L1)3]
[Al(L2)3]
[Al(L3)3]
⁄p < 0.001. Values are means SD of six determinations.
Figure 4. Effect of aluminum complexes of curcuminoids on Ascites tumor reduction.

1516
V.D. John et al.
Figure 5. Effect of aluminum complexes of curcuminoids on solid tumor development.
3.2.4. Effect of compounds on solid tumor development. Reductions of solid tumor
volume in mice by the administration of compounds (ip) are given in figure 5 and Supple-
mentary material. Compared to free curcuminoids, their respective aluminum(III)
complexes are remarkably active in reducing tumor volume in mice. Tumor volumes were,
respectively, 5.102, 4.657, 3.390, and 3.885 cm3 on day 31 for control, HL1, HL2, and
HL3. The tumor volumes on day 31 for aluminum complexes of HL1, HL2, and HL3 were,
respectively, 4.431, 1.879, and 3.398 cm3.

Aluminium curcuminoid complexes
1517
4. Conclusion
Three curcuminoid analogues were prepared by condensation between acetylacetone and
aromatic aldehydes (benzaldehyde, salicylaldehyde, and 4-ethoxybenzaldehyde) under
specified conditions. The analytical and spectral data indicate the existence of the
compounds in the intramolecularly hydrogen-bonded keto-enol form. Their aluminum(III)
complexes, AlL3, were synthesized and characterized by UV, IR, 1H NMR, and mass
spectral data. In complexes, curcuminoids are monobasic bidentate in which the
intramolecularly hydrogen-bonded enolic proton is replaced by Al(III). The compounds
were investigated for their possible cytotoxic and antitumor activities. The results clearly
reveal that HL2, with hydroxyl on the phenyl ring, shows largest cytotoxicity on Ehrlich
ascites and cultured L929 cells, percentage increase in lifespan and reduction of solid
tumor volume in mice. This may be due to the nature of curcuminoid which can yield
phenolic structure upon metabolism as well as due to the extended conjugation. Among
the compounds studied, HL1 with unsubstituted benzene ring showed least activity.
Complexation with aluminum significantly increased the cytotoxic and antitumor activities
of curcuminoids. Aluminum forms stable complexes with curcuminoid analogues and sig-
nificantly enhances antitumor activity of these compounds, more than their transition metal
complexes. This may be due to comparatively higher solubility of aluminum complexes in
body fluids than transition metal complexes. Further studies have to be conducted to
elucidate the exact mechanism of action.
Acknowledgments
The authors are grateful to Dr Girija Kuttan and the Director of the Amala Cancer
Research Centre, Thrissur, Kerala, India, for their help in the antitumor studies.
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