Journal of Cancer Therapy, 2013, 4, 113-123

http://dx.doi.org/10.4236/jct.2013.41016 Published Online February 2013 (http://www.scirp.org/journal/jct)

Synthesis and Anticancer Activity of Mono-Carbonyl

Analogues of Curcumin
Song Yin1,2,3, Xing Zheng1,2*, Xu Yao1, Yuhong Wang2, Duanfang Liao2
1
Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China; 2Division of Stem Cell Regulation and Ap-
plication, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of
Chinese Medicine, Changsha, China; 3The Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing,
China.
Email: *[email protected]

Received November 8th, 2012; revised December 10th, 2012; accepted December 18th, 2012

ABSTRACT
Curcumin has been reported to possess multifunctional bioactivities with low toxicity. However, the clinical application
of curcumin has been significantly limited by its instability and poor metabolic property. Up to now, multiple ap-
proaches are being sought to overcome these limitations to obtaining “super curcumin”, and many analogues of curcu-
min have been designed and synthesized. In all of those analogues, a series of mono-carbonyl curcumin analogues de-
leting the β-diketone draw our attention. Since the seven-carbon β-diketone linker in curcumin may be responsible for
its instability, the series of mono-carbonyl curcumin analogues deleting the β-diketone may be potential prodrug with
improved pharmacokinetic and pharmacodynamic properties. This review just focuses on these more stable mono-car-
bonyl analogues of curcumin, and shows the new class of active structure by introducing the synthesis and anticancer
activity of them.

Keywords: Curcumin; Mono-Carbonyl Analogues; Anticancer Activity; SAR

1. Introduction ditions [8,9]. Multiple approaches have been sought to

overcome these limitations, and many analogues of have
Curcumin,1,7-bis-(3-hydroxy-4-methoxyphenyl)-1,6-he-
been designed and synthesized [10-16].
ptadiene-3,5-dione, (Figure 1) is a key active compo-
Evidences from both in vitro and in vivo studies show
nent in the traditional herb Curcuma Longa and has been
that the β-diketone moiety is responsible for the instabi-
used for centuries throughout Asia as a food additive,
lity and weak pharmacokinetic profiles of curcumin. In
cosmetic, and as a traditional herbal medicine. As a spice,
vitro, curcumin is unstable at a pH above 6.5 because of
it provides curry with its distinctive color and flavor.
the highly reactive β-diketone moiety in the structure of
Furthermore, traditional Indian medicine has considered
curcumin [17,18]. And in vivo, recent studies indicate
curcumin a drug effective for various respiratory condi-
that the β-diketone moiety appears to be a specific sub-
tions (asthma, bronchial hyperactivity, and allergy) as
strate of a series of aldo-keto reductases [19-21] and can
well as for other disorders including anorexia, coryza,
be decomposed rapidly. In 2009, G. Liang et al. [22]
cough, hepatic diseases, and sinusitis [1,2]. Over the past
have made some studies on in vitro stability and in vivo
decade, several studies have substantiated the potential
pharmacokinetic about a series of mono-carbonyl ana-
prophylactic or therapeutic value of curcumin and have
logues of curcumin, and the results indicated that the
unequivocally supported reports of its potential biologi-
stability of these mono-carbonyl analogues was greatly
cal benefits, including anti-tumor, anti-inflammation, car-
enhanced in vitro and their pharmacokinetic profiles were
dio-protection and anti-virus [3-6]. Clinical studies re-
also significantly improved in vivo. And in some recent
ported that curcumin could be orally administered up to
12 g/day without any toxic effect in humans [7]. In spite O O
of the favorable biological properties and low toxicity of
HO OH
curcumin, there are drawbacks that limit the development
of curcumin as a potential therapeutic agent, including
low bioavailability and instability at neutral to basic con- H3CO OCH3

*
Corresponding author. Figure 1. Structure of curcumin.

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114 Synthesis and Anticancer Activity of Mono-Carbonyl Analogues of Curcumin

studies,some activities of the mono-carbonyl analogues approach to obtain large amounts of ‘natural inspired’
of curcumin are even better than curcumin. This review chemicals to therapeutics than by extracting few milli-
will focus on these more stable mono-carbonyl analogues grams from the nature. The synthesis of this kind of ana-
of curcumin. logues of curcumin is based on aldol condensation. Many
scholars have explored the method to this kind of ana-
2. Anticancer Activity of Curcumin and Its logues.
Limitations As early as in 1997, owing to the unstable β-diketone
moiety in curcumin, Sardjiman et al. [44] had synthe-
In all of those biological activities of curcumin, the anti-
sized a series of mono-carbonyl analogues of curcumin
cancer activity was investigated more. In basic cancer
by coupling the appropriate aromatic aldehyde with cy-
research, Curcumin’s beneficial effects have been shown
clohexanone, cyclopentanone or acetone in the presence
in prostate cancer cells [23], ovarian cancer cells [24],
of concentrated hydrochloric acid. And then Z.-Y. Du et
gastric carcinoma cells [25], liver cancer cells, hepatocel-
al. [45] synthesized some others mono-carbonyl ana-
lular carcinoma cells [26], cervical cancer cells [27], breast
logues of curcumin based on the procedure of Sardjiman.
cancer cells [28], colon cancer cells [29], lung carcinoma
A mixture of the appropriate aldehyde (2 equiv) and the
cell [30], bladder cancer cells [31], pancreatic adenocar-
ketone (1 equiv) was dissolved in glacial acetic acid satu-
cinoma cell [32] and so on, providing strong preliminary
rated with anhydrous hydrogen chloride and heated in a
data for the justification of clinical studies in humans.
water bath at 25˚C - 30˚C for 2 h. After standing for 2 d,
Probably the first indication of curcumin’s anticancer
the mixture was treated with cold water and filtered. The
activities in human participants was shown in 1987 by
solid obtained was then washed and dried. The crude
Kuttan and co-workers [33], who conducted a clinicaltrial
product was recrystallized from appropriate solvents
involving 62 patients with external cancerous lesions.
(methanol or ethanol). In 2009, K.-H. Lee et al. [46] got
Topical curcumin was found to produce remarkable symp-
some mono-carbonyl analogues of curcumin with better
tomatic relief as evidenced by reductions in smell, itching,
procedure with shorter reaction time. A mixture of the
lesion size, and pain. Although the effect continued for
aromatic aldehyde (2 equiv) and the appropriate ketone
several months in many patients, only one patient had an
(1 equiv) was dissolved in 15 ml of ethanol in a single
adverse reaction [33]. Since then, curcumin, either alone
necked round bottomed flask and stirred for several mi-
or in combination with other agents, has demonstrated
nutes at 5˚C (ice bath). Into this solution 10 ml of a 40%
potential against colorectal cancer [34], pancreatic can-
NaOH solution in water was then added drop wise over
cer [35], breast cancer [36], prostate cancer [37], multiple
several minutes. The mixture is then allowed to stir at
myeloma [38], lung cancer [39], oral cancer [40], and
room temperature for approximately 10 h. The reaction
head and neck squamous cell carcinoma (HNSCC) [41].
was neutralized with a dilute HCl solution to form a pre-
To date, no studies have reported any toxicity associated
cipitate, which was then collected by suction filtration.
with the use of curcumin in either animals or humans.
The product, obtained after removal of the solvent under
However studies over the past several decades related
reduced pressure, was crystallized from an appropriate
to absorption, distribution, metabolism and excretion of
solvent. G. Liang et al. [47] also got some compounds
curcumin have revealed poor absorption and rapid me-
under alkaline conditions. Instead of ethanol/sodium hy-
tabolism of curcumin that severely curtails its bioavail-
droxide, they got a higher yied in the solution of metha-
ability. For example, Wahlstrom and Blennow in 1978
nol/sodium methoxide. A method for the preparation of
reported the first study to examine the uptake, distribu-
an kind of mono-carbonyl analogues of curcumin, by
tion, and excretion of curcumin using Sprague-Dawley
Claisen condensation, starting from vanillin or vanillin
rats. They found negligible amounts of curcumin in blood
derivatives, respectively, and acetone in acid medium
plasma of rats after oral administration of 1 g/kg curcu-
under ultrasonic irradiation conditions with good yield
min, indicating its poor absorption from the gut [42].
and purity, which was patented in 2002, was adopted by
Similarly, in a study by Pan et al., a curcumin dose of 0.1
J. A. Quincoces Suarez et al. [48]. They also synthesized
g/kg i.p. produced the maximum amount of curcumin in
some mono-carbonyl analogues of curcumin under ul-
the intestine (117 μg/g) one hour after dosing. Spleen,
trasonic irradiation (40 kHz) in the presence of concen-
liver, and kidney showed moderate curcumin amounts of
trated hydrochloric acid with good yield.
26.1, 26.9, and 7.5 μg/g, respectively whereas only a
All the reported procedures for the preparation of the
trace amount (0.4 μg/g) was found in brain tissue [43].
mono-carbonyl analogues of curcumin are divided into
two conditions, namely under acidic conditions or alka-
3. Synthesis of the Mono-Carbonyl
line conditions. Both of the two procedures could gain a
Analogues of Curcumin
high yied, and that can provided the basis for the further
Organic synthesis provides a cheaper and more efficient studies of pharmacological activity (Figure 2).

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 Synthesis and Anticancer Activity of Mono-Carbonyl Analogues of Curcumin 115

O
CHO
O
H. Ohori et al. [56] selected forty-five compounds
+ R R R structurally analogous to curcumin, resveratrol or capsai-
n
n n=0, 2, 3 cin and tested their abilities to suppress the growth of the
Figure 2. Synthesis of the mono-carbonyl analogues of
colon cancer cell line DLD-1. Only one compound,
curcumin. Conditions: HCl/EtOH, NaOH/CH3OH, NaOH. compound 34, which is nominated as an mono-carbonyl
analogue of curcumin, was found to have a stronger abil-
4. Anticancer Activity of the Mono-Carbonyl ity to suppress the growth of DLD-1 compared with cur-
Analogues of Curcumin cumin. The growth-suppressive activity of compound 34
was examined in other cancer cell lines, including lines
It has been reported that curcumin possesses a wide- derived from stomach (GCIY, SH10TC), lung (LK87),
spectrum of anti-tumor properties [4,5]. The mono-car- breast (MCF7), ovary (OVK18), prostate (PC3), pancreas
bonyl analogues derived from curcumin has also been (PK9), bile duct (HuCCT1), thyroid gland (8505c), skin
reported possessing a wide-spectrum of anti-tumor prop- (A431), kidney (ACHN), and liver cancers (HepG 2) and
erties. That will be strong basis for further studies about also melanoma (G361), and the compound also showed
anticancer activity of these mono-carbonyl analogues. high growth-suppressive activity. Five related com-
H. Ligeret et al. [49] synthesized two fluoride curcu- pounds were also synthesized and tested to be having
min derivatives and studied their effects on mitochon- high growth-suppressive activity. In the subsequent stu-
drial. They induced the collapse of mitochondrial mem- dies, H. Shibata et al. [57] examined the availability of
brane potential, increased mitochondrial respiration, and compound 6 and its oxicity, which showed a thirtyfold
decreased O2− production and promoted Ca2+ release. greater growth suppression in vitro via similar molecular
These effects were reversed by the recoupling agent mechanisms to curcumin, by using the familial adeno-
6-Ketocholestanol, but not by cyclosporin A, an inhibitor matous polyposis (FAP) mouse, in vivo. In this study,
of the permeability transition pore (PTP), suggesting that oral administration of compound 6 improved chemopre-
these compounds act as uncoupling agents. Compound ventive ability in FAP mouse without apparent toxicities
71, one of the two fluoride curcumin derivatives, is a in vivo.
mono-carbonyl analogue. It was known to all that treat- H. Chandru et al. [58] synthesized four novel dienone
ment with uncouplers can induce apoptotic cell death in cyclopropoxy curcumin analogs 8 - 11 by nucleophilic
tumor lines [50]. Therefore, compound 71 may represent substitution reaction with cyclopropyl bromide and stud-
interesting antitumor agent. ied their tumor inhibitory and antiangiogenic effects on
B. K. Adams et al. [51] synthesized thirteen mono- mouse Ehrlich ascites tumor (EAT) in vivo. Their find-
carbonyl analogues of curcumin and screened for anti- ings demonstrated that the tumor growth inhibitory
cancer and antiangiogenesis activities at Emory Univer- effects of synthetic mono-carbonyl analogues of curcu-
sity and at the National Cancer Institute (NCI). The ma- min 8 - 11 could be mediated by promoting apoptosis
jority of the analogs demonstrated a moderate degree of and inhibiting tumor angiogenesis.
anti-cancer activity. And compounds 77 and 98 exhibited G. Liang et al. [22] designed and synthesized a series
a high degree of cytotoxicity, in addition, these com- of mono-carbonyl analogues of curcumin and examined
pounds inhibit tumor cell growth with a higher potency their stability in vitro and pharmacokinetic in vivo, the
than the commonly used chemotherapeutic drug, cis- results indicated that the stability of these mono-carbonyl
platin. Sun et al. [52] used compound 98 to propose a analogues was greatly enhanced in vitro and their phar-
new drug delivery system, drug-linker-Phe-Phe-Arg- macokinetic profiles were also significantly improved in
mk-fVIIa, which can associate with TF on the surface of vivo. Furthermore, the cytotoxic activities of mono-car-
cancer cells, but release the cytotoxic agent in the cyto- bonyl analogues were evaluated in seven different tumor
plasm, for a further study. The result showed when breast cell lines by MTT assay. The results suggested that the
cancer cells (MDA-MB-231) and human melanoma cells five-carbon linker-containing analogues of curcumin may
(RPMI-7951) are treated with the complex, the cells are be favorable for the curcumin-based drug development
arrested to a greater extent than compound 98 alone by both pharmacokinetically and pharmacologically.
comparison with controls. Kasinski et al. [53] demon- J. R. Fuchs et al. [59] have done a research for struc-
strate that compound 11 induces death of lung, breast, ture-activity relationship of curcumin analogues. And in
ovarian, and cervical cancer cells, with a potency about their studies ten mono-carbonyl analogues of curcumin
ten times higher than that of curcumin. were synthesized and evaluated. The most potent com-
Youssef et al. [54,55] tested the anticancer activity of pound, compound 39, showed potent growth inhibitory
fifteen mono-carbonyl analogues of curcumin they syn- activities on both prostate and breast cancer lines with
thesized. The result revealed that compound 95 shows IC50 values in sub-micromolar range, fifty times more
high anticancer activity. potent than curcumin.

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116 Synthesis and Anticancer Activity of Mono-Carbonyl Analogues of Curcumin

B. Yadav et al. [60] synthesised a series of eighteen resistance phenotype for adriamycin NCI-ADR/RES,
heterocyclic cyclohexanone analogues of curcumin and prostate PC-3, and leukemia K-562.
screened for their activity in both adherent and non-ad- J. Xiao et al. [63] synthesized a new mono-carbonyl
herent cancer cell models. And found some of the com- analogue of curcumin 18 and investigate the apoptosis of
pounds showed potent cytotoxicity towards MBA-MB- human hepatocellular carcinoma cell line HepG 2. The
231, MDA-MB-468, SkBr3 cell lines and inhibition of result suggests that 18 has more potent antitumor activity
NF-jB activation and were also able to cause MDA- than curcumin, which is associated with activation of ER
MB-231 cells to undergo apoptosis after 18 h. This level stress and induction of apoptosis in HepG 2 cells.
of activity warrants further investigation for the treatment All of those reported about the anticancer activity of
of ER-negative breast cancer and/or chronic myeloge- the mono-carbonyl analogues of curcumin indicated that
nous leukemia as prototypical cellular models for solid this kind of compounds may provided a series of nice
and liquid tumors. leading compounds with anticancer activity. And all
H. Yamakoshi et al. [61] synthesized a series of mono- compounds with anticancer activity show in Tables 1-4.
carbonyl analogues of curcumin and evaluated for their
cytotoxicities against human colon cancer cell line HCT- 5. Structure Activity Relationship Analysis
116 to conclude the SAR of mono-carbonyl analogues of of the Mono-Carbonyl Analogues of
curcumin for further development of their use in cancer Curcumin
chemotherapy.
P. Lagisetty et al. [62] obtained a potent and novel As mentioned above, many researchers have studied
curcuminoid 161 from structure activity relationship of about anticancer activity of mono-carbonyl analogues of
3,5-bis(benzylidene)-4-piperidones for their anti-proli- curcumin, SAR about anticancer activity have been also
ferative activity in lung adenocarcinoma H441 cells. discussed. In the research group of G Liang, they have
J. A. Quincoces Suarez et al. [48] found that the set of concluded the SAR of mono-carbonyl analogues from
synthetic compound 21 exhibited high antitumoral ac- their data: 1) A strong electron-withdrawing substituent
tiveties regarding in vitro screening against several hu- in 2’position may increase bioactivity and the more elec-
man tumor cell lines as lung carcinoma NCI-460, mela- tronegative is the moiety, the more cytotoxic is the com-
noma UACC-62, breast MCF-7, colon HT-29, renal pound; 2) A weak electron-donating substituent in
786-O, ovarian OVCAR-03 and ovarian expressing the 4’position is most favorable to the anti-tumor activity of

Table 1. Compounds 1 - 48.

R1 O R6
R2 R7

R3 R5 R10 R8
R4 R9
Compounds R1 R2 R3 R4 R5 R6 R7 R8 R9 R10

1 -OH -H -H -H -H -OH -H -H -H -H

2 -H -OH -H -H -H -H -OH -H -H -H

3 -H -H -OH -H -H -H -H -OH -H -H

4 -H -H -H -F -H -H -H -H -F -H

5 -H -OCH3 -OCH2OCH3 -OCH3 -H -H -OCH3 -OCH2OCH3 -OCH3 -H

6 -H -OCH2OCH3 -H -OCH2OCH3 -H -H -OCH2OCH3 -H -OCH2OCH3 -H

7 -H -H -OH -OCH3 -H -H -OH -OCH3 -H -H

8 -H -OCH3 O -OCH3 -H -H -OCH3 O -OCH3 -H

9 -H -OCH3 O -H -H -H -OCH3 O -H -H

10 -H -H O -H -H -H -H O -H -H

11 -H -CH3 O -CH3 -H -H -CH3 O -CH3 -H

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 Synthesis and Anticancer Activity of Mono-Carbonyl Analogues of Curcumin 117

Continued
12 -H -H -OCH3 -OH -H -H -OCH -OH -H -H

13 -H -H -OCH2CH=CH2 -H -H -H -H -OCH2CH=CH2 -H -H
-(Terahyro-2H- -(Terahyro-2H-
14 -H -H -H -H -H -H -H -H
pyran-yl)oxy pyran-yl)oxy
15 -CH3 -H -H -CH3 -H -CH3 -H -H -CH3 -H

16 -H -H -C(CH3)3 -H -H -H -H -C(CH3)3 -H -H

17 -H -H -F -H -H -H -H -F -H -H

18 -Br -H -H -H -H -Br -H -H -H -H

19 -Cl -H -H -H -H -Cl -H -H -H -H

20 -CF3 -H -H -H -H -CF3 -H -H -H -H

21 -H -OCH3 -OH -H -H -H -OCH3 -OH -H -H

22 -H -OH -OCH3 -H -H -H -OH -OCH3 -H -H

23 -H -OCH3 -OH -OCH3 -H -H -OCH3 -OH -OCH3 -H

24 -H -OCH3 -OSO2NH2 -H -H -H -OCH3 -OSO2NH2 -H -H

25 -H -H -OSO2NH2 -OCH3 -H -H -H -OSO2NH2 -OCH3 -H

26 -H -OCH3 -OSO2NH2 -OCH3 -H -H -OCH3 -OSO2NH2 -OCH3 -H

27 -OCH3 -H -H -H -H -OCH3 -H -H -H -H

28 -H -OCH3 -H -H -H -H -OCH3 -H -H -H

29 -H -H -OCH3 -H -H -H -H -OCH3 -H -H

30 -OCH3 -OCH3 -H -H -H -OCH3 -OCH3 -H -H -H

31 -OCH3 -H -OCH3 -H -H -OCH3 -H -OCH3 -H -H

32 -OCH3 -H -H -OCH3 -H -OCH3 -H -H -OCH3 -H

33 -OCH3 -H -H -H -OCH3 -OCH3 -H -H -H -OCH3

34 -H -OCH3 -OCH3 -H -H -H -OCH3 -OCH3 -H -H

35 -H -OCH3 -H -OCH3 -H -H -H -OCH3 -OCH3 -H

36 -OCH3 -OCH3 -OCH3 -H -H -OCH3 -OCH3 -OCH3 -H -H

37 -OCH3 -OCH3 -H -H -OCH3 -OCH3 -OCH3 -H -H -OCH3

38 -OCH3 -H -OCH3 -OCH3 -OCH3 -OCH3 -H -OCH3 -H

39 -OCH3 -H -OCH3 -H -OCH3 -OCH3 -H -OCH3 -H -OCH3

40 -H -OCH3 -OCH3 -OCH3 -H -H -OCH3 -OCH3 -OCH3 -H

41 -OCH3 -OCH3 -OCH3 -OCH3 -H -OCH3 -OCH3 -OCH3 -OCH3 -H

42 -H -H -H -H -H -H -OCH3 -OCH3 -OCH3 -H

43 -H -H -OCH3 -H -H -H -OCH3 -OCH3 -H -H

44 -H -H -OCH3 -H -H -H -OCH3 -OCH3 -OCH3 -H

45 -H -OCH3 -H -H -H -H -OCH3 -OCH3 -OCH3 -H

46 -H -OCH3 -OCH3 -H -H -H -OCH3 -OCH3 -OCH3 -H

47 -OCH3 -OCH3 -OCH3 -H -H -H -OCH3 -OCH3 -OCH3 -H

48 -OCH3 -H -OCH3 -OCH3 -H -H -OCH3 -OCH3 -OCH3 -H

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118 Synthesis and Anticancer Activity of Mono-Carbonyl Analogues of Curcumin

Table 2. Compounds 49 - 68.

R1 O R6
R2 R7

R3 R5 R10 R8
R4 R9
Compounds R1 R2 R3 R4 R5 R6 R7 R8 R9 R10
49 -H -H -OH -H -H -H -OH -H -H
50 -H -H -OH -OCH3 -H -H -H -OH -OCH3 -H
51 -H -CH3 -OH -CH3 -H -H -CH3 -OH -CH3 -H
52 -H -C2H5 -OH -C2H5 -H -H -C2H5 -OH -C2H5 -H
53 -H t-C4H9 -OH t-C4H9 -H -H t-C4H9 -OH t-C4H9 -H
54 -H i-C3H7 -OH i-C3H7 -H -H i-C3H7 -OH i-C3H7 -H
55 -H -OCH3 -OH -OCH3 -H -H -OCH3 -OH -OCH3 -H
56 -H -Cl -OH -Cl -H -H -Cl -OH -Cl -H
57 -H -H -OCH2CH3 -H -H -H -H -OCH2CH3 -H -H
58 -OCH3 -OCH3 -H -H -H -OCH3 -OCH3 -H -H -H
59 -OCH3 -H -H -H -H -OCH3 -H -H -H -H
60 -H -OCH3 -OCH3 -OCH3 -H -H -OCH3 -OCH3 -OCH3 -H
61 -H -OCH2CH=CH2 -OCH3 -H -H -H -OCH2CH=CH2 -OCH3 -H -H
62 -H -H -O(CH2)3N(CH3)2 -H -H -H -H -O(CH2)3N(CH3)2 -H -H
-(Tatrahydro-2H- -(Tatrahydro-2H-
63 -H -H -H -H -H -H -H -H
pyra-2-yl)oxy pyra-2-yl)oxy
64 -H -H -N(CH3)2 -H -H -H -H -N(CH3)2 -H -H
65 -H -H -F -H -H -H -H -F -H -H
66 -Br -H -H -H -H -Br -H -H -H -H
67 -Cl -H -H -H -H -Cl -H -H -H -H
68 -CF3 -H -H -H -H -CF3 -H -H -H -H

Table 3. Compounds 69 - 92.

R1 O R6
R2 R7

R3 R5 R10 R8
R4 R9
Compounds R1 R2 R3 R4 R5 R6 R7 R8 R9 R10
69 -H -H -OH -H -H -H -H -OH -H -H
70 -H -CH3 -OH -CH3 -H -H -CH3 -OH -CH3 -H
71 -H -H -OH -F -H -H -H -OH -F -H
72 -H -H -OH -OCH3 -H -H -H -OH -OCH3 -H
73 -H -C2H5 -OH -C2H5 -H -H -C2H5 -OH -C2H5 -H
74 -H i-C3H7 -OH i-C3H7 -H -H i-C3H7 -OH i-C3H7 -H
75 -H t-C4H9 -OH t-C4H9 -H -H t-C4H9 -OH t-C4H9 -H
76 -H -OCH3 -OH -OCH3 -H -H -OCH3 -OH -OCH3 -H
77 -OH -H -H -H -H -OH -H -H -H -H
78 -F -H -H -H -H -F -H -H -H -H
79 -H -OCH3 -OCH3 -H -H -H -OCH3 -OCH3 -H -H
80 -H -OCH3 -OH -H -H -H -OCH3 -OH -H -H
81 -H -H -OCH2CH3 -H -H -H -H -OCH2CH3 -H -H
82 -H -OCH3 -OCH3 -OCH3 -H -H -OCH3 -OCH3 -OCH3 -H
83 -H -H -OCH2CH=CH2 -H -H -H -H -OCH2CH=CH2 -H -H
84 -H -OCH3 -OCH2CH=CH2 -H -H -H -OCH3 -OCH2CH=CH2 -H -H
85 -H -H -(Tetrahydro-2H-pyran-yl)oxy -H -H -H -H -(Tetrahydro-2H-pyran-yl)oxy -H -H
86 -CH3 -H -H -CH3 -H -CH3 -H -H -CH3 -H
87 -H -H -C(CH3)3 -H -H -H -H -C(CH3)3 -H -H
88 -H -H -F -H -H -H -H -F -H -H
89 -H -Br -H -H -H -H -Br -H -H -H
90 -Br -H -H -H -H -Br -H -H -H -H
91 -Cl -H -H -H -H -Cl -H -H -H -H
92 -CF3 -H -H -H -H -CF3 -H -H -H -H

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 Synthesis and Anticancer Activity of Mono-Carbonyl Analogues of Curcumin 119

Table 4. Compounds 93 - 110.

O

R1 R2
N
R3

Compounds R1 R2 R3 Compounds R1 R2 R3

93 2-OH 2-OH -CH3 102 2-F 2-F -H

94 4-OH 4-OH -CH3 103 4-OCH3 4-OCH3 -CH3

95 4-OH; 5-OC2H5 4-OH; 5-OC2H5 -CH3 104 4-OH; 5-OC2H5 4-OH; 5-OC2H5 -C2H5

96 4-OCH3 4-OCH3 -C2H5 105 4-OH 4-OH -C2H5

97 4-OH 4-OH -C3H7 106 -H -H -H

98 2-F 2-F -H 107 2-Cl 2-Cl -H

99 2-Br 2-Br -H 108 2-NO2 2-NO2 -H

100 3-Cl 3-Cl -H 109 4-F 4-F -H

101 4-Cl 4-Cl -H 110 4-N(CH3)3 4-N(CH3)3 -H

compound, a strong electron-donating moiety may re- meaningful to do further researches on the mono-car-
move the bioactivity and a strong electron-withdrawing bonyl curcumin analogues. What more, some other pha-
one may reduce it; 3) The acetone and cyclohexanone rmacological activity were also been found in those
spacers are much more favorable than the cyclopenta- mono-carbonyl curcumin analogues. such as antioxi-
none one; 4) The introduction of heteroaromatic ring is dant [64-66], anti-inflammatory [67,68], anti-bacterial
also pharmacologically accessible. And the following [69], anti-AD [70], with which the class of compounds
conclusions about SAR were drawn by the the research will having good development prospects.
group of H. Yamakoshi; 5) Bis(aryl methylidene) ace-
tone serves as the most promising skeleton for eliciting 7. Acknowledgements
cytotoxicity; 6) The 3-oxo-1,4-pentadiene structure is
This research was supported by the National Natural
essential for eliciting cytotoxicity; 7) Hexa-substituted
Science Foundation of China (No. 81273537), Scientific
compounds exhibit strong activities; 8) 3,4,5-Hexasub- Research Fund of Hunan Provincial Education Depart-
stitution results in the highest potency; 9) The symmetry ment (No. 12K095), and the Key Project of Ministry of
between two aryl rings is important for tetra-substituted Education of the People’s Republic of China (No.
analogues but not a requirement for hexa-substituted 20809).
analogues; 10) para-positions are allowed to introduce of
additional functional groups for use as molecular probes.
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