Recent developments in chemistry and biology of curcumin analogues

Abstract

Curcumin, a prominent constituent of the rhizome of Curcuma longa L., possesses versatile biological properties, which is evidenced from the extensive research during the last half century. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has potential against various malignant diseases, such as allergies, arthritis, Alzheimer's disease, and other chronic illnesses. In the last decade it has been much explored and various synthetic analogues have been prepared and evaluated for various pharmacological activities that render it as a lead molecule against several biological targets. To accelerate this lead molecule from kitchen to clinic, around 65 clinical trials are underway worldwide to assess its therapeutic potential. Thus, there is continued interest in the synthesis of new curcumin analogues with a similar safety profile, but increased activity and improved oral bioavailability. The present review article describes recent developments in curcumin chemistry with emphasis on the semi-synthesis, synthesis pharmacological properties and SAR of various curcumin analogues reported from 1994 to mid 2013.

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Khemraj Bairwa

Khemraj Bairwa is a Ph.D. Scholar (4^th year) at the Department of Natural Products, National Institutes of Pharmaceutical Education and Research (NIPER), SAS Nagar, working under the supervision of Dr Sanjay M. Jachak. He did his M.S. (Pharm.) in the same department in 2009. He completed his B. Pharm. at Seth G. L. Bihani S. D. College of Technical Education, Rajasthan University of Health Sciences in June 2007. Currently, he is working on isolation, characterization and biological evaluation of compounds from medicinal plants and development of nano-formulations of plant extracts.

Jagdeep Grover

Jagdeep Grover was born in 1988 in Kotkapura city, Punjab, India. He received his B. Pharm. from Guru Nanak Dev University (GNDU), Amritsar in June 2009, and his M. S. (Pharm.) from the National Institute of Pharmaceutical Education and Research (NIPER), Mohali, India in June 2011. In july 2011, he joined a Ph.D. program under the supervision of Associate Professor Dr Sanjay M. Jachak at NIPER. Currently he is a third year Ph.D. student working on design and synthesis of natural product analogues and their biological evaluation for anti-inflammatory activity.

Mihir Kania

Mihir Kania was born in 1985 in Bharuch District, Gujarat, India. He received his B. Pharm. L. M. College of Pharmacy, Gujarat Technological University, Ahmedabad in 2007, and his M. S. (Pharm.) from NIPER, Mohali, India in June 2009, under the supervision of Dr Sanjay M. Jachak; under this program he worked on isolation and characterization of phytoconstituents from plant/extracts. Currently he is a working as Jr Officer Production, Sun Pharma Ltd.

Sanjay M. Jachak

Sanjay M. Jachak is Associate Professor in the Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India. He received a Ph.D. in Pharmacy (specialization: Phytochemistry) from Karl Franzens University, Graz, Austria in 1997. He was a lecturer at the College of Pharmacy, Nashik, India from 1998–1999. He joined NIPER, Mohali as Assistant Professor of Natural Products in 1999 and became Associate Professor in 2006. His research interests include characterization of anti-inflammatory and antimycobacterial natural products, and design and synthesis of bioactive natural products.

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Introduction

In Asia more than 30 Curcuma species (Zingiberaceae) are found, where the rhizomes of these plants have been used worldwide as spices (e.g. curry), flavouring agents, food preservatives and colouring agents since ancient times. These plants are usually aromatic, carminative and are used to treat various ailments in India, China and other Asian countries. Among the Curcuma species known, C. longa (turmeric), C. xanthorrhiza (Javanese turmeric), C. zedoaria and C. aromatica (wild turmeric) are recognized to contain curcuminoids.¹ The main constituents of these Curcuma species are curcuminoids and bisabolane-type sesquiterpenes.² Curcuminoids share a common unsaturated alkyl-linked biphenyl structural feature and are responsible for their major pharmacological effects. Curcuminoids in C. longa and other Curcuma species are mainly curcumin 1, demethoxycurcumin (DMC) 2, and bis-demethoxycurcumin (BDMC) 3 (Fig. 1); amongst which curcumin is the most studied and showed a broad range of biological activities. Commercially available curcuminoid mixture contains 77% curcumin, 17% DMC, and 3% BDMC. A lesser known curcuminoid from turmeric is cyclocurcumin 4, which differs from curcumin in the β-diketone moiety. In this molecule, the α,β-unsaturated β-diketone moiety of curcumin is replaced by an α,β-unsaturated dihydropyrone moiety.³ Curcumin was first isolated in 1815, obtained in crystalline form in 1870 and ultimately identified as 1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione-(1E,6E).⁴ In 1910, the diferuloylmethane skeleton of curcumin was confirmed and synthesized by Lampe.⁵ A number of metabolites of curcumin have been reported till date, which includes dihydrocurcumin (DHC) 5, tetrahydrocurcumin (THC) 6, hexahydrocurcumin (HHC) 7, octahydrocurcumin (OHC) 8, curcumin sulphate 9 and curcumin glucuronide 10 (Fig. 1).⁶

Fig. 1 Curcuminoids and curcumin metabolites.

During the last two decades, numerous studies have shown that curcumin possess a variety of biological activities (Table 1) such as anti-carcinogen,^7,8 immunomodulation,⁹ antioxidant,¹⁰ anti-inflammatory,^11,12 anti-angiogenesis,¹³ antitumor,¹⁴ chemo-prevention,¹⁵ Alzheimer's disease,¹⁶ antimicrobial,¹⁷ antimalarial,¹⁸ antithrombotic,¹⁹ myocardial infarction protective,²⁰ rheumatoid arthritis,²¹ inhibition of human immunodeficiency virus (HIV) replication,²² enhancement of wound healing,²³ antihepatotoxic,²⁴ psoriasis,²⁵ hypoglycemic,²⁶ and antihyperlipidaemic.^27,28 Curcumin interacts with numerous molecular and biochemical targets which includes inflammatory cytokines, transcriptional factors, kinases, enzymes, receptors, growth factors, anti-apoptotic proteins, adhesion molecules and ligands.^28–30 These diverse biological properties attracted clinicians to explore the therapeutic potential of curcumin by conducting clinical trials. Around 65 clinical trials are underway world wide to verify the therapeutic potential of curcumin for various diseases.^28,31,32 In spite of the broad spectrum activities and safety profile exhibited by curcumin, it is not yet approved as a therapeutic agent due to its poor oral bioavailability.³³ Curcumin is non-toxic even at high dosages, to date no toxicity has been found in any animal and human studies and has been classified as ‘generally recognized as safe’ (GRAS) by the National Cancer Institute.^33,34 The pharmacokinetic and pharmacodynamics studies on curcumin has proved that one of the major limitations of using curcumin as a drug is its poor water and plasma solubility; even doses as high as 8 g of curcumin per day administered to human subject's results in an average peak serum concentration of ∼1.77 μM of curcumin.^33,34 Also, because curcumin strikes the cell at several sites, it is difficult to determine which target is causing the desired effect in a certain disease. Thus, there is a continued interest in the synthesis of new curcumin analogues with a similar safety profile, but increased activity and improved oral bioavailability.

Table 1 Biological activities of curcumin^a

Compound	Activity	Assay/target	IC50 (μM)	References
a * indicates % inhibition in mg ml^−1; ** indicates % inhibition at 6 μg ml^−1; ^# indicates GI50 value in μM; ^## indicates MIC. b Against vincristine induced cytotoxicity. c Against paclitaxel induced cytotoxicity.
Curcumin (1)	Antioxidant	Lipid peroxidation	1.30	40
		ABTS^+ assay	3.37	40
		DPPH assay	20.02	40 and 41
		NBT assay	41	41
	Anti-inflammatory	COX-1	50	43
		COX-2	>100	43
	Antitumor	COX-2	15.9	47
		Fos–Jun DNA complex	0.48*	45
		NF-κB	8.2	44
		Leukaemia	3.7^#	55
		NSCL	9.2^#	55
		Colon	4.7^#	55
		CNS	5.8^#	55
		Melanoma	7.1^#	55
		Ovarian	8.9^#	55
		Renal	8.9^#	55
		Prostate	11.2^#	55
		Breast	5.9^#	55
		MDR reversal activity	0.82^b	61
		MTS assay	0.42^c
	Cytotoxic	PC-3	7.7	48
			19.8	50
		LNCaP	3.8	48
			19.6	50
		DU-145 (mutant & wild AR)	Inactive	49
		HepG2	4.6	46
		SMMC-7721	5.4	46
		CT26	16.6	46
		Hela	7.5, 17.5	46 and 75
		Skov3	7.8	46
		A549	10.3	46
		MCF-7	21.5	50
		MDA-MB-231	25.6	50
		BGC 823	16.7	72
		CNE	32.8	72
		HL-60	11.6	72
		KB	35.9	72
		LS 174T	6.4	72
		A16-F10	18.6	69
		EGFR	8.6	69
	Anti-angiogenesis	HUVEC	10.84	70
		SVR cell line	56.2**, 9.8^#	53,55 and 76
	Anti-HIV	Strand transfer	140	51
	Antimalarial	P. falciparum (strain FCK2)	3.25	50
		P. falciparum (strain MP-14)	4.21	50
	Antimicrobial	Escherichia coli	20^##	83 and 84
		Staphylococcus aureus	20^##	83 and 84
		Staphylococcus epidermidis	10^##	83 and 84
		Enterococcus	20^##	83 and 84

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Recent strategies for synthesis of curcumin analogues

Curcumin has a unique conjugated, linear diarylheptanoid structure including two methylated phenols linked together through a seven-carbon chain to form a heptadiene-3,5-diketone. Curcumin exhibits two tautomers: 1,3-diketone and 1,3-keto–enol which may assume different conformations. The theoretical calculations have proved 1,3-keto–enol form is more stable than 1,3-diketone form.³⁵ Except for the keto–enol moiety, the C₇ chain is generally unsubstituted and the unsaturation in the linker unit has an E-configuration (trans C=C bonds). The computational chemistry calculations have shown that structure of curcumin is planar and linear.^35,36 The single crystal X-ray diffraction studies on curcumin reported by several groups indicate the enol form as the preferred tautomer and the methoxy groups are pointed in the opposite direction with respect to the 1,3-keto–enol group.³⁶ The aryl and enol moiety is the polar part of the structure where as the heptadiene bridge region is quite hydrophobic. Thus, the computationally derived structure differs somewhat with that seen in the solid state.

The broad-spectrum activities and the least bioavailability led the path for the semi-synthesis and synthesis of various curcumin analogues. The curcumin analogues are those which encompass some ostensible or claimed structural analogy or likeness to curcumin. The structure of curcumin includes two feruloyl moieties, non-polar heptadiene bridge and 1,3-keto–enol or diketo moiety (Fig. 2). A preliminary structure–activity relationship (SAR) study of symmetrical curcuminoids explained that the feruloyl moiety plays a critical role in various biological functions. However, curcumin is stable at a pH below 6.5. The instability of curcumin at a pH above 6.5 is caused by the active methylene group.³³ It has been proved that the biological efficacy of curcumin arises from the electrophilic nature of its central β-diketone component. It is suggested that the presence of the methylene group and β-diketone moiety contributes to the instability of curcumin under physiological conditions.³⁷ Therefore; the deletion of the β-diketone moiety may contribute to the enhancement of stability of curcuminoids. On the basis of the former information and research on curcumin, there have been considerable efforts to synthesize various bioactive analogues of curcumin and the process is still on the way of progress with a large number of successes. In the present article, we have focused on different curcumin analogues prepared by both synthetic or semi-synthetic route and being described as per following schemes;

Fig. 2 Structural features of curcumin.

(1) Changes in aryl substitution pattern of curcumin,

(2) Changes in the β-diketone structure which includes,

(2.1) Monocarbonyl analogues (cyclic and acyclic, symmetrical and asymmetrical),

(2.2) Dicarbonyl analogues,

(2.3) Heterocyclic analogues,

(2.4) Change in the 1,3-keto–enol moiety,

(2.5) Change in the conjugation,

(2.6) Substitution on the 1,6-heptadiene moiety (β-carbon of dicarbonyl chain),

(3) Curcumin bioconjugates,

(3.1) Amino-acid conjugates,

(3.2) Curcuminoid glycosides,

(3.3) Curcumin–taxoid conjugate,

(4) Miscellaneous.

1. Changes in aryl substitution pattern of curcumin

The antioxidant activity of curcumin is not only due to phenolic groups but also the ortho-methoxy functionality. The ortho-methoxy group can form an intramolecular hydrogen bond with the phenolic hydrogen, making the H-atom abstraction from the ortho-methoxy phenols surprisingly easy. The methoxy group of curcuminoids is related to the antioxidant activity, while increasing the number of hydroxyl substitutions on the aryl ring to form polyhydroxycurcuminoids (11) are potent scavengers of superoxide and DPPH free radicals.^38,39 Methylation of curcumin to form dimethoxycurcumin (12) resulted in similar antioxidant activity as curcumin.⁴⁰ All the non-phenolic analogues (12–16) were either less active or inactive. It has been suggested that the steric crowding in compounds (17, 18–20) (Table 2) at ortho-positions frees the phenolic group from hydrogen bonding to the media and enhances the facile transfer of the hydrogen atom. Steric crowding also increases the stability of the phenoxy radical. The antioxidant activity of α-tocopherol is attributed to the steric crowding effect of two methyl groups at the ortho-position to the phenolic group. But, in case of curcuminoids, it appears that there is an optimum requirement for the steric crowding. When the methoxy group was replaced by the ethoxy group (18), the antioxidant, anti-inflammatory and lipid peroxidation activities were enhanced (Table 3). The activity was increased when the phenolic group was hindered by the presence of two methyl groups (19) at the ortho position to the phenolic group. When the two methyl groups ortho to the phenolic group were replaced with more bulky tert-butyl groups (20), the activity was reduced significantly. Compounds with better activity can be designed by investigating steric and electronic factors in a systematic manner. The diacetyl derivative (21) of curcumin also showed better antioxidant activity. It is possible that the acetyl group may be hydrolysing to some extent during the test to release the free phenolic group.^40,41 Substitution with aminodimethyl group led to decrease in antioxidant activity.⁴¹ The replacement of methoxy group of curcumin to carboxyl group (22) led to decrease in antioxidant activity.⁴¹

Table 2 Chemical structures of curcumin analogues with changes in aryl substitution pattern (Class 1)

General structure for Class-1 compounds (11–39)
Comp.	R1	R2	R3	R4	R5
11	H	OH	OH	OH	H
12	H	OCH3	OCH3	H	H
13	H	OCH3	OCH3	OCH3	H
14	OCH3	OCH3	OCH3	H	H
15	H	OCH3	OCH3	H	OCH3
16	H	H	OCH3	H	H
17	H	OCH3	OH	OCH3	H
18	H	OCH2CH3	OH	H	H
19	H	CH3	OH	CH3	H
20	H	C(CH3)3	OH	C(CH3)3	H
21	H	OCH3	OCOCH3	H	H
22	H	COOH	OH	H	H
23	H	H	SCH3	H	H
24	H	CH2CH=CHCOOCH2CH3	OCH3	H	H
25	H	NO2	OH	H	H
26	H	F	F	H	H
27	H	F	OH	H	H
28	H	OCH3	OCH2COOH	H	H
29	H	OCH3	OCH2COONa	H	H
30	H	OCH3	OCH2CH2OH	H	H
31	H	OCH3	OCH2CH(OH)CH2OH	H	H
32	H	CH2COOCH2CH3	OCH3	H	H
33	H	OCH3	OSO2NH2	H	H
34	H	OCH3	OSO2NH2	OCH3	H
35	H	OSO2NH2	OCH3	H	H
36	H	OCH3		H	H
37	H	OCH3		H	H
38	H	OH	OH	H	H
39	H	H	OH	H	H

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General structure for Class-1 compounds (40–62)
Compounds	R1	R2	R3	R4
40	H	H	OCH3	H
41	OH	H	OCH3	OH
42	H	H	OH	H
43	OCH3	CH3	OCH3	H
44	OCH3	C3H7	OCH3	H
45	OCH3	C3H7	OCH3	C3H7
46	OCH3	CH2CH2OH	OCH3	H
47	OCH3	CH2–CH=CH2	OCH3	H
48	OCH3	CH2–CH=CH2	OCH3	CH2–CH=CH2
49	OCH3	CH2(CH2)3CH3	OCH3	H
50	OCH3	CH2(CH2)3CH3	OCH3	CH2(CH2)3CH3
51	OCH3	Ac	OCH3	H
52	H	Ac	OCH3	H
53	H	H	OCH3	Ac
54	H	Ac	OCH3	Ac
55	H	Ac	H	H
56	H	CH3	OCH3	H
57	H	CH3	OCH3	CH3
58	H	CH3	H	H
59	OCH3	CH2CH=CH(CH3)2	OCH3	H
60	H	CH2CH=CH(CH3)2	OCH3	CH2CH=CH(CH3)2
61	H	CH2CH2OH	OCH3	H
62	H	H	OCH3	CH2CH2OH

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Table 3 Biological activity of curcumin analogues with changes in aryl substitution pattern (Class-1)^a

Activity	Assay/target	Compound(s)	IC50 (μM)	Ref.
a * indicates % inhibition in mg ml^−1; ** indicates % inhibition at 1 μM; ^# indicates GI50; NA, not active (MIC > 200 mg ml^−1); ND, not determined; INS = insoluble; ^## indicate MIC (μg ml^−1).
Antioxidant	Lipid peroxidation	18, 19	1.1, 0.6	40
	ABTS^+ assay	12, 18, 20, 21, 16	2.6, 3.3, 1.0, 2.3, 2.1	40
	DPPH assay	38, 11, 17, 18, 19, 20, 39	6, 4.6, 26, 30.3, 21.7, 23.7, >300	40–42
	NBT assay	38, 11, 20, 22	11.8, 4.8, 37.6, 27.8	41
Anti-inflammatory	COX-1	14, 26, 23	0.06, 0.3, 2.6	44
	COX-2	26	12.5	44
Antitumor	COX-2	27	23.7	48
	Fos–Jun DNA complex	25	0.38*	46
Cytotoxic	PC-3	12, 14, 15, 17, 33, 34, 35, 65, 66, 67, 68, 69, 70, 71	1.1, 8.1, 2.4, 14.0, 7.5, 13.1, 7.4, 39, 100.3, 48.1, 52.1, >100, >100, >100	49–51 and 59
	LNCaP	12, 14, 15, 17, 33, 34, 35, 39, 65, 66, 67, 68, 69, 70, 71	1.3, 4.8, 2.9, 2.6, 5.9, 10.4, 7.7, 19.7, 41.8, 73.0, 55.0, 54.8, >100, >100, >100	49,51 and 59
	MCF-7	12, 33, 34, 35, 36, 37	5.4, 5.5, 4.7, 5.5, >100, 49.2	51 and 52
	MDA-MB-231	12, 33, 34, 35	4.9, 3.1, 5.5, 6.5	51
	DU-145 (mutant AR)	12	45**	50
	DU-145 (wild AR)	12	49**	50
	HepG2	28, 29, 30, 31, 36, 60	10.1, 18.2, 7.2, 15.7, 71.6, 43.6	47 and 52
	SMMC-7721	28, 29, 30	53.1, 38.6, 24.2	47
	CT26	28, 29, 30, 31	6.1, 38.6, 25.1, 10.0	47
	Hela	28, 29, 30	12.1, 31.2, 15.5	47
		31, 36, 60	11.7, 37.1, 23.8	52
	Skov3	28, 30, 31, 36, 37	41, 76, 62.6, 55.5, 38.3	47 and 52
	A549	28, 29, 31, 58, 37	21, 42.4, 53.7, >100, >100	47 and 52
	A431	36, 37	7.2, 9.4	52
	U-251	36, 37	7.1, 7.7	52
	HEp-2	36, 37	>100, >100	52
	HEK	39, 41, 42, 12, 56, 57, 58, 45, 47, 48, 59, 60, 46, 30, 61, 21, 54	200, 36, 30, 200, 79, 690, 400, >500, 270, >500, >500, >500, 25, 20, 46, 80, 49	54
	A549 cells	16, 12, 13, 63, 64	>25, 5.80, 19.26, >25, >25	56
Anti-HIV	Strand transfer	38, 39	3.1, 80	53
Anti-malarial	P. falciparum (strain FCK2)	12, 21	7.86, 2.34	57
	P. falciparum (strain MP-14)	12, 21	8.4, 2.51	57
M. tuberculosis	H37Ra strain	40, 39	50, 25	55
		41, 42	200, 200
		43, 12, 44	50, 100, 25
		45, 46, 30	200, 200, 200
		47, 48, 49	100, NA, 12.5
		50, 51, 21	100, 100, 200
		52, 53, 54	50, 50, 100
		55, 24, 32	25, 7.81^##, 125^##	58
Antitrypanosomal	T. brucei strain 427	40, 39, 41, 42, 12, 56, 57, 58, 45, 47, 48, 59, 60, 46, 30, 61, 21, 54	4.6, 7.7, 0.87, 0.65, 0.45, 1.7, 1.6, 8.9, 1.3, 2.4, 1.6, 1.4, 1.9, 2.9, 1.8, 0.7, 1.6, 1.5	54
	T. brucei ΔTbat1	40, 39, 41, 42, 12, 56, 57, 58, 45, 47, 48, 59, 60, 46, 30, 61, 21, 54	5.9, 9.5, 1.1, 1.8, 0.62, 2.0, 1.9, 8.8, 1.8, 2.2, 1.9, 1.7, 2.9, 2.9, 2.3, 0.85, 2.2, 2.0	54
	T. brucei clone B48	40, 39, 41, 42, 12, 56, 57, 58, 45, 47, 48, 59, 60, 46, 30, 61, 21, 54	2.2, 4.5, 2.7, 1, 0.77, 2.1, 1.9, 2.9, 1.6, 12, 5.8, 2, 3.1, 1.8, 1.6, 1.1, 1.2, 0.92	54
Antileishmanial	L. major promastigotes	40, 39, 41, 42, 12, 56, 57, 58, 45, 47, 48, 59, 60, 46, 30, 61, 21, 54	37, 72, 4.3, 22, 2.8, 23, 23, 87, 28, 5.7, 25, 7.6, 48, 22, 33, 9.7, 73, >100	54
	L. mexicana amastigotes	40, 39, 41, 42, 12, 56, 57, 58, 45, 47, 48, 59, 60, 46, 30, 61, 21, 54	37, 63, 3.2, 21, 10, 38, 61, 32, 34, 12, >100, 21, 27, 30, 37, 32, 34, 43	54

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In contrast to curcumin analogues that retained the 7-carbon spacer (39), the compounds with a 5-carbon linker had lower activity. In case of the later, the introduction of a ring further decreased DPPH-scavenging activity. However, the introduction of a ring did increase anti-haemolysis activity, suggesting that the lipophilicity of these compounds might play an important role in the antioxidant activity.⁴²

Substitution with thiomethyl group (23), which can be found in some COX-2-selective compounds, exhibited a distinct affinity towards COX-1, while substitution with sulphonylmethyl group resulted in no activity. The para-hydroxy group on the phenyl ring of curcuminoids was proved to be essential for an anti-inflammatory activity. Introduction of an additional methoxy group ortho to hydroxy group, gives no change in cytotoxic activity and COX-2 inhibitory activity. Introduction of methylenedioxy group or nitro group (24, 25) or bulkier tert-butyl groups (20) diminished the ability to inhibit COX-2 enzyme, while addition of a fluorine atom (26, 27) in aromatic ring at meta or para-positions enhanced COX-2 selectivity.^43,44

Since curcumin is maximally active, DMC is intermediate and BDMC is least active, this suggests that the methoxy groups do contribute to the suppression of NF-κB activation. It has been postulated that hydrogen bonding between ortho-methoxy oxygen and phenolic hydrogen influences the planarity, conformation and ability to undergo oxidation. This may probably influence the interaction with the proteins such as NF-κB. There is no correlation between anti-oxidant activity and ability to inhibit the TNF-α-induced activation of NF-κB.⁴⁵ The para-position and polar group substituted curcuminoids have a tendency to inhibit the Fos–Jun DNA complex formation more potently. Introduction of a nitro group on phenyl ring increases the ability to inhibit the Fos–Jun DNA complex formation more potently.⁴⁶ Replacement of para-hydroxy group with amino methyl group (24) resulted in no activity to all tested tumor cell lines. Introduction of polar groups (28–31) at para-position of phenyl group resulted in enhancement of cytotoxic activity. These results indicated that substitution at para-position of phenyl group had significant influence on the cytotoxicity of curcumin analogues. Substitution at para-position of phenyl group is responsible for the cytotoxicity of the compounds.⁴⁷ Therefore; introduction of appropriate substitution at para-position of phenyl group might be a potential option for structural modification of curcumin. Demethylation or methylation of curcumin to form the dihydroxy and trimethoxy (13, 14) derivatives significantly increased cytotoxic activity against 1A9, KB and HCT-8 cell lines. Increase in the number of hydroxyl substitutions (11) on the aryl ring with or without methoxy substitutions (12–16) or tert-butyl substitutions (20) at ortho position showed promising tumor reducing activity. Thus, the presence of catechol or 3,4-dimethoxyphenyl substituents enhanced the cytotoxic properties.^41,48–50 Introduction of methoxycarbonylmethyl group (32) at the phenolic hydroxyls contributed to increased antitumor activity.⁵⁰ Conversion of para-hydroxy group into methoxy, acetate and sulfamate (12, 33–35), resulted in increase in cytotoxic activity.⁵¹

Compound 36 and 37, exhibited selective and potent cytotoxic activity against human epidermoid carcinoma cell line A-431 and human glioblastoma cell line U-251, implying their specific potential in the chemoprevention and chemotherapy of skin cancer and glioma. The preliminary SAR information extracted from the results suggested that introduction of appropriate substituents to the 4^th-positions could be a promising approach for the development of new cytotoxic curcumin analogues with special selectivity for A-431 and U-251 cell lines.⁵²

Curcumin derivatives without hydroxyl group showed no activity against HIV-1 integrase, while compounds retaining hydroxyl groups (38, 39) showed comparable activity as that of curcumin. In addition, the compounds with catechol group exhibited better HIV-1 integrase inhibitory activity.⁵³

Decrease in oxygenated (hydroxyl and alkyl) substituents in the aromatic rings of curcuminoids (40–50) resulted in decreased antitrypanosomal activity of the curminoids and analogs; demethylation of various analogues of curcumin tends to increase the antitrypanosomal activity and decrease the antimycobacterial activity. Whereas higher alkyl ether analogues (compound 43–62) showed better activity than the parent compound.^54,55

Qiu et al. synthesized new arylidene curcumin analogues (63, 64) and established SAR which concluded that the triarylvinyl skeleton of 4-arylidene curcumin analogues acts as a phamacophore, and the 4-arylmethylene modification is an effective strategy to improve the NF-κB inhibitory activity of curcumin analogues.⁵⁶

Methylation of curcumin to form dimethoxycurcumin (12) resulted in loss of antimalarial activity while diacetylcurcumin (21) retained almost similar potency as curcumin. This suggests that hydroxy group is important for antimalarial activity of curcumin analogues with substitution on the aryl ring.⁵⁷

Agrawal et al. synthesized semi-synthetic analogues (24, 32) of demethoxy curcumin and screened the compounds for antitubercular activity. The objective of the synthesis of 24 and 32 was to increase the lipophilicity of demethoxycurcumin by attaching fatty acid ester chains at the phenolic hydroxy groups due to the lipophilic nature of the Mycobacterium tuberculosis cell wall. These compounds showed better antitubercular activity than the parent compound.⁵⁸

Shi et al. synthesized the cytotoxic curcumin analogues conjugated with anti-androgens. The synthesized compounds were evaluated against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Compound 65, exhibited the most potent cytotoxicity against both cell lines with IC₅₀ values of 41.8 μM against LNCaP and 39.1 μM (Table 3) against PC-3 proliferation. Compound 65 was almost two-fold more potent than flutamide and bicalutamide. SAR revealed that replacement of the nitro group on the aniline ring of the hydroxyflutamide-related substructure of 65 with a cyano group in 66 resulted in two-fold decrease of activity. Substitution of cyano and fluoro groups (67, 68) on the aniline ring in the flutamide substructure with nitro (69), chloro (70), and methyl (71) groups diminished the activity against both the cell lines. So, it could be suggested that the substituents on the flutamide substructure may be important for interaction of the conjugate molecule with the target protein.⁵⁹

2. Changes in β-diketone structure

2.1. Changes in β-diketone structure: monocarbonyl analogues (symmetric, asymmetric and cyclic). As we described above that the presence of the methylene group and β-diketone moiety contributes to the instability of curcumin under physiological conditions, the deletion of the β-diketone moiety may contribute to the enhancement of stability of curcuminoids. To obtain the substantial modification on the curcumin structure, symmetrical, asymmetrical and cyclic monocarbonyl analogues were evaluated for different activities.

Constructing the asymmetric monocarbonyl curcumin analogues having phenyl ring with alkyl amide (72–78), chloro-substituted benzamide (79–83) (Table 4) and heteroaromatic amide moieties (84–85), increased the anti-angiogenic potential as compared to curcumin. The aromatic amides exhibited higher activity than alkyl amides, but benzamide, furan amide (84), thiophene amide (85) exhibited highest potential to inhibit angiogenesis process (asymmetric monocarbonyl analogues). The analogues with aromatic dienone moiety showed good inhibition of in vitro (HUVEC assay) (Table 5), especially compound with pyridyl substitution showed excellent activity. In short, curcumin analogues having a weak electron-donating substituent at 4′ position or a strong electron-withdrawing substituent at 2′ position increased the cytotoxic activity.⁶⁰

Table 4 Chemical structures of curcumin analogues with changes in the β-diketone structure, monocarbonyl analogues (asymmetrical, Class 2.1)

General structure for Class 2.1 compounds: asymmetrical (72–130)
Compounds	Ar1	Ar2
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130

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General structure for Class 2.1 compounds: asymmetrical (131–137)
Compounds	R1	R2	R3	R4
131	OCH3	H	OCH3	H
132	OCH3	H	OH	H
133	OH	H	OCH3	H
134	OCH3	CH3	OCH3	H
135	OCH3	H	OCH3	CH3
136	OCH3	Ac	OCH3	H
137	OCH3	H	OCH3	Ac

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General structure for Class 2.1 compounds: asymmetrical (138–148)
Com.	R1	R2	R3	R4	R5	R6
138	OCH3	OH	H	OCH3	OCH3	H
139	OCH3	OCH3	H	OCH3	OCH3	OCH3
140	OCH3	OCH3	H	OCH3	OCH3	OCH3
141	H	OCH3	OCH3	OCH3	OCH3	OCH3
142	OH	H	H	OCH3	OCH3	OCH3
143	OCH3	OH	OCH3	OCH3	OCH3	OCH3
144	OCH3	COCH2CH2OH	OCH3	OCH3	OCH3	OCH3
145	OCH3	COCH2OH	OCH3	OCH3	OCH3	OCH3
146	OCH3	COCH2O2Me	OCH3	OCH3	OCH3	OCH3
147	OCH3	OCH(CH3)OCH2CH3	OCH3	OCH3	OCH3	OCH3
148	OCH3	OCH3	OCH3	OCH3	ORc	OCH3

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Table 5 Biological activity of curcumin analogues with changes in the β-diketone structure, monocarbonyl analogues (Class-2.1)

Activity	Assay/target	Compound(s)	IC50 (μM)	Ref.
a Indicates IC50 for compound of series-A.b Indicates IC50 for compound of series-B.c Indicates IC50 for compound of series-C.d Indicates GI50 value in μM.e Indicates % inhibition at 10 μM.f Indicates % inhibition at 6 μg ml^−1.g Indicates % inhibition at 3 μg ml^−1.h Indicates zone of inhibition in mm.i Indicates % increased life span; NA, not active (MIC > 200 mg ml^−1); ND, not determined.
Antioxidant	Lipid peroxidation	170^a, 170^b, 170^c, 171^a, 171^b, 172^a, 172^b, 172^c	2.8, 2.5, 1.3, 2.0, 2.2, 11.6, 0.9, 2.9	71
	TRAP assay	91, 92, 93, 167^a, 168^a, 169^c	36^e, 41^e, 69^e, 64^e, 76^e, 55^e	70
	FRAP assay	91, 93, 169^c	53^e, 60^e, 69^e	70
Anti-inflammatory	COX-2	192^c	5.5	48
	LPS-induced TNF-α	169^a, 169^b, 169^c, 177^a, 177^c, 189^c, 190^b, 191^a, 191^b	64, 38, 34.5, 34, 60, 34, 46, 36, 38	75
	LPS-induced IL-6	169^a, 169^b, 169^c, 178^b, 190^a	68, 36, 70, 80, 90	75
Antitumor	NF-κb	91, 168^a, 169^a, 169^c, 183^a, 184^a	6.2, 4.2, 9.6, 4.4, 7.0, 5.0	45
	Leukaemia	166^c	1.6^d	63
	NSCL	166^c	3.1^d	63
	Colon	166^c, 84^a, 85^a, 138, 179^a, 182^c, 182^a, 181^a, 180^a, 139, 140, 141, 142, 174^a, 143, 144, 145, 146, 147, 201^a, 202^a, 148	2.1^d, 15^d, 0.8^d, 0.7^d, 1.5^d, >50, 2.0, 2.3, 0.3, 0.4, 1.9, 3.3, 0.9, 0.8, 0.8, 1.1, 38, 7.0, 1.5, 0.3, 7.6, 0.3	63 and 67
	CNS	166^c	2.5^d	63
	Melanoma	166^c	2.2^d	63
	Ovarian	166^c	3.3^d	63
	Renal	166^c	2.0^d	63
	Prostate	166^c	1.7^d	63
	Breast	166^c	2.5^d	63
	MDR reversal activity (in presence of vincristine)	72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85	1.26, 1.26, 1.89, 1.92, 3.31, 3.81, 3.82, 0.48, 0.72, 1.23, 0.85, 0.41, 0.44, 1.41	61
	MDR reversal activity (in presence of paclitaxel)	72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85	0.83, 0.72, 0.21, 0.24, 1.09, 0.32, 0.42, 0.063, 0.045, 0.1, 0.026, 0.022, 0.21, 0.18	61
	IGROVI	202^c	1.6	77
	SK-OV-3	202^c	2.4	77
	Ehrlich ascites tumor	185, 186, 187, 188	34.4^i, 48.8^i, 77.7^i, 28.8^i	73
	MCF-7	149, 150, 151, 152, 153, 154	3.7, 4.5, 3.5, 3.7, 2.9, 1.9	68
	SH-SY5Y	149, 150, 151, 152, 153, 154	4.7, 4.7, 1.0, 4.6, 4.8, 4.6	68
	Hep-G2	149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165	2.9, 4.2, 1.9, 3.7, 3.6, 3.7, 6.1, 5.6, 16.6, 29.2, 12.0, 25.4, 17.2, 1.0, >100, 10.4, 11.0	68 and 69
	A16-F10	155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165	5.1, 3.2, 10.7, 12.2, 7.6, 18.4, 9.7, 0.7, >100, 3.2, 7.0	69
	EGFR	155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165	2.2, 1.5, 6.8, 7.1, 5.6, 15.3, 6.1, 0.4, 20.8, 4.6, 5.3	69
	H460	149, 150, 151, 152, 153, 154	7.0, 7.7, 3.0, 6.7, 7.6, 7.2	68
	P388 cells IC50 (mM)	212, 123, 124, 125, 126, 127, 128, 129, 130	0.77, 0.623, 0.755, 0.312, 0.371, 0.919, 0.477, 0.399, 0.221	66
	L1210 cells IC50 (mM)	212, 123, 124, 125, 126, 127, 128, 129, 130	7.96, 5.56, 94.1, 32.7, 44.2, 57.1, 9.79, 9.67, >20^d	66
	Molt 4/C8 cells IC50 (mM)	212, 123, 124, 125, 126, 127, 128, 129, 130, 214, 215, 217, 218, 219, 226	1.67, 1.94, 2.3, 9.71, 32.1, 29.2, 4.56, 1.67, >20^d, 0.02, 0.03, 0.1, 0.5, 0.3, 0.7	66 and 81
	CEM cells IC50 (mM)	212, 123, 124, 125, 126, 127, 128, 129, 130	1.70, 1.58, 32.3^a, 6.35, 23.0, 30.0, 4.60, 1.92, >20^d	66
Ant-angiogenesis	HUVEC	72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85	2.87, 7.06, 1.27, 1.44, 13.3, 1.50, 0.37, 0.76, 0.40, 0.46, 2.97, 0.75, 0.38, 0.38	60
	B16	72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85	11.48, 3.62, 1.43, 1.09, 7.03, 4.41, 0.82, 0.59, 12.81, 1.58, 3.88, 4.83, 5.46, 6.93	60
	Vero	72, 73, 74, 75, 76, 77, 81, 82, 83, 84, 85	6.02, 14.48, 2.04, 3.47, 3.55, 3.47, 3.48, 27.22, 2.48, 3.11, 3.98	60
	U87	72, 73, 74	7.71, 5.56, 8.31	60
	SiHa	72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 83, 84, 85	12.33, 15.75, 3.94, 5.96, 7.71, 4.57, 2.30, 34.43, 3.56, 25.28, 17.67, 0.76, 6.57	60
	SVR cell line	86, 87, 88, 89, 90, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117	98.2^g, 97.5^f, 94.4^f, 94.7^f, 96.9^f, 58.5^f, 59.2^f, 89.6^f, 89.5^f, 87.3^f, 73.4^f, 96.9^f, 93.7^f, 85.2^f, 88.7^f, 60.8^f, 63.5^f, 96.9^f, 85.2^f 88.6^f, 75.4^g, 96.8^f,62.9^f, 69^f, 1.3^f, 68.2^f, 80.8^f, 68.9^f, 78.4^f	62 and 64
	PC-3	167^a, 169^a, 175^a, 179^a, 180^a, 81^a, 182^a, 172^a, 184^a, 193^a, 194^a, 195^a, 190^a, 214, 215, 217, 218, 219, 226	9.5, 3.9, 5.9, 2.9, 8.8, 2.1, 4.6, 3.6, 0.35, 5.1, 6.1, 2.4, 10.3, >5, >5, 6.9, 0.28, 0.5, 1.5	51 and 72
	LNCaP	167^a, 169^a, 175^a, 179^a, 181^a, 182^a, 172^a, 193^a, 194^a, 195^a	5.8, 2.7, 2.6, 2.2, 0.5, 1.7, 2.5, 5.1, 2.4, 1.9	51
	MCF-7	167^a, 169^a, 175^a, 179^a, 181^a, 182^a, 172^a, 193^a, 194^a, 195^a	6.9, 2.4, 2.9, 2.5, 0.4, 2.4, 1.7, 3.5, 6.6, 1.5	51
	MDA-MB-231	167^a, 169^a, 175^a, 179^a, 181^a, 182^a, 172^a, 193^a, 194^a, 195^a	3.9, 2.8, 2.1, 1.6, 0.6, 2.4, 2.7, 4.2, 1.7, 0.6	51
		203^c, 204^c, 205^c, 206^c, 207^c, 208^c, 209^c, 210^c, 211^c, 180^c, 169^c, 203^f, 204^f, 207^f, 210^f, 180^f, 182^f, 203^d, 204^d, 180^d, 204^b	1.1, 1.5, 3.3, 3.2, >30, >30, >30, 1.9, >10, >30, 2.6, 0.8, 2.1, >30, >30, 0.3, 3.8, 1.1, 12.9, >30, 8.6	78
	NF-κB activation	203^c, 204^c, 205^c, 206^c, 207^c, 208^c, 209^c, 210^c, 211^c, 180^c, 169^c, 203^f, 204^f, 207^f, 210^f, 180^f, 182^f, 203^d, 204^d, 204^d, 204^b	2.5, 2.5, 2.2, 3.8, >200, >200, 140, 48, >200, NT, 10, 1.0, 0.8, >200, 47, 0.9, 4.0, 1.5, 4.0, >200, 34	78
	CNE	169^a, 169^c, 178^b	6.8, 17.6, 2.4	72
	HL-60	184^a	<10	72
	KB	169^c, 178^b, 184^a, 189^a, 214, 215, 217, 218, 219, 226	<10.10, 3.3, <3.70, 24.5, 4.4, >5, 1.6, 0.6, 0.5, 2.5	72 and 81
	LS 174T	169^a, 169^c, 283^a	3.7, 4.6, 4.0	72
	HeLa	190^a, 214, 215, 217, 218, 219, 226	6.2, 0.4, 0.5, 1.9, 0.7, 0.4, 3.6	72 and 81
	HEK	131, 132 + 133, 134 + 135, 136 + 137	24, 63, 20, 25	54
Alzheimer	Aβ	196^a, 197^b, 198^c, 199^c, 200^c, 201^c	21.5, 12.6, 6.0, 2.5, 17.6, 17.2	76
Osteoporosis	TRAP	118, 119, 120, 121, 122	19.79, 9.79, 16.81, 6.45, 2.50	65
Anti-haemolysis	DPPH	169^a, 167^a, 173^a, 174^a, 169^b, 167^b, 173^b, 174^b, 169^c, 167^c, 173^c, 174^c	45.65, >300, 9.63, 38.07, 101.8, >300, 9.52, 15.8, 68.83, >300, 13.11, 53.66	42
M. tuberculosis	H37Ra strain	131, 200	25, 25	55
Antitrypanosomal EC50 (μM)	T. brucei strain 427	131, 132 + 133, 134 + 135, 200, 202, 136 + 137	0.053, 0.75, 0.14, 4.1, 0.22, 0.089	54
	T. brucei ΔTbat1	131, 132 + 133, 134 + 135, 136 + 137	0.082, 0.73, 0.29, 0.079	54
	T. brucei clone B48	131, 132 + 133, 134 + 135, 136 + 137	0.023, 0.30, 0.032, 0.045	54
Antimalarial	P. falciparum (D6 clone)	214, 215, 218, 219, 220, 222, 223	0.5, 0.4, 0.69, 1.7, 0.5, 0.4, 0.3	81
	P. falciparum (W2 clone)	214, 215, 218, 219, 220, 222, 223	0.5, 0.6, 0.6, 2.8, 0.5, 0.37, 0.4	81
Antileishmanial	L. major promastigotes	131, 132 + 133, 134 + 135, 136 + 137	8.9, 10, 13, 7.5	54
	L. mexicana amastigotes	131, 132 + 133, 134 + 135, 136 + 137	17, 7.4, 28, 29	54
Gram-positive anti-bacterial^h	S. aureus	167^a, 169^a, 169^b, 169^c, 180^a, 189^a, 189^b, 189^c	17, 15, 12, 11, 14, 18, 12, 15	82
	S. aureus	167^a, 169^a, 169^b, 169^c, 180^a, 189^a, 189^b, 189^c	17, 15, 12, 11, 14, 18, 12, 15	82
Gram-negative anti-bacterial^h	Enterobacter cloaceae	167^a, 167^b, 169^a, 169^b, 169^c, 176^a, 176^b, 176^c, 180^a, 180^b, 180^c, 189^a, 189^b, 189^c	11, 10, 12, 11, 10, 10, 9, 11, 11, 10, 10, 10, 10, 11	82

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Um et al. synthesized the unsymmetrical curcumin mimics with various amide moieties (72–85) and evaluated for MDR reversal activities in MDR cell line KBV20C. SAR revealed that chlorobenzamide curcumin mimics (79–83) showed strong MDR reversal activity indicating that one chloro group at the meta or para-position on benzamide resulted can increase the activity. Furan carboxamide (84) and a thiophene carboxamide (85) showed only mild MDR reversal activity.⁶¹

Transformation of curcumin into asymmetric monocarbonyl analogues with enone or dienone (86–90) moiety, helps to boost the inhibition of angiogenesis process even better than curcumin.^62,63

The presence of ortho-hydroxyl group is significant for the activity. Moving the hydroxyl group from ortho to para-position (91–93), in hydroxy-substituted derivatives cytotoxicity decreased. In case of asymmetric monocarbonyl analogues, replacement of hydroxyl group by methyl (94–98), chloro (99, 101, 103, 109, 111), trifluromethane (100), methoxy (102, 104, 105), flouro (110) methylenedioxy (115–117) led to decrease in activity. Introduction of heteroaromatic ring (106–107) or naphthalene (108–109) or anthracene (112–114) ring replacing the aryl ring, decreased the cytotoxic activity in asymmetric monocarbonyl analogues.⁶⁴

(1) Triazole analogues (118–121) of curcumin exhibited moderate to strong inhibitory activity against the osteoclastogenesis induced by RANKL. Substitution of hydrogen with fluoride in the phenyl group of (121) and (122) resulted in an improved activity. To conclude (3-hydroxy-4-methoxyphenyl)propenone was found to be a promising template to develop novel antiresorptive agents to treat osteoporosis.⁶⁵

(2) A novel series of cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones (123–130). The synthesized compounds showed marked cytotoxicity and selective toxicity towards different tumour cell lines along with lack of murine toxicity.⁶⁶

(3) Chatchawan et al. synthesized curcuminoids (131–137) as antitrypanosomal agents. Compound 131 exhibited very high antitrypanosomal activity, which was 47-fold more active than the curcumin. Therefore, the compound 131 was taken as a lead molecule and further modification were done on this molecule. However, none of them showed higher activity than the lead 131.⁵⁴

(4) SAR study of C₅-curcuminoids (138–148) for their cytotoxicities against human colon cancer cells indicates that (i) bis(aryl-methylidene) acetone serves as the most promising skeleton for eliciting cytotoxicity. (ii) The 3-oxo-1,4-pentadiene structure is essential for eliciting cytotoxicity. (iii) Hexasubstituted compounds (143–147) exhibited strong activities. (iv) para-Positions allowed the introduction of additional functional groups for use as the molecular probes.⁶⁷

(5) Woo et al. synthesized novel benzimidazolyl curcumin mimics library (149–154). The synthesized compounds were screened against various cancer cell lines. The MTT assay of the cancer cells MCF-7, SH-SY5Y, HEP-G2, and H460 showed that compound 151 with IC₅₀ of 1.0 and 1.9 μM has a strong inhibitory effect on the growth of SH-SY5Y and Hep-G2 cells, respectively, and that compound 154 with IC₅₀ of 1.9 μM (Table 5) had a strong inhibitory effect on the growth of MCF-7 cancer cells. A comparison of the growth inhibitory effect of each group of curcumin mimics showed that the positional variation of the methoxy and hydroxyl functionality did not affect the potency of the anticancer activity. From SAR study, it was found that the introduction of the benzimidazole moiety increased the potency by 10–50 times.⁶⁸

(6) Xu et al. synthesized α,β-unsaturated cyclohexanone analogous of curcumin and tested for antiproliferative activity against two human tumor cell lines (Hep G2 and B16-F10). The result showed that the compounds 156 and 162 displayed the most potent EGFR inhibitory activity (IC₅₀ = 0.43 μM and 1.54 μM, respectively). The SAR study revealed that the compounds with hydroxyl substitution on R-phenyl ring (162 and 164) displayed more potent antiproliferative activity compared to other compounds. While compounds with methoxyl group on R-phenyl ring (161 and 163) showed the significant effects on the antiproliferative activity. Compounds with halogen substitution on R-phenyl ring, the activity order was as Cl ≥ F > Br in the series. Compounds with R1 substitution at meta-position (155, 157, 161 and 165) showed better antiproliferative activity than the compounds substituted at para-position (158, 159, 160 and 164).⁶⁹

(7) Eliminating one carbonyl and one methylene from curcumin yields less active derivatives. But, the antioxidant potential of monocarbonyl analogues (symmetrical, asymmetrical and cyclic) retained only with the analogues possessing hydroxyl substituents (91–93, 166–169) and others were less active or inactive than curcumin. The analogues with ortho-alkyl groups to para-hydroxy group are more potent than curcumin but the increase in the bulkiness of the substituents group adjacent to the para-hydroxy group had a negative influence on the activity (170–172). The dimethoxy analogues are the most active of all monocarbonyl analogues.^70,71

(8) The analogues with para-hydroxy substitution were more active while replacing the para-hydroxy group (173–174) to methoxy (175, 179–182) or sulphamate (178–180) (Table 6) did not cause any increase in cytotoxicity. Increasing the number of methoxy substituents on phenyl ring in case of symmetric, monocarbonyl analogues (181, 182), resulted in an incredible rise in selectivity against cancer cells.⁵¹ In case of symmetric monocarbonyl analogues, replacement of phenyl ring with any heteroaromatic ring (189–191) gave broad spectrum cytotoxic activity.⁷² The compound with cyclopropoxy (185–188) group at para-position and methoxy group at ortho- and meta-positions, showed potent antitumor and anti-angiogenic activities on mouse Ehrlish ascites tumor (EAT) in vivo, whereas the absence of methoxy group at meta-position decreased the tumor inhibitory effect.⁷³

Table 6 Chemical structures of curcumin analogues with changes in the β-diketone structure, monocarbonyl analogues (symmetrical, Class 2.1)

General structure for Class 2.1 compounds: symmetrical (166–198)
Compound	R1	R2	R3	R4	R5	Series
166	H	OH	H	H	H	c
167	H	H	OH	H	H	a, b, c
168	OH	H	H	H	H	a
169	H	OCH3	OH	H	H	a, b, c, d, e
173	H	OH	OH	H	H	a, b, c
174	H	OCH3	OH	OCH3	H	a, b, c
175	H	OH	OCH3	H	H	a
176	H	H	N(CH3)2	H	H	a, b, c
177	H	H	OCH2CHCH2	H	H	a,c
178	H	H	O(CH2)3N(CH3)2	H	H	a, b, c
179	H	OCH3	OCH3	H	H	a
180	H	OCH3	OCH3	OCH3	H	a, b, c, d, e
181	OCH3	H	OCH3	H	OCH3	a
182	OCH3	H	OCH3	OCH3	H	a, b, c, d, e
170	H	CH3	OH	CH3	H	a, b, c
171	H	CH2CH3	H	CH2CH3	H	a, b
172	H	OCH3	H	OCH3	H	a, b, c
183	H	CF3	H	H	H	a
184	CF3	H	H	H	H	a
185	H	H		H	H	a
186	H	OCH3		H	H	a
187	H	OCH3		OCH3	H	a
188	H	CH3		CH3	H	a
189						a, b, c
190						a, b, c
191						b, c
192	H	H	F	OH	H	c
193	H	H	OSO2NH2	H	H	a
194	H	OCH3	OSO2NH2	H	H	a
195	H	OCH3	OSO2NH2	OCH3	H	a
196	H	H		H	H	a
197	H	H		H	H	b
198	H	H		H	H	c

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General structure for Class 2.1 compounds: symmetrical (199–202)
Compound	R1	R2	R3	R4	R5	X
199	H	H		H	H	NH
200	H	H		H	H	NCH3
201	H	H		H	H	NH
202	F	H	H	H	H	NH

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General structure for Class 2.1 compounds: symmetrical (203–213)
Compounds	Ar = Ar′	Series
203		b, c, d, e
204		b, c, d, e
205		b, c, d, e
206		b, c, d, e
207		b, c, d, e
208		b, c, d, e
209		b, c, d, e
210		b, c, d, e
211		b, c, d, e
212		b, c, d, e
213		c, e

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(9) The properties and position of the substituents and the space of the linking chain determine the anti-inflammatory activities. The compounds with cyclohexanone moiety were more effective than compounds with acetone and cyclopentanone moieties.⁷⁴ Monocarbonyl analogues having a long chain allyl-oxyl substituent group or 3-(dimethylamino)propoxyl substituent group exhibited enhanced activity than curcumin (177, 178), while analogues possessing dimethylamino (176) or trifluromethane (183, 184) substituent group exhibited less activity. Fluoro substitution in cyclohexanone analogue of monocarbonyl curcumin enhanced the activity (192) while, nitro, tert-butyl substitution decreased anti-inflammatory activity. In case of bromo substitution, contradictory results were obtained. When substitution was at 2-position, no activity was observed but substitution at 3-position, anti-inflammatory activity comparable to curcumin was obtained. The monocarbonyl analogues possessing 3-methyoxy group showed superior activity than curcumin, suggesting that the presence of a 3-methyoxy group is critical for the activity. Analogues with trimethoxy substitution possessed higher activity than curcumin (181, 182). On the other hand, heteroaromatic ring substituted monocarbonyl analogues showed moderate anti-inflammatory activity (LPS induced TNF-α, IL-6 expression) (189–191).^45,48,74,75

(10) Chen et al. synthesized multifunctional agents (196–198, 199–201) for the treatment of Alzheimer disease (AD). The in vitro studies showed that these compounds had better inhibitory properties against Aβ aggregation than curcumin. Structure–activity relationships suggested that introduction of flexible moieties at the linker is crucial to the inhibitory potencies of the compounds against Aβ aggregation compound 199 was found to be the most potent with IC₅₀ value of 2.5 μM.⁷⁶

(11) Difluorinated analogue of curcumin (202) showed cytotoxicity against IGROV1 and SK-OV-3 human ovarian cancer cells.⁷⁷ Yadav et al. synthesized cyclohexanone analogues (203–212) of curcumin and developed a SAR study regarding their cytotoxic potential and observed that cyclohexanone analogues showed five-fold decreased in activity than cyclopentanone analogues. The analogues with fluorine substituted pyridine rings were found to be 2–3 times less active than the parent pyridine compounds 203 and 204. Replacement of the pyridine ring with different heterocyclic rings, thiophene 207, N-methylpyrrole 208, N-methylindole 209 and 4-substituted N-methylimidazole 211 exhibited no activity.⁷⁸ Compound 213 as demethylating agent has been found several fold more potent than curcumin in pancreatic cancer cell lines and displayed better solubility and bioavailability. It inhibits HSP-90 and NF-κB leading to downregulation of DNA methyltransferase-1 (DNMT-1) expression.⁷⁹ In addition, it was also evaluated for the treatment of colorectal cancer using colorectal cancer cells HCT-116 and HT-29. It significantly inhibited the VEGF synthesis and secretion in both colon cell lines in concert with the loss of Hypoxia-inducible factors (HIFs) expression, which transcriptionally regulate VEGF.⁸⁰

(12) Substitution of the pyridyl groups with electron rich trimethoxyphenyl and dimethoxyphenyl give analogues 180 and 181 but they did not show any increase in cytotoxicity and NF-κB activation activity, N-methylpiperidone analogues had similar or slightly increased activity over cyclohexanone core. The more sterically hindered tropinone analogues showed reduced activity in all cases, indicating that bulky groups in this area of the molecule led to decreased activity. Additionally, the incorporation of a fluorine substituent into the aromatic rings did not increase the activity of these compounds.⁷⁸

(13) Manohar et al. synthesized a series of monocarbonyl analogues of curcumin and evaluated for the antimalarial and cytotoxic activity against Molt4, HeLa, PC3, DU145, and KB cancer cell lines. It has been found that six analogues showed potent cytotoxic activity against these cell lines with IC₅₀ values below 1 μM, which was better than the standard drug doxorubicin. The SAR revealed that the rigidity did not play important role in the activity as compound 214, 217, 219, and 226 having different ring sizes at the carbonyl position were showed very good activity with the IC₅₀ in the low micro molar range in HeLa cells. However, some other compounds (216, 221, 224, and 225) have the same five- or six-member ring did not show cytotoxicity even at 50 μM. The length of side chain did not have a major effect on the cytotoxic activities; methoxy group on the phenyl ring favoured the inhibitory effect. These analogues were also screen for their antimalarial activity against CQ-sensitive (D6 clone) and CQ-resistant (W2 clone) strains of P. falciparum. Compounds 214, 215, 218, 220, 222, and 223 having the amine probe via ethylene/butylene linker with cyclopentanone ring showed better activity with IC₅₀ ranging from 0.35–0.69 μM in comparison to standard drug chloroquine.⁸¹

(14) Monocarbonyl analogues were more effective against Gram-positive organisms than against Gram-negative. The cyclopentanone and cyclohexanone analogues (167, 169, 176, 180, and 189) showed moderate activity; however, had low activity than curcumin, which illustrated that the space structure of the linking C-strain can make some influence on the anti-bacterial ability. Compounds with cyclohexanone and acetone moiety were more effective than compounds with cyclopentanone moieties. But, the most of the compounds exhibited better activity against the Gram-negative E. cloacae which is completely resistant to the clinical drug ampicillin.⁸²

2.2. Changes in β-diketone structure: dicarbonyl analogues. The β-diketone compounds (227–238) exhibited moderate cytotoxicity, whereas β-triketone and β-tetraketone were inactive. Thus, it showed that the β-diketone moiety enhanced the cytotoxic properties. Introduction of the tert-butyl group proved to be more potent than unsubstituted, 3,5-dimethylphenyl and 2,4-dimethoxyphenyl substitution. Thus, introducing the tert-butyl group (an electron-donating substituent) on the phenyl ring led to increased cytotoxicity (229). Replacement of hydrogen atom with fluorine and chlorine (an electron-withdrawing substituent) at the para position on the benzene rings increased activity (231–233). β-Bromination between the keto groups led to enhanced activity compared with the unsubstituted compounds (230, 234–237) (Fig. 3). However, nitroso, benzoyl methyl, and furan substitution at this position abolished activity. Compounds that possess a α-bromo substituent and para-nitro and para-methoxy groups on separate benzene rings, demonstrated the strongest cytotoxic activity. Introduction of the nitro group led to increase in activity while amino group led to decrease in activity (235, 236). Asymmetrical substitution led to enhanced activity and different electronegative aryl substituents led to increased activity (Table 7).⁸³

Fig. 3 Chemical structures of curcumin analogues with changes in the β-diketone structure, dicarbonyl analogues (Class 2.2).

Table 7 Biological activity of curcumin analogues with changes in the β-diketone structure, dicarbonyl analogues (Class-2.2)

Activity	Assay/target	Compound(s)	ED50 (μM)	Ref.
a Indicates % inhibition at 1 μM.
Cytotoxic	KB	230, 231, 232, 233, 234, 235, 236, 237	16.5, 20.0, 19.5, 19.7, 15.5, 3.8, 14.4, 4.5	83
	A549	227, 228, 231, 233, 234, 235, 236, 237	20.0, 20.0, 16.5, 17.5, 18.0, 4.4, 18.8, 8.9	83
	MCF-7	227, 228, 230, 231, 233, 234, 235, 236, 237	20.0, 14.5, 15.0, 13.5, 17.5, 15.0, 7.0, 16.7, 4.0	83
	IA9	227, 228, 229, 230, 231, 233, 234, 235, 236, 237	6.0, 4.8, 3.9, 4.0, <10, 5.0, 3.9, <0.63, 13.6, 2.1	83
	HCT-8	227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237	7.5, 7.5, 10.0, 12.0, 5.8, 8.0, 9.7, 6.0, 1.8, 18.3, 3.0	83
	SK-MEL-2	230, 234, 235, 237	16.0, 7.0, 2.0, 6.0	83
	U-87-MG	230, 234, 235, 236, 237	16.3, 15.0, 3.8, 18.8, 8.7	83
	HOS	227, 228, 229, 230, 232, 233, 234, 235, 236, 237	<10, <10, 16.0, 8.0, 9.0, 10.0, 12.0, 0.97, 18.0, <2.5	83
	PC-3	230, 234, 235, 237	16.0, 14.0, 5.0, 8.0	83
	KB-VIN	230, 232, 234, 235, 237	16.5, 19.5, 15.0, 4.5, 7.4	83
	DU-145	238	40^a	83

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2.3. Changes in β-diketone structure: heterocyclic analogues. It has been proved that at higher concentrations, the α,β-unsaturated ketone, as a Michael acceptor, can form adducts with the –SH groups and generate reactive oxygen species. This may lead to induction of apoptosis through different possible mechanisms involving endoplasmic reticulum stress, loss of mitochondrial membrane potential, activation of terminal caspases or also other mitochondria and caspase-independent pathways. Inhibition of the transcription factor NF-κB, TNF-α and suppression of the Bcl-2 and IAP family proteins, is also considered to be important for the different activities of curcumin. Here, replacement of β-diketo group by pyrazole and isoxazole demonstrated various change in activities as shown by curcumin.^82–85

(1) The pyrazole analogues of curcumin demonstrated increase in antioxidant, COX-2 inhibitory activity, antitumor and antimalerial activity as compared to curcumin, whereas the isoxazole analogues also showed increase in activity as compared to curcumin but not as better as pyrazole analogues (239–244) (Table 8).⁸⁶

Table 8 Chemical structures of curcumin analogues with changes in the β-diketone structure, heterocyclic analogues (Class 2.3)

General structure for Class 2.3 compounds (239–257)
Compounds	R1	R2	R3	R4	X	R5
239	OCH3	OCH3	OH	OH	N	H
240	OCH3	H	OH	OH	N	H
241	H	H	OH	OH	N	H
242	OCH3	OCH3	OH	OH	N	t-Bu
243	OCH3	OCH3	OH	OH	O
244	OCH3	H	OH	OH	O
245	OCH3	OCH3	OH	OH	N
246	OCH3	OCH3	OH	OH	N
247	OCH3	OCH3	OH	OH	N
248	OCH3	OCH3	OH	OH	N
249	H	OCH3	OH	OH	O
250	H	H	OH	OH	O
251	OCH3	OH	OH	OH	O
252	OH	OCH3	OH	OH	O
253	OH	OH	OH	OH	O
254	OCH3	OCH3	OH	OH	N
255	OCH3	OCH3	OH	OH	N
256	OCH3	H	OH	OH	N
257	H	H	OH	OH	N

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258
259

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General structure for Class 2.3 compounds (260–278)
Compounds	R1	R2	R3	R4
260	OCH3	OH	OCH3	OH
261	OCH3	CH2–(CH2)3–CH3	OCH3	H
262	OCH3	H	OCH3	CH2–(CH2)3–CH3
263	OCH3	CH2–(CH2)3–CH3	OCH3	CH2–(CH2)3–CH3
264	OCH3	CH2CH=C(CH3)2	OCH3	H
265	OCH3	H	OCH3	CH2CH=C(CH3)2
266	OCH3	CH2CH=C(CH3)2	OCH3	CH2CH=C(CH3)2
267	OCH3	CH2CH3	OCH3	H
268	OCH3	H	OCH3	CH2CH3
269	OCH3	CH2CH3	OCH3	CH2CH3
270	OCH3	Ac	OCH3	H
271	OCH3	H	OCH3	Ac
272	OCH3	Ac	OCH3	Ac
273	OCH3	Me	OCH3	H
274	OCH3	H	OCH3	CH3
275	OCH3	CH3	OCH3	CH3
276	H	CH3	OCH3	CH3
277	OCH3	CH3	H	CH3
278	H	CH3	H	CH3

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279
280
281
282
283
284
285
286

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(2) Both pyrazole (239) and isoxazole (243) analogues having two methoxy group showed better antioxidant activity than curcumin while the other analogues (240 and 244) were not as much active. The pyrazole analogues proved to be better than the isoxazole analogues (239 and 242).⁸⁶

(3) It has been postulated that pyrazole analogues increased COX-1 inhibitory activity slightly as compared to curcumin but there was a two-fold increase in COX-2 inhibition. Thus pyrazole analogue showed significant enhancement in the selectivity towards COX-2 enzyme (COX-2/COX-1 = 0.70) compared to curcumin (COX-2/COX-1 = 0.43). Since these compounds exhibited good COX inhibitory and antioxidant activities, they were investigated for in vivo anti-inflammatory activity using carrageenan induced rat paw edema assay at 75 mg kg⁻¹. Among these compounds, pyrazole analogue of curcumin, exhibited the highest activity. Molecular docking studies further supported the strong inhibitory activity of pyrazole analogue compared to curcumin and isoxazole analogues (239–244).⁸⁶

(4) Pyrazole analogue (239–241) of curcumin showed a broad spectrum cytotoxic activity against KB, A549, CAKI-1, MCF-7, 1A9, HCT-8, SK-MEl-2, U-87-MG, HOS, PC-3, LNCaP, MDA-MB-231, KB-VIN, HepG2, and LNCaP (clone FGC) cell lines (Table 9), where as isoxazole analogue (243) showed better antitumor activity than curcumin in the hepatocellular carcinoma HA22T/VGH cell line, which is known to innately produce remarkable amounts of drug resistance and anti-apoptotic factors.^51,83,85

Table 9 Biological activity of curcumin analogues with changes in the β-diketone structure, heterocyclic analogues (Class-2.3)^a

Activity	Assay/target	Compound(s)	IC50 (μM)	Ref.
a * indicates % inhibition at 100 μM; ** indicates IC50 values in nM; ^# indicates ED50 value; NA, not active (MIC > 200 mg ml^−1); ND, not determined.
Antioxidant	DPPH	239, 240, 243, 244	9.7, 15.45, 10.71, 18.96	86
Anti-inflammatory	COX-1	239, 240, 243	87.0*, 73.9*, 80.8*	86
	COX-2	239, 240, 241, 243, 244	61.0*, 43.8*, 35.8*, 58.1*, 35.0*	86
Cytotoxic	KB	239, 240, 241	1.0^#, 9.0^#, 10.7^#	83
	A549	239, 240, 241	1.7^#, >20^#, 20^#	83
	CAKI-1	239	2.4^#	83
	MCF-7	239, 240, 241, 242, 243	3.9^#, 8.8^#, 13.5^#, 15.8, 13.1	51,83 and 85
	MCF-7R	243	12.0	85
	IA-9	239, 240, 241	1.8^#, 4.2^#, 1.2^#	83
	HCT-8	239, 240, 241	1.9^#, 7.0^#, 10.0^#	83
	SK-MEL-2	239, 240, 241	2.4^#, 13.6^#, 14.1^#	83
	U-87-MG	239, 240, 241	2.4^#, 14.0^#	83
	HOS	240, 241	10.2^#, 10.5^#	83
	PC-3	239, 240, 241, 242	2.8^#, 13.0^#, 15.0^#, 16.2	51 and 83
	KB-VIN	240, 241	>20^#, 9.5^#	83
	HepG2	239	2.5^#	83
	LNCaP clone FCG	239	2.0^#	83
	LNCaP	239, 242	3.4, 12.1	51 and 83
	HA22T/VGH	243	12.8	85
	MDA-MB-231	239, 242	6.6, 20.4	51
	BAECs**	239, 240, 241, 255, 256, 257	0.52, 1.8, 5.8, 9.3, 2.4, 8.7	88
Antimalarial	P. falciparum (strain FCK2)	239, 243, 245, 246, 247, 248	0.48, 8.44, 8.48, 2.42, 0.87, 4.65	57
	P. falciparum (strain MP-14)	239, 246, 247	3.9, 14.3, 4.9	57
Inflammatory bowel disease	MMP-9 activity in Caco-2 cell line	239, 258, 259	19.4, 17.6, 8.0	84
M. tuberculosis	H37Ra strain	239, 240, 241, 254, 243, 249/244 (1 : 1), 250, 260, 279, 280, 261, 262, 263, 264/265 (2 : 1), 266, 267/268 (5 : 2), 269, 270, 271, 272, 273, 274, 275, 276/277 (1 : 1), 278, 251, 253	200, 100, 25, 25, 1.56, 12.5, 12.5, 6.25, ND, 100, 0.39, 6.25, NA, 1.56, ND, 12.5, ND, 1.56, 1.56, 1.56, 0.09, 0.78, 0.39, 100, ND. 6.25, 200	55

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(5) Pyrazole analogues demonstrated moderate increase of anti-malarial potency against CQ-S and CQ-R. Pyrazole derivative of curcumin inhibited the CQ-S and CQ-R P. falciparum cultures at nanomolar concentrations. Electron withdrawing substituents at N-phenyl curcumin pyrazole system affect the anti-malarial potency of corresponding compounds (245–248). Previous reports showed that electron-withdrawing groups enhanced the biological activity, while electron donating groups decreased the activity. In N-(substituted) phenylcurcumin pyrazole analogues, 3-nitrophenylpyrazole curcumin (247) was found to be most potent.⁵⁷

(6) Pyrazole analogues of the curcumin showed enhanced inhibition of matrix metalloproteinases on Caco-2 cell line (239, 258, and 259).⁸⁴

(7) The isoxazole analogues (249–254, 260–280) were synthesized and evaluated for their antimycobacterial activity. The most active class of analogues, with mono-O-methylcurcumin isoxazole (273) being the most active compound (MIC 0.09 mg ml⁻¹). It was 1131-fold more active than curcumin (1). The structural requirements for a curcuminoid analogue to exhibit antimycobacterial activity are the presence of an isoxazole ring and two unsaturated bonds on the heptyl chain. The presence of a suitable para-alkoxyl group (270–274) on the aromatic ring which is attached in close proximity to the nitrogen function of the isoxazole ring and a free para-hydroxyl group (261) on another aromatic ring enhanced the biological activity.⁵⁵

(8) Cristina et al. synthesized pyrazole analogues (281–286) of curcumin. The SAR of aggregation inhibitors based on curcumin, revealed that the predominant features affecting inhibition of amyloid aggregation is the co-planarity of the two aromatic rings and the distance between them (from 8 to 16 Å). On the other hand, the different chains present on the pyrazole ring did not contribute to the interaction. However, the formation of pyrazole moiety, locks the keto–enol tautomerism in an enol type arrangement, important for its Aβ-binding capability.⁸⁷

(9) A novel hydrazino curcuminoids (239–241) and hydrazinobenzoyl (255–257) curcuminoids were synthesized and evaluated for anti-angiogenic activity using bovine aortic endothelial cells (BAECs). Among the six analogues tested, the compound 239 showed the most potent growth inhibitory activity against BAECs with an IC₅₀ of 0.52 nM. Compound 256 also showed an enhanced anti-proliferative activity against BAECs. However, the potency of 256 was relatively weaker than that of 239.⁸⁸

2.4. Changes in β-diketone structure: change in the 1,3-keto–enol moiety. The β-diketone moiety in curcumin appears to be important for its antitumor activity. Therefore, bioisosteric replacement of 1,3-diketone with enamino, oxime and β-enaminoketone functions with regard to different activities was carried out. The β-enaminoketone compound bearing an N-alkyl substituent demonstrated a little lower cytotoxic activity than curcumin in MCF-7 and in MCF-7R (288). Conversely, compounds bearing an aromatic portion at the amine substituents were found to be inactive. For the dioxime derivatives, the results showed that the benzyl analogue being more active than methyl analogue. The modification of the β-diketone functionality in curcumin into curcumin semicarbazone serves to up-regulate its liposolubility and retain its antioxidant property and free radical scavenging ability. In addition, curcumin semicarbazone showed better activity than curcumin against oestrogen dependant breast cancer cell line MCF-7 (287 and 288).^85,89

Curcumin was converted into diarylheptylamine and the synthesized new analogues were evaluated for (i) inhibition of iNOS expression; (ii) inhibition of NO production; (iii) inhibition of biosynthesis of COX-2 downstream product PGE₂; and (iv) cytotoxicity (Table 10). These analogues exhibited moderate inhibition of NO and iNOS, whereas they showed significant inhibitory activity of PGE₂ (289–292) (Fig. 4).⁹⁰

Table 10 Biological activity of curcumin analogues with changes in the β-diketone structure, change in 1,3-keto–enol moiety (Class-2.4)^a

Activity	Assay/target	Compound(s)	IC50 (μM)	Ref.
a * indicates % inhibition at 10 μM; ** indicates oxidation potential; ^$ indicates % inhibition at 1 μg ml^−1.
Antioxidant	Lipid peroxidation	287	85*	89
	DPPH assay	287	0.28**	89
Anti-inflammatory	LPS-induced PGE2 production	289, 290, 291	1.4, 1.0, 7.4	90
		292	16.0
	LPS-induced NO production	289, 290, 291	72, 100, 68	90
		292	62
Cytotoxic	HA22T/VGH	288	5.9	85
	MCF-7	287, 288	74^$, 7.1	85
	MCF-7R	288	9.3	85

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Fig. 4 Chemical structures of curcumin analogues with changes in the β-diketone structure, change in 1,3-keto–enol moiety (Class 2.4).

2.5. Changes in β-diketone structure: change in the conjugation. Hydrogenated derivatives of curcumin showed a remarkably higher antioxidant activity than curcumin, suggesting that the hydrogenation at conjugated double bonds of the central seven carbon chain and β-diketone of curcumin improved antioxidant activities.⁷⁰ THC (6) showed the highest antioxidant activity while HHC (7) and OHC (8) showed similar antioxidant activity as curcumin.^39,40 THC also showed similar anti-inflammatory activity (cPLA₂, COX and 5-LOX), while it failed to inhibit TNF-α induced NF-κB activation.^43,90,91 When converting the 6 carbon chain into 8 carbon chain with two additional double bonds, the COX inhibitory was increased (293).⁴⁴ Hydrogenation of curcumin (6–8, 294–300) (Fig. 5) had no effect on cytotoxic and antitumor activity. It proved that dienone moiety has no effect on cytotoxic or antitumor activity.⁵⁴

Fig. 5 Chemical structures of curcumin analogues with changes in the β-diketone structure, change in the conjugation (Class 2.5).

The antimycobacterial activity of compound (5–8) against M. tuberculosis H37Ra strain was less than isoxazole analogues of curcumin. This reflected that structural requirements for the curcuminoid analogues to exhibit antimycobacterial activity are the presence of an isoxazole ring and two double bonds on the heptyl chain.⁵⁵

The parent curcuminoids exhibited low antitrypanosomal activity (T. brucei strain 427) (Table 11). The number and nature of the oxygen functions on the aromatic rings strongly determined the antitrypanosomal activity of the tetrahydro analogues. Compound 295 was almost 9-fold more active than compound 294. Compound 296 was even 42-fold more active than the methylated analogue 6.⁵⁴

Table 11 Biological activity of curcumin analogues with changes in the β-diketone structure, change in the conjugation (Class-2.5)^a

Activity	Assay/target	Compound(s)	IC50 (μM)	Ref.
a * indicates % inhibition at 10 μM; ** indicates % inhibition at 10 μM; NA, not active (MIC > 200 mg ml^−1); ND, not determined.
Antioxidant	TRAP assay	6	94*	70
	FRAP assay	6	60*	70
	Lipid peroxidation	6	1.83	40
	DPPH assay	6, 7, 8	18.22, 21.6, 23.6	40
	ABTS^+ assay	6	2.52	40
Anti-inflammatory	LPS-induced iNOS expression	6, 7, 8	62**, 64**, 67**	91
	LPS-induced iNOS Promoter activity	6, 7, 8	42**, 34**, 40**	91
	COX-1	293	1.14	44
	COX-2	293	5.13	44
	cPLA2	6	40^#	90
	5-LOX	6	2.99	91
M. tuberculosis	H37Ra strain	5, 6, 7, 8	200, 50, 100, NA	55
Antitrypanosomal	T. brucei strain 427	6, 7, 8, 294, 295, 296, 297 + 298, 299, 300	21, 17, 78, 22, 2.5, 0.50, 3.07, 1.9, 33	54
	T. brucei ΔTbat1	6, 7, 8, 294, 295, 296, 297 + 298, 299, 300	37, 38, 61, 34, 4.0, 0.52, 2.9, 1.5, 22	54
	T. brucei clone B48	6, 7, 8, 294, 295, 296, 297 + 298, 299, 300	12, 5.9, >100, 18, 5.1, 0.43, 2.5, 1.7, 19	54
Antileishmanial	L. major promastigotes	6, 7, 8, 294, 295, 296, 297 + 298, 299, 300	90, >100, >100, >100, 80, 11, >100, >100, 41	54
	L. mexicana amastigotes	6, 7, 8, 294, 295, 296, 297 + 298, 299, 300	43, >100, >100, >50, 64, 16, 40, 53, >100	54
Cytotoxic	HEK	6, 7, 8, 294, 295, 296, 297 + 298, 299, 300	120, 370, ND, ND, 350, 130, 77, 150, 150	54

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2.6. Changes in β-diketone structure: substitution on the β-carbon. Substitution at central methylene carbon plays an important role in formation of stable phenoxy radical which is initiated either through direct abstraction of the phenolic hydrogen, or by way of initial ionization of an acidic proton from the central methylene, followed by electron transfer to form a carbon centered radical that can isomerise to the phenoxy radical. In the case of monoalkylated analogues, stabilized tertiary carbon centered radicals can form in the reaction with ABTS in the TRAP assay for antioxidant activity (301 and 303). This is not possible with the dialkylated analogues.⁷⁰ Kim et al. evaluated both phenolic and non-phenolic curcumin analogues having various substituents (methyl, allyl, methoxy, xanthate, and acetoxy) at central methylene position (304–314) (Table 12) for antioxidant activity. The antioxidant potential of these groups were in increasing order of methyl < allyl < methoxy < xanthate ≪ acetoxy, which is in correlation with the polar inductive effects of these substituents.⁹²

Table 12 Chemical structures of curcumin analogues with substitution β-carbon of dicarbonyl chain (Class2.6)

General structure for Class-2.6 compounds (301–325)
Compound(s)	R1	R2	R3	R4	R5
301	CH3	H	H	H	H
302	CH3	H	OCH3	OCH3	H
303	CH2C6H5	H	H	H	H
304	H	H	OCH3	OH	H
305	H	H	OCH3	OCH3	H
306	H	H	H	H	H
307	H	H	H	H	H
308	CH3	H	OCH3	OH	H
309	CH2CH=CH2	H	OCH3	OH	H
310	SC(S)OEt	H	OCH3	OH	H
311	CH2CH=CH2	H	OCH3	OCH3	H
312	OCOCH3	H	H	OH	H
313	OCOCH3	H	H	OCH3	H
314	OCOCH3	H	H	H	H
315	CH2CH2COOEt	H	OCH3	H	H
316	CH2CH2COOEt	H	H	OCH3	OCH3
317	CH2CH2COOEt	H	OCH3	OCH3	OCH3
318	CH2CH2COOEt	H	N(CH3)2	OCH3	H
319	CH2CH2COOEt	H	OCH3	OH	H
320	CH=CHCOOEt	H	OCH3	OTHP	H
321	CH=CHCOOEt	H	OCH3	OCH3	H
322	CH=CHCOOMe	H	OCH3	OCH3	H
323	CH=CHCONHEt	H	OCH3	OCH3	H
324	CH=CHCN	H	OCH3	OCH3	H
325	CH=CHCH2OH	H	OCH3	OCH3	H

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326
327
328
329

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General structure for Class-2.6 compounds (330–337)
Compound(s)	R1	R2	R3	R4	R5	R6
330	H	OCH3	H	OCH3	OH	H
331	H	OCH3	H	H	OCH3	OCH3
332	H	OCH3	H	OCH3	OCH3	OCH3
333	OCH3	OCH3	H	N(CH3)2	H	H
334	OCH3	OCH3	H	OCH3	H	OCH3
335	OCH3	OH	H	OH	OCH3	H
336	OCH3	OH	OCH3	OCH3	H	H
337	OCH3	OH	H	OCH3	H	OCH3

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Substitution at central methylene carbon with 4-ethoxycarbonylethyl ester enhances the anti-androgen activity (315–319 and 329). The replacement of ethoxy with methoxy or N-ethylamino resulted in loss of activity, which implied that a long chain ester may be more favourable. The reduction of ester to alcohol also led to loss of activity, emphasizing the necessity for an ester in the side chain. The nitrile functional group did not enhance the anti-androgen activity or the cytotoxicity. The –CH=CHCOOEt side chain is superior to –CH=CHCOOMe, –CH₃, –CHCONHEt, –CH=CHCN, and –CH=CHCH₂OH (320–325). The monoalkylated analogues were more potent in inhibiting NF-κB than dialkylated analogues and curcumin.^45,49,93,94

Replacement of an acidic proton from the central methylene with benzylidene derivatives proved to be as effective antimalarial as curcumin. The 4-hydroxy-3-methoxy-benzaylidene derivative of curcumin was more active than curcumin, 4-hydroxy-benzylidene derivative and benzylidene derivative (326–328). This suggested that the presence of methoxy group (electron donor group) at the meta position of 4-hydroxy-3-methoxy-benzylidene derivative of curcumin appears to play an important role for the potency of antimalarial compounds.⁵⁷

Qiu et al. synthesized new 4-arylidene curcumin analogues as potential anticancer agents and were screened against A549 cell growth. Most of the 4-arylidene curcumin analogues (4-arylidene-1,7-bisarylhepta-1,6-diene-3,5-diones, 330–341) showed potent anticancer activities with a GI₅₀ in the sub-micromolar range (0.23–0.93 μM), except 332, 333, 335, and 338 which exhibited slightly lower activities (GI₅₀ of 1.12–2.62 μM) (Table 13). The potency of 4-arylidene analogues was improved by 10–60 folds over the parent compound curcumin in this assay. 4-Hydroxymethylene curcumin analogues (339–341), however, showed poor activity, suggesting the importance of the third arylvinyl moiety.⁵⁶

Table 13 Biological activity of curcumin analogues with changes in the β-diketone structure, Substitution on the 1,6-heptadiene moiety (Class-2.6)^a

Activity	Assay/target	Compound(s)	IC50 (μM)	Ref.
a * indicates % inhibition at 10 μM; ** indicates ED50 value in μg ml^−1; *** indicates EC50 (μM); ^# indicates % inhibition at 1 μM; ^## indicates % inhibition at 5 μM; ^$ indicates GI50 in μM.
Antioxidant	TRAP assay	301, 303	52*, 55*	70
	FRAP assay	303	39*	70
	DPPH assay***	304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314	22.6, >100, >100, >100, 23.2, 23.2, 29.7, >100, 26.3, 32.8, 47.8	92
Antitumor	NF-κB	338	6.3	45
	DU145/wtAR	315, 316, 317, 318	30–40^#, 30–40^#, 30–40^#, 30–40^#	92
	PC-3/wtAR	315, 302	30–40^#, 5.2	92
	KB	302	7.5**	83
	A549^$	302	7.9**	83
		330, 331, 332, 333, 334, 335, 336, 337, 338	1.64, 0.93, 1.12, 2.62, 0.65, 2.00, 0.43, 0.69, 1.31	56
	MCF-7	302	6.5**	83
	IA9	302	1.1**	83
	HCT-8	302	2.2**	83
	SK-MEL-2	302	4.6**	83
	U87-MG	302	3.0**	83
	HOS	302	4.0**	83
	KB-VIN	302	6.7**	83
	HepG2	302	5.4**	83
	LNCaP clone FGC	302	13.0**	83
Anti-androgenic	LNCaP	319, 320, 321, 322, 323, 324, 325, 319, 329	96^## & 1.5, 2.6, 94^## & 0.2, 0.4, 0.6, 60^## & 0.2, 0.2, 30, 160	49,93 and 94
	PC-3	302, 319, 320, 321, 322, 323, 324, 325, 319, 329	3.5, 90^## & 5.1, 3.1, 60^## & 1.0, 0.2, 1.2, 30^## & 0.7, 1.3, 6.4, 6.3	49,93 and 94
Antimalarial	P. falciparum	326, 327, 328	3.89, 5.85, 0.92	57

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3. Curcumin bioconjugates

3.1. Amino-acid conjugates of curcumin. Construction of conjugates of curcumin with some amino acids (glutamic acid, glycine, valine) showed much better antibacterial, antifungal and antioxidant properties (Table 14), which may be attributed to their better solubility, enhanced accumulation in the cells, resulting from better cellular uptake and decreased metabolic rate. The diesters of curcumin (344–350) showed more antibacterial activity than curcumin which may be due to their increased solubility, better cellular uptake and slow down of metabolic process due to the masking of free phenolics. The monoesters (342 and 343) showed better activity than their corresponding diesters since monoesters have both the advantages, i.e., as a ligand helping in cellular uptake and a free phenolic for binding at active site (343–348) (Table 15). In case of antifungal activity, only the analogues having monoester of glycine showed good activity than its diester analogue and curcumin. The diesters analogues of curcumin showed better anticancer activity than the monoester analogues. In addition, the diester of glutamic acid showed the best anticancer activity among the all ester analogues. The conjugates of curcumin with piperoyl glycine, i.e. conjugate of piperic acid and glycine, showed improved antimicrobial activity due to enhanced solubility (349 and 350).^95,96

Table 14 Biological activity of amino-acid conjugates of curcumin (Class-3.1)^a

Activity	Target	Compound(s)	MIC	Ref.
a * indicates zone of inhibition in mM; ** indicates IC50 values in μM.
Antimicrobial	Micrococci	343, 344, 345, 346, 347, 348, 349, 350	2.5, 5, 10, 10, 10, 10, 10, 5	95 and 96
	Enterococcus	349	5	96
	Klebsiella aeruginosa	342, 343, 350	5, 5, 10	95 and 96
	Staphylococcus saprophyticus	345, 349, 350	10, 5, 10	95
	Enterobacter cloaceae	343, 345, 349, 350	2.5, 5, 10, 10	95 and 96
	Escherichia coli	343, 349, 350	10, 10, 10	95 and 96
	Pseudomonas aeruginosa	349, 350	2.5, 2.5	96
	Pseudomonas pyocynin	349, 350	2.5, 5	96
	Staphylococcus epidermidis	349, 350	10, 10	96
	Staphylococcus aureus	349, 350	10, 5	96
	Enterococcus aerogen	350	10	96
Antifungal	Candida albincans	349	24*	96
DPPH-scavenging and anti-haemolysis**	DPPH	351, 352, 353, 354, 345, 355, 356, 357, 346, 358	0.068, 0.082, 0.055, 0.058, 0.049, 0.048, 0.036, 0.092, 0.076, 0.098	97
	β-carotene bleaching method	351, 352, 353, 354, 345, 355, 356, 357, 346, 358	0.064, 0.077, 0.047, 0.06, 0.037, 0.043, 0.03, 0.086, 0.066, 0.091	97

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Table 15 Chemical structures of amino-acid conjugates of curcumin (Class 3.1)

General structure for Class-3.1 compounds (342–350)
Compound(s)	R1	R2
342		H
343		H
344
345
346
347		H
348
349
350

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The enhancement in the activity of these curcumin bioconjugates may be due to:

(i) Enhanced metabolic stability due to masking of phenolic hydroxyl groups and delay in their glucuronide formation during metabolism, (ii) better cellular uptake due to the transportation of the conjugate via the amino acid carrier protein, i.e., drug smuggling, and (iii) more solubility of the conjugates because of enhancement in polar character (hydrophilicity). The curcumin analogues with alkyl-substituted amino acids (351–358), such as alanine, valine, serine and cysteine, exhibited lower IC₅₀ values than did curcumin in antioxidant assays. The enhancement in the antioxidant activities of curcumin amino acid conjugates could be principally attributed to the scavenging activity of the keto–enol group in curcumin. The phenolic hydroxyl of curcumin was substituted with amino acids blocking the route of the HAT (hydrogen atom transfer) mechanism of antioxidant activity. Here, the mechanism involved may be sequential proton loss electron transfer (SPLET), because the keto–enol moiety of curcumin has a more easily dissociable proton, and this is supposed to be faster than other mechanisms as the enolic proton is more acidic than the other two phenolic groups on curcumin.⁹⁷

3.2. Curcumin glycosides. The diglucoside (359) (Fig. 6) of curcumin proved to be a good antimicrobial agent (Table 16) than curcumin (359)⁹⁶ while the sugar (glucose and galactose) glycoside of curcumin and THC were unable to inhibit histamine release and failed to prove antioxidant activity.

Fig. 6 Curcuminoid glycosides (Class 3.2).

Table 16 Biological activity of sugar conjugate of curcumin (Class-3.2)

Activity	Target	Compound(s)	MIC	Ref.
Antimicrobial	Escherichia coli	359	10	96
	Staphylococcus aureus	359	10	96
	Klebsiella aeruginosa	359	5	96
	Staphylococcus saprophyticus	359	10	96
	Micrococci	359	10	96

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3.3. Taxoid conjugate of curcumin. The taxoid conjugate (Fig. 7) of curcumin showed good cytotoxic activity (Table 17) against various cancer cell lines better than paclitaxel (360).⁹⁸

Fig. 7 Taxoid conjugate of curcumin (Class 3.3).

Table 17 Biological activity of taxoid conjugate of curcumin (Class-3.3)

Activity	Assay/target	Compound(s)	ED50 (μM)	Ref.
Cytotoxic	A549	360	0.03	98
	IA9	360	0.03	98
	A431	360	0.03	98
	KB	360	0.01	98
	KB-VIN	360	0.2	98

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4. Miscellaneous

The cyclohexanone analogues containing two or three phenolic groups (367, 364 and 368) or three methoxyl groups (363) were less potent than the analogue with one methoxy and one phenolic group (362). The enone functionality in these molecules was critical for anticancer activity, as demonstrated by the lack of activity of the reduced form of 261 and 362. Substitution of the 2,6-bis-phenyl groups with either pyridine (365 and 366) or thiophene (369) did give greater activity than 362 Specifically, the 2,6-bis(thiophene) cyclohexanone (369) showed an EC₅₀ value of 0.27 μM (Table 18) in SKBr3 cells.⁹⁹

Table 18 EC₅₀ values for curcumin and analogs (miscellaneous) in ER-negative human breast cancer cells (Class-4)^a

Activity	Assay/target	Compound(s)	EC50 (μM)	Ref.
a ^# indicates GI50, ^_aindicates no EC50 value could be obtained, ^_bindicates drug potency was too low to obtain an EC50 value, ^_cindicates drug increased cell number.
Anticancer	MDA-MB-231 cells	362, 363, 367, 364, 361, 368, 365, 366, 369	2.55, ^_a, 8.64, ^_a, ^_a, 20.05, 1.54, 1.10, ^_c	99
	SKBr3 cells	362, 363, 367, 364, 361, 368, 365, 366, 369	1.16, ^_a, 9.78, ^_b, ^_c, 6.21, 0.51, 0.23, 0.27	99
	HUVEC	376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389	2.2, 12.6, 2.0, 9.3, 7.2, 10.8, >50, >50, >50, >50, 9.2, 1.5, 22.8, 9.9	100
Alzheimer	Aβ	370, 371, 372, 373	>50, >50, 37.8, >50	76
Anticancer	HCT-116	374, 375	>50^#, 22^#	67

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Woo et al. synthesized symmetrical bis-alkynyl pyridine and thiophene derivatives (376–389) by Sonogashira reaction and tested for antiangiogenic activity using human umbilical vein endothelial cells (HUVEC). Compounds 376, 378, and 380 (Fig. 8), with rigid mimetic structure of curcumin, showed the potent growth inhibitory activity.¹⁰⁰

Fig. 8 Miscellaneous compounds.

Various metal complexes of curcumin and curcumin analogues^101–105 sugar conjugates of curcumin,^106,107 dipeptide conjugate, fatty acid and folic acid conjugates of curcumin,¹⁰⁸ dihydropyridone derivatives of curcumin,¹⁰⁹ cyclopalladated complexes of curcumin,¹¹⁰ unsymmetrical curcumin analogues¹¹¹ and monofunctional curcumin derivative, clicked curcumin dimer¹¹² have been synthesized. The various metal complexes include copper and manganese complexes of curcumin and their analogues while various mono and diglycosylcurcumin derivatives were synthesized. The monofunctional curcumin derivatives includes monocarboxylic acid derivative monoazide derivative, monoalkyne derivative, monotriazole–PEG derivative has been synthesized.

Conclusion

Curcumin has been explored in almost all therapeutic areas among which cancer is the major one. In particular, the impact of curcumin on breast cancer has received substantial focus in clinical oncology as preclinical findings witnessed an anti-breast cancer effect of curcumin on various breast cancer cell lines.¹¹³ Although, traditionally used as an anti-inflammatory agent, curcumin might be a good lead molecule for cancer treatment, which is reflected by the considerable scientific literature on cancer. Apart from cancer, curcumin exhibited good antioxidant, anti-inflammatory, anti-angiogenesis, chemo-prevention, Alzheimer's disease prevention, antimicrobial, antimalarial, antithrombotic, myocardial infarction protective, rheumatoid arthritis prevention, inhibition of human immunodeficiency virus (HIV) replication, enhancement of wound healing, antihepatotoxic, psoriasis, hypoglycemic, and antihyperlipidaemic activities. In spite of possessing these broad range of biological activities and safety profile, curcumin has not yet been approved as a drug because of its poor oral bioavailability. Therefore, to overcome this major limitation, several researchers attempted synthesis of curcumin analogues with better efficacy and improved pharmacokinetic profile.

Curcumin in general showed better biological activities as compared to DMC and BDMC. Enhanced antioxidant activity was observed as the number of phenolic groups on the aryl rings increased. The picture is more complex in case of anticancer and cytotoxic activities. In general curcumin analogues with cyclohexanone moiety showed better anti-inflammatory, cytotoxic activities than compounds with acetone and cyclopentanone moieties. Some heterocyclic analogues also showed promising COX inhibitory activities. Our group has synthesized and screened the pyrazole and isoxazole analogues of curcumin against COX-1/COX-2. The pyrazole analogues of curcumin showed better antioxidant, COX-2 inhibitory, antitumor and antimalarial activities as compared to curcumin and isoxazole analogues. Hydrogenated analogues showed better antioxidant, similar anti-inflammatory and cytotoxic activities as that of curcumin. In-spite of better activity profile of curcumin analogues, their pharmacokinetic and pharmacodynamic studies have not been performed so far. Therefore, further studies are required to reveal detailed mechanism of action of these analogues and to make them suitable candidate for clinical trials.

Abbreviations

ABTS	2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)
BDMC	Bisdemethoxycurcumin
COX	Cyclooxygenase
cPLA2	Cytosolic phospholipase A2
DHC	Dihydrocurcumin
DMC	Demethoxycurcumin
DPPH	2,2-Diphenyl-1-picrylhydrazyl
FRAP	Ferric reducing ability of plasma
HHC	Hexahydrocurcumin
IL	Interleukin
LOX	Lipoxygenase
LPS	Lipopolysaccharide
LT	Leukotriene
NBT	Nitroblue tetrazolium
NF-κB	Nuclear factor-κB
NO	Nitric oxide
OHC	Octahydrocurcumin
PGE2	Prostaglandin E2
SAR	Structure–activity relationship
THC	Tetrahydrocurcumin
TNF-α	Tumor necrosis factor-α
TRAP	Telomeric repeat amplification protocol

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