Next Article in Journal
Identification of Novel Covalent XPO1 Inhibitors Based on a Hybrid Virtual Screening Strategy
Previous Article in Journal
Effects of Sphingomyelin-Containing Milk Phospholipids on Skin Hydration in UVB-Exposed Hairless Mice
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 8
10.3390/molecules27082547
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Improved Synthesis of Asymmetric Curcuminoids and Their Assessment as Antioxidants

by
Yang-Je Cheng
1,
Cai-Wei Li
2,
Cing-Ling Kuo
1,
Tzenge-Lien Shih
1,* and
Jih-Jung Chen
3,4,*
1
Department of Chemistry, Tamkang University, Tamsui Dist., New Taipei City 251301, Taiwan
2
Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
3
Department of Pharmacy, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
4
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404332, Taiwan
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(8), 2547; https://doi.org/10.3390/molecules27082547
Submission received: 17 March 2022 / Revised: 31 March 2022 / Accepted: 11 April 2022 / Published: 14 April 2022
Browse Figures
Versions Notes

Abstract

:
In this paper, the syntheses of twelve asymmetric curcumin analogs using Pabon’s method are reported. Generally, the previously reported yields of asymmetric curcuminoids, such as 9a (53%), 9c (38%), and 9k (38%), have been moderate or low. Herein, we propose that the low yields were due to the presence of water and n-BuNH2 in the reaction media. To prove this formulated hypothesis, we have demonstrated that the yields can be improved by adding molecular sieves (MS) (4 Å) to the reaction mixture, thus reducing the interference of water. Therefore, improved yields (41–76%) were obtained, except for 9b (36.7%), 9g (34%), and 9l (39.5%). Furthermore, compounds 9b, 9d, 9e, 9f, 9g, 9h, 9i, 9j, and 9l are reported herein for the first time. The structures of these synthetic compounds were determined by spectroscopic and mass spectrometry analyses. The free radical scavenging ability of these synthetic asymmetric curcuminoids was evaluated and compared to that of the positive control butylated hydroxytoluene (BHT). Among the synthesized asymmetric curcuminoids, compounds 9a (IC50 = 37.57 ± 0.89 μM) and 9e (IC50 = 37.17 ± 1.76 μM) possessed effective 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging abilities, and compounds 9h (IC50 = 11.36 ± 0.65 μM) and 9i (IC50 = 10.91 ± 0.77 μM) displayed potent 2,2’-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS) radical scavenging abilities comparable to that of curcumin (IC50 = 10.14 ± 1.04 μM). Furthermore, all the synthetic asymmetric curcuminoids were more active than BHT.

1. Introduction

Turmeric is an orange-yellow powder that is obtained from the rhizomes of the natural plant Curcuma longa, and is used as a spice and traditional herbal medicine in South Asian countries like India and China. Although turmeric has been used for thousands of years, its major constituent curcumin was discovered in 1815 [1]. Thereafter, the structure of curcumin was determined [2], and it was synthesized [3] in the 1910s. The active components of turmeric that are used for medicinal purposes and as food additives for human health [4] are called curcuminoids. Their biological activities have attracted increasing attention from many researchers since the 1970s [5], and research on curcuminoids has grown rapidly since the 1990s [6]. The most abundant constituents of curcuminoids isolated from Curcuma longa are curcumin (CUR, curcumin I), demethoxycurcumin (DMC, curcumin II), and bisdemethoxycurcumin (BDMC, curcumin III), with contents of approximately 60–75%, 15–30%, and 3–15% yields, respectively (Figure 1) [7,8]. However, their contents vary depending on their origin and species [8]. Curcumin possesses a bis-α,β-unsaturated framework, which equilibrates in either a keto form or a keto-enol form in solution (Figure 2). This phenomenon is called tautomerism, which is dependent on solvent, temperature, and pH, and is determined by detailed NMR analysis [8]. Neutral or acidic conditions favor the keto-enol form, whereas the keto form is dominant under alkaline conditions [9]. Among the aforementioned curcuminoids, DMC has an asymmetric structure.
Natural curcuminoids and their synthetic derivatives exhibit a wide range of biological activities and are safe for consumers [10,11]. They possess anti-Alzheimer’s disease (AD) [12,13,14,15], anti-bacterial [16], anti-cancer [17,18,19,20,21,22,23], anti-inflammatory [12,24,25,26,27,28,29,30,31], and antioxidant properties [20,25,27,29], and are used in therapeutic treatments [9,32,33,34,35]. Curcuminoids have recently been used to synthesize diazepine derivatives, such as α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs), which are involved in neurodegenerative diseases [36]. However, the limitations of using curcuminoids as pharmacological agents are due to their insolubility in water, instability, poor absorption, and rapid metabolism, which prevent their bioavailability. Furthermore, curcuminoids have been linked to over 100 cellular targets, limiting their use as therapeutic agents [12]. Therefore, improvements in the synthesis of curcuminoids are still underway, with the aim of obtaining oral bioavailable analogs [37,38].
The syntheses of symmetric or asymmetric curcumin analogs were performed using Pabon’s method [39] or modified versions of Pabon’s method [12,40,41]. Symmetric curcuminoids are generally prepared by treating 2,4-pentanedione and B2O3 in EtOAc, followed by the addition of two equivalents of the corresponding aldehydes, (BuO)3B and n-BuNH2, to yield 2 (Figure 3, path a). Following the same procedure, monosubstituted intermediate 3 was synthesized by adding one equivalent of aldehyde in the first step [9,12,42,43]. This intermediate can be either isolated or directly subjected to one-pot treatment with another equivalent of different aldehydes to afford 4 (Figure 3, path b). The drawback of asymmetric curcuminoid synthesis is low yields (<38–2%) [15,44]. Therefore, the synthesis of symmetric curcuminoids is more convenient, and their biological activities have been reported more routinely than those of asymmetric ones.
Oxidative stress is caused by an imbalance between free radical production and quenching. Active free radicals can react strongly with biomacromolecules, including DNA, carbohydrates, proteins, and membrane lipids, causing oxidative damage [45]. Furthermore, reactive oxygen species (ROS) play a vital role in many diseases, including atherosclerosis, cancer, mitochondrial diseases, and chronic diseases [46]. The property of hydrogen donation under oxidation allows curcumin to serve as a scavenger for most ROS [9,26,34]. Therefore, the ability to remove ROS can reduce cancer risk. In the pursuit of better oxidants than curcumin, we found that asymmetric curcumin analogs are relatively underexplored compared to symmetric ones. Therefore, the class of asymmetric curcuminoids reported here was evaluated for their antioxidant ability, and compared with curcumin and BHT as positive controls.

2. Results and Discussion

2.1. Chemistry

The syntheses of the asymmetric curcumin analogs are shown in Scheme 1 and Scheme 2. Monosubstituted intermediate 6 was prepared in the first step in order to synthesize asymmetric curcuminoids (Scheme 1). In this way, compound 6 was synthesized via Pabon’s method in moderate yield (45%) [22], and symmetric curcumin 7 was isolated as a by-product (6%) [16]. However, the yields of monosubstituted intermediates during the preparation of asymmetric curcuminoids have not been reported in the literature [14,15,16,21,42]. Monosubstituted 6 was therefore used as the starting material for condensation with another equivalent of the corresponding aldehydes 8a–l by employing the aforementioned procedure (Scheme 2). Unfortunately, these reactions are not clean, and repeated column chromatography purification is required to afford compounds 7, 9a–l, and 10a–l. The corresponding yields are listed in Table 1.
The results shown in Table 1 are interesting. The combined yields of compounds 7, 9a–l, and 10a–l were low to moderate (~27–59%, entries 1–12) [47]. Symmetric curcumin analogs 7 and 10a–l (except 10d) were isolated during the synthesis of asymmetric curcumin analogs. Additionally, asymmetric curcumin analogs 9a–l were obtained in low yields (~11–38%) throughout this study, which is consistent with the results reported in the literature [16]. We were interested in this phenomenon and proposed a plausible mechanism for the formation of by-products 7 and 10a–l, as shown in Figure 4.
First, compound 6 was complexed with B2O3 to form compound 11, and then reacted with aldehydes 8a–l in the presence of (BuO)3B and n-BuNH2 to afford the target compounds 9a–l. Conversely, compound 11 may be hydrolyzed in the presence of trace amounts of water. Therefore, 11 underwent an accessible 1,4-addition with water to afford 12, followed by hydrogen abstraction to afford 13. Notably, compound 5 was recovered during this step. Compound 13 was deprotonated by n-BuNH2 via a retro aldol process to convert back to intermediate 14, which is suspected to immediately recombine with hydrolyzed 5 to yield 7 in a faster manner [34]. Intermediate 14 also reacted with aldehydes 8a–l to yield 10a–l at a relatively slower rate. It has been reported that the removal of water in the reaction can increase curcumin yield [34].
The formation of intermediate 14 is most likely derived from the retro aldol reaction of boronic complex 11, because its conjugated system serves as a Michael acceptor. Compound 11 was hydrolyzed by n-BuNH2; otherwise, compound 7 was not obtained. This evidence supports the hypothesis that the low yields of asymmetric curcuminoids are due to the presence of water. Notably, compound 10l has previously been used to kill Gram-positive bacteria efficiently via a photodynamic method [48]. Spectroscopy data for compounds 7 and 10a–c, and 10f–l were compared with previously reported ones [48], except for compound 10e.
To prove the hypothesis of the retro aldol reaction of compound 13 proposed herein, the identities of water and n-BuNH2 must be clarified. Therefore, a control experiment was designed by adding an MS of 4 Å to the reaction mixture (see Experimental Section 3.4). It was concluded that the yields of compounds 9a–l were enhanced, although symmetric curcumin 7 was inevitably formed in every case (see parentheses in Table 1). However, no 10a–l was isolated by column chromatography in either case in the control experiment. This proves that the removal of water from the reaction mixture favors the target molecules. It is crucial to enhance the yields of compounds 9a–l and reduce the formation of compounds 10a–l.

2.2. Pharmacology/Biology

2.2.1. DPPH Free-Radical Scavenging Activity of Compounds 9a–l

DPPH, a kind of stable free radical, accepts an electron or hydrogen radical in order to be reduced to a pale-yellow molecule [49]. The changes in absorbance can be used to determine the antioxidant capacity of the sample. The inhibitory activity data of the compounds 9a–l as regards DPPH radical scavenging are shown in Figure 5 and Table 2. The commercially available antioxidant BHT was used as the positive control. From the results of the DPPH radical scavenging assay, the following conclusions can be drawn: (a) compounds 9a–l exhibited potent DPPH radical scavenging activities and were more effective than the positive control, BHT (IC50 = 122.78 ± 0.96 μM); (b) compounds 9a (with 4-fluorophenyl moiety) and 9e (with 3-fluorophenyl moiety) showed the strongest DPPH radical scavenging activity among the synthesized compounds, with IC50 values of 37.57 ± 0.89 and 37.17 ± 1.76 μM, respectively, and displayed more effective inhibition than their analog 9h (with 2-fluorophenyl moiety); (c) compounds 9b, 9c, 9f, and 9g (with 4-chlorophenyl, 4-bromophenyl, 3-chlorophenyl, and 3-bromophenyl moieties, respectively) exhibited more effective inhibition than their analogs, 9i and 9j (with 2-chlorophenyl and 2-bromophenyl moieties, respectively); (d) compound 9k (with thiophen-2-yl moiety) displayed more effective inhibition than its analog 9l (with 5-methylthiophen-2-yl moiety).

2.2.2. ABTS Radical Cation Scavenging Activity of Compounds 9a–l

Potassium persulfate converts ABTS into the blue ABTS radical cation, and it becomes colorless when neutralized by antioxidants [50]. The inhibitory activity data of the compounds 9a–l in terms of ABTS radical scavenging, using BHT as the positive control, are shown in Figure 5 and Table 2. From the results of the ABTS radical scavenging assay, the following conclusions can be drawn: (a) compounds 9a–l showed stronger ABTS radical scavenging activities than BHT (IC50 = 71.94 ± 1.81 μM); (b) compound 9i proved the most effective among the synthesized compounds, with IC50 = 10.91 ± 0.77 μM, in the scavenging of the ABTS free radicals; (c) compounds 9h and 9i (with 2-fluorophenyl and 2-chlorophenyl moieties, respectively) displayed more effective inhibition than their analogs 9a, 9b, 9e, and 9f (with 4-fluorophenyl, 4-chlorophenyl, 3-fluorophenyl, and 3-chlorophenyl moieties, respectively); (d) compound 9g (with 3-bromophenyl moiety) showed stronger ABTS inhibitory action than its analogs 9c and 9j (with 4-bromophenyl and 2-bromophenyl moieties, respectively); (e) compound 9k (with thiophen-2-yl moiety) exhibited more effective inhibition than its analog 9l (with 5-methylthiophen-2-yl moiety).

3. Materials and Methods

3.1. General Procedures

All chemicals were purchased from the Uni-Onward Corporation in Taiwan and used without further purification. Ethyl acetate was dried over CaH2 and distilled before use. Flash column chromatography was performed on 230–400 mesh SiO2 gel (SiliaFlash® P60, 40–63 μm 60 Å; SiliCycle® Inc., Quebec City, QC, Canada). Structural determinations were based on 1H and 13C nuclear magnetic resonance spectroscopy (NMR) data and were recorded on a Bruker 600 MHz Ultrashield instrument. The chemical shifts were reported in parts per million (ppm) relative to the residual of the solvents: 1H (7.26 ppm) and 13C (77.0 ppm) for CDCl3, and 1H (4.78 ppm) and 13C (49.15 ppm) for CD3OD. Melting points were measured using an MP-2D apparatus and were uncorrected. The molecular weights of the compounds were determined by high-resolution mass spectrometry (HRMS) using a TMS-700 instrument in the electrospray ionization (ESI) mode. MS 4 Å was oven-dried overnight at 100 °C before use.

3.2. Synthesis of Monosubstituted 6 (Pabon’s Method)

An oven-dried flask was charged with a mixture of 2,4-pentanedione (1.09 mL, 10.60 mmol) and B2O3 (0.5130 g, 7.33 mmol) in dry EtOAc (4.0 mL), and then heated at 85 °C for 30 min. A mixture of compound 5 (0.807 g, 5.30 mmol) and (BuO)3B (0.372 mL, 1.38 mmol) in EtOAc (3.0 mL) was stirred at ambient temperature for 30 min before this mixture was added to the aforementioned solution. This mixture was heated at 85 °C for 30 min, and n-BuNH2 (0.21 mL, 2.12 mmol) and EtOAc (1.0 mL) were added to the mixture using a syringe pump at 0.5 mL/h. The reaction was monitored by TLC till completion (18–24 h, depending on the aldehydes used; the reaction time for aldehyde 8d was 48 h). The mixture was then cooled to 50 °C, followed by the addition of 2 N HCl (5.5 mL) and stirring for 30 min. Then the mixture was diluted in H2O and extracted with EtOAc. The organic layer was dried (MgSO4), concentrated, and purified using flash column chromatography.

3.3. Synthesis of Asymmetric Curcumin Analogs

Compound 6 (1 equivalent) was reacted with B2O3 (0.5 equivalent), (BuO)3B (2 equivalent), and n-BuNH2 (1 equivalent) by Pabon’s method, except that different aldehydes (2 equivalents) were used. The organic layer was purified by flash column chromatography to obtain compounds 7, 9a–l, and 10a–l.

3.4. Controlled Experiment

A mixture of compound 6 (1 equivalent), B2O3 (0.5 equivalent), and MS 4 Å (3.5-fold w/w relative to the amount of compound 6) in dry EtOAc was heated at 85 °C for 30 min. We then followed the procedure described in Section 3.2. The crude mixture was purified using column chromatography. Please note that using more than 3.5 times the amount of MS 4 Å gave rise to low yields of compounds 9a–l.

3.5. Biological Assay

3.5.1. Materials

2,2-Diphenyl-1-picrylhydrazyl (DPPH) was obtained from the Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). 2,2’-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) was purchased from Sigma-Aldrich (St. Louis, MO, USA). Potassium peroxodisulfate was obtained from SHOWA Chemical Co., Ltd. (Chuo-ku, Japan).

3.5.2. DPPH Radical Scavenging Assay

The DPPH radical-scavenging activity of each compound was measured as previously described [51]. Briefly, the DPPH solution (400 µM, dissolved in ethanol, 100 µL) and different concentrations (6.25, 12.5, 25, 50, 100, and 200 μM) of each compound (dissolved in ethanol, 100 µL) were mixed in a 96-well microplate. After incubation in the dark at room temperature for 30 min, the absorbance was measured at 520 nm using an ELISA plate reader (µ Quant; Tecan Group Ltd., Switzerland) (µ Quant). The DPPH radical scavenging activity was determined using the following formula:
DPPH radical inhibiting activity (%) = (Ac − At)/Ac × 100,
Here, Ac and At are the absorbances of the control (untreated group) and test sample, respectively. Commercially available BHT was used as a positive control. All half-maximal inhibitory concentration (IC50) values of the tested activities were determined using linear regression of the percentage of remaining radicals against the sample concentration.

3.5.3. ABTS Cation Radical Scavenging Activity

The ABTS cation radical scavenging activity was determined using the reference method [50]. The mixture of 28 mM ABTS solution and 9.6 mM potassium peroxydisulfate (1/1, v/v) was incubated in the dark at room temperature for 16 h to prepare the ABTS cation solution. The solution was diluted with ethanol to obtain an absorbance of 0.70 ± 0.02 at 740 nm. Different concentrations of extracts (10 μL) were then mixed with the working solution (190 μL) and incubated at room temperature for 6 min. ABTS cation radical scavenging activity was determined by calculating the decrease in absorbance measured at 740 nm using the following equation:
ABTS radical inhibiting activity (%) = (Ac − At)/Ac × 100,
Commercially available BHT was used as a positive control. All the IC50 values of the tested activities were determined using linear regression of the percentage of remaining radicals against the sample concentration.

3.5.4. Statistical Analysis

All data are expressed as mean ± standard deviation (SD). Statistical analysis was performed using Student’s t-test. A probability of ≤ 0.05 or less was considered statistically significant. All experiments were performed at least three times.

3.6. Synthetic Compounds

The following reactions were all conducted under the Section 3.4.

3.6.1. (E)-6-(4-Hydroxy-3-methoxyphenyl)hex-5-ene-2,4-dione (6)

Purification by flash chromatography (EtOAc:Hexane = 1:4–1:2–1:1; EtOAc:Hexane = 1:2, Rf = 0.6) afforded a yellow solid. Yield: 45%. (literature [22] 45%; [23] 50%). Mp147–149 °C (literature [22,23] 146–147 °C). 1H NMR (600 MHz, CDCl3) δ 7.53 (d, J = 15.8 Hz, 1H), 7.08 (dd, J = 8.2, 1.7 Hz, 1H), 7.00 (d, J = 1.7 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.32 (d, J = 15.8 Hz, 1H), 3.93 (s, 3H), 2.17 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 196.9, 177.9, 147.7, 146.8, 140.0, 127.7, 122.6, 120.3, 114.8, 109.5, 100.7, 55.9, 26.8. HRMS (ESI) calculated for C13H13O4 [M–H]+ 233.0814. Found: 233.0817.

3.6.2. (1E,6E)-1-(4-Fluorophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (9a)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.3) afforded an orange-red solid. Yield: 58% (literature [16] 53%). Mp 154–155 °C (literature [16] 146–147 °C). 1H NMR (600 MHz, CDCl3) δ 7.60 (d, J = 15.7 Hz, 2H), 7.53 (dd, J = 8.6, 5.4 Hz, 2H), 7.13 (dd, J = 8.2, 1.6 Hz, 1H), 7.08 (t, J = 8.5 Hz, 2H), 7.05 (d, J = 1.6 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 15.8 Hz, 1H), 6.53 (d, J = 15.8 Hz, 1H), 5.89 (s, 1H), 5.81 (s, 1H), 3.95 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 184.3, 182.1, 163.7 (1JC-F = 249.0 Hz), 148.0, 146.8, 141.1, 138.8, 131.3, 129.8 (3JC-F = 7.5 Hz), 127.6, 123.8, 123.0, 121.7, 115.9 (2JC-F = 22.5 Hz), 114.8, 109.6, 101.5, 56.0. HRMS (ESI) calculated for C20H18FO4 [M+H]+ 341.1189. Found: 341.1184.

3.6.3. (1E,6E)-1-(4-Chlorophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (9b)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.4) afforded a red solid. Yield: 36.7%. Mp 115–120 °C. 1H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 15.4 Hz, 1H), 7.58 (d, J = 15.4 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.12 (dd, J = 8.2, 1.7 Hz, 1H), 7.05 (d, J = 1.7 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 15.8 Hz, 1H), 6.49 (d, J = 15.8 Hz, 1H), 5.92 (s, 1H), 5.81 (s, 1H), 3.94 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 184.7, 181.5, 148.0, 146.8, 141.3, 138.6, 135.8, 133.6, 129.2, 127.5, 124.5, 123.1, 121.7, 114.9, 109.7, 101.7, 56.0. HRMS (ESI) calculated for C20H18ClO4 [M+H]+ 357.0894. Found: 357.0905.

3.6.4. (1E,6E)-1-(4-Bromophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (9c)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.46) afforded an orange solid. Yield: 73% (literature [16] 32%; [44] 38%). Mp 113–116 °C (literature [16] 148–149 °C). 1H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 15.8 Hz, 1H), 7.57 (d, J = 15.8 Hz, 1H), 7.52 (d, J = 8.3 HZ, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.13 (dd, J = 8.2, 1.4 Hz, 1H), 7.05 (d, J = 1.3 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 15.8 Hz, 1H), 6.49 (d, J = 15.8 Hz, 1H), 5.89 (s, 1H), 5.81 (s, 1H), 3.93 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 184.8, 181.4, 148.1, 146.8, 141.3, 138.6, 134.0, 132.1, 129.4, 127.5, 124.6, 124.1, 123.1, 121.8, 114.9, 109.7, 101.7, 56.0. HRMS (ESI) calculated for C20H1879BrO4 [M+H]+ 401.0383. Found: 401.0383.

3.6.5. (1E,6E)-1-(4-Hydroxy-3-methoxyphenyl)-7-(4-nitrophenyl)hepta-1,6-diene-3,5-dione (9d)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.45) afforded an orange-red solid. Yield: 20% (27% based on the recovery of compound 6). Mp 149–151 °C. 1H NMR (600 MHz, CDCl3) δ 8.25 (d, J = 8.8, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 15.8 Hz, 1H), 7.65 (d, J = 15.8 Hz, 1H), 7.15 (dd, J = 8.3, 1.9 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 15.8 Hz, 1H), 6.53 (d, J = 15.8 Hz, 1H), 5.88 (s, 1H), 5.87 (s, 1H), 3.96 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 186.4, 179.0, 148.3, 148.1, 146.9, 142.2, 141.4, 136.7, 128.4 (2 X), 127.9, 127.4, 124.2 (2 X), 123.3, 121.8, 114.9, 109.7, 102.4, 56.0. HRMS (ESI) calculated for C20H16NO6 [M–H]+ 366.0978. Found: 366.0975.

3.6.6. (1E,6E)-1-(3-Fluorophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (9e)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.5) afforded an orange solid. Yield: 51.6%. Mp 154–155 °C. 1H NMR (600 MHz, CD3OD) δ 7.58 (d, J = 15.8 Hz, 1H), 7.54 (d, J = 15.8 Hz, 1H), 7.40–7.37 (m, 1H), 7.34 (d, J = 8.0, 1.8 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 7.10–7.06 (m, 2H), 6.81 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 15.8 Hz, 1H), 6.61 (d, J = 15.8 Hz, 1H), 5.99 (s, 1H), 3.89 (s, 3H). 13C NMR (150 MHz, CD3OD) δ 187.2, 181.8, 164.6 (1JC-F = 243.0 Hz), 150.7, 149.4, 143.2, 139.5, 139.1 (3JC-F = 7.5 Hz), 131.7 (3JC-F = 7.5 Hz), 128.4, 126.5, 125.3, 124.4, 122.4, 117.5 (2JC-F = 21.0 Hz), 116.6, 115.0 (2JC-F = 23.0 Hz), 111.9, 102.7, 56.5. HRMS (ESI) calculated for C20H18FO4 [M+H]+ 341.1189. Found: 341.1189.

3.6.7. (1E,6E)-1-(3-Chlorophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (9f)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.4) afforded an orange-red solid. Yield: 49.2%. Mp 67–71 °C. 1H NMR (600 MHz, CD3OD) δ 7.64 (s, 1H), 7.61 (d, J = 15.8 Hz, 1H), 7.55 (d, J = 16.1 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.40–7.35 (m, 2H), 7.21 (d, J = 1.5 Hz, 1H), 7.11 (dd, J = 8.4, 1.8 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 13.2 Hz, 1H), 6.65 (d, J = 15.8 Hz, 1H), 6.02 (s, 1H), 3.91 (s, 3H). 13C NMR (150 MHz, CD3OD) δ 187.3, 181.7, 150.8, 149.5, 143.2, 139.1, 138.8, 136.0, 131.5, 130.7, 128.7, 128.4, 127.5, 126.7, 124.0, 122.4, 116.6, 111.4, 102.7. HRMS (ESI) calculated for C20H18ClO4 [M+H]+ 357.0894. Found: 357.0893.

3.6.8. (1E,6E)-1-(3-Bromophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (9g)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.5) afforded an orange solid. Yield: 34%. Mp 74–78 °C. 1H NMR (600 MHz, CDCl3) δ 7.70 (s, 1H), 7.61 (d, J = 15.8 Hz, 1H), 7.55 (d, J = 15.8 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.13 (dd, J = 8.2, 1.8 Hz, 1H), 7.06 (d, J = 1.7 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 15.8 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H), 5.89 (s, 1H), 5.82 (s, 1H), 3.95 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 185.2, 180.9, 148.1, 146.8, 141.5, 138.2, 137.3, 132.6, 130.5, 130.4, 127.5, 126.8, 125.3, 123.2, 123.0, 121.8, 114.9, 109.7, 101.8, 56.0. HRMS (ESI) calculated for C20H1879BrO4 [M+H]+ 401.0388. Found: 401.0381.

3.6.9. (1E,6E)-1-(2-Fluorophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (9h)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.5) afforded an orange-yellow solid. Yield: 44.7%. Mp 124–127 °C. 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 16.0 Hz, 1H), 7.61 (d, J = 15.8 Hz, 1H), 7.55 (td, J = 7.6, 1.4 Hz, 1H), 7.36–7.31 (m, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.12 (dd, J = 8.2, 1.9 Hz, 1H), 7.10 (dd, J = 10.1, 8.4 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 16.1 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H), 5.91 (s, 1H), 5.85 (s, 1H), 3.95 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 184.9, 181.5, 161.4 (1JC-F = 253.5 Hz), 148.0, 146.8, 141.2, 132.7, 131.2 (3JC-F = 7.5 Hz), 129.2, 127.6, 126.6 (3JC-F = 6.0 Hz), 124.5, 123.2, 123.1, 121.8, 116.2 (2JC-F = 21.0 Hz), 114.8, 109.2, 101.7, 56.0. HRMS (ESI) calculated for C20H18FO4 [M+H]+ 341.1189. Found: 341.1189.

3.6.10. (1E,6E)-1-(2-Chlorophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (9i)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.33) afforded an orange-red solid. Yield: 52.1%. Mp 118–120 °C. 1H NMR (600 MHz, CDCl3) δ 8.30 (d, J = 15.8 Hz, 1H), 7.66–7.63 (m, 1H), 7.61 (d, J = 15.8 Hz, 1H), 7.43–7.40 (m, 1H), 7.30–7.26 (m, 2H), 7.12 (dd, J = 8.3, 1.3 Hz, 1H), 7.05 (s, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 15.8 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H), 5.95 (s, 1H), 5.86 (s, 1H), 3.93 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 184.9, 181.3, 148.0, 146.8, 141.3, 135.7, 135.0, 133.3, 130.7, 130.2, 127.5, 127.0, 126.5, 123.1, 121.8, 116.2, 114.8, 109.6, 101.5, 55.9 HRMS (ESI) calculated for C20H18ClO4 [M+H]+ 357.0894. Found: 357.0891.

3.6.11. (1E,6E)-1-(2-Bromophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (9j)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.4) afforded an orange solid. Yield: 40.9%. Mp 132–133 °C. 1H NMR (600 MHz, CD3OD) δ 7.93 (d, J = 15.8 Hz, 1H), 7.77 (d, J = 6.9, 1.0 Hz, 1H), 7.62 (dd, J = 7.6, 0.8 Hz, 1H), 7.60 (d, J = 15.9 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.24 (td, J = 8.6, 1.4 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 15.8 Hz, 1H), 6.64 (d, J = 15.8 Hz, 1H), 4.67 (s, 1H), 3.90 (s, 3H). 13C NMR (150 MHz, CD3OD)δ 187.8, 181.3, 150.9, 149.6, 143.5, 138.8, 136.4, 134.7, 132.3, 129.3, 129.0, 128.5, 127.9, 126.4, 124.6, 122.6, 116.8, 112.0, 56.6. HRMS (ESI) calculated for C20H1879BrO4 [M+H]+ 401.0388. Found: 401.0403.

3.6.12. (1E,6E)-1-(4-Hydroxy-3-methoxyphenyl)-7-(thiophen-2-yl)hepta-1,6-diene-3,5-dione (9k)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.31) afforded a red solid. Yield: 48.6% (literature [23] 38%). Mp 127–129 °C (literature [23] Mp 130–132 °C). 1H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 15.5 Hz, 1H), 7.59 (d, J = 15.8 Hz, 1H), 7.38 (d, J = 5.1 Hz, 1H), 7.25 (s, 2H), 7.12 (dd, J = 8.2, 1.8 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 7.05 (dd, J = 8.2, 1.9 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.47 (d, J = 15.8 Hz, 1H), 6.41 (d, J = 15.5 Hz, 1H), 5.89 (s, 1H), 5.77 (s, 1H), 3.95 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 183.9, 182.0, 147.9, 146.8, 140.9, 140.6, 132.8, 130.7, 128.2 (2 X), 127.6, 123.1, 123.0, 121.8, 114.8, 109.6, 101.5, 56.0. HRMS (ESI) calculated for C18H17O4S [M+H]+ 329.0848. Found: 329.0851.

3.6.13. (1E,6E)-1-(4-Hydroxy-3-methoxyphenyl)-7-(5-methylthiophen-2-yl)hepta-1,6-diene-3,5-dione (9l)

Purification by flash chromatography (EtOAc:Hexane = 1:3–1:1; EtOAc:Hexane = 1:2, Rf = 0.35) afforded an orange-red solid. Yield: 39.5%. Mp 155–157 °C. 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 15.4 Hz, 1H), 7.57 (d, J = 15.7 Hz, 1H), 7.11 (dd, J = 8.2, 1.6 Hz, 1H), 7.06 (d, J = 3.5 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 3.3 Hz, 1H), 6.46 (d, J = 15.7 Hz, 1H), 6.27 (d, J = 15.4 Hz, 1H), 5.74 (s, 1H), 3.93 (s, 3H), 2.51 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 183.3, 182.7, 147.9, 146.8, 144.0, 140.5, 138.6, 133.4, 131.6, 127.7, 126.7, 122.9, 121.8, 114.8, 109.6, 101.3, 56.0, 15.9. HRMS (ESI) calculated for C19H19O4S [M+H]+ 343.1004. Found: 343.1010.

4. Conclusions

All conditions used for the synthesis of asymmetric curcumin analogues were similar, and their yields reported in the literature were low to moderate. Our results clearly indicate that the moderate yield of monosubstituted 6 is due to the competitive formation of bissubstituted 7. The subsequent step also involves the cleavage of 11 by water, mediated by n-BuNH2, to yield three different compounds, as shown in Figure 3. Our finding is crucial and provides the optimized conditions for the synthesis of asymmetric curcuminoids by adding MS 4Å. In conclusion, compound 9a–l possessed antioxidant potential and might be useful against free radical-induced disorders. It is worthy of note that symmetric 10l was previously investigated for its photodynamic killing of Gram-positive microbes under blue light, with great potential. Compounds 9a–l will be evaluated via their photodynamic effects on bacteria, and the results will be reported in due course. The synthetic compounds 9a–l showed more potent DPPH and ABTS radical scavenging activities than the known antioxidant BHT. The present study suggests that the bioactive synthetic compounds 9a–l (especially 9a, 9e, 9h and 9i) are worthy of further investigation, and should developed as candidates for the treatment or prevention of oxidative stress-related diseases.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27082547/s1. 1H and 13C NMR data for compounds 6, 9a–l and 10e.

Author Contributions

Y.-J.C. and C.-L.K. conducted the synthesis of curcumin analogues. J.-J.C. and C.-W.L. performed bioassays and analyzed the antioxidant data. T.-L.S. and J.-J.C. planned, designed, and organized all of the research of this study and reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by a grant (No. MOST 110-2113-M-032-004) from the Ministry of Science and Technology (MOST) of Taiwan, awarded to Prof. T.-L. Shih. This research was also supported by a grant (No. MOST 109-2320-B-010-029-MY3) from the Ministry of Science and Technology (MOST) of Taiwan, awarded to Prof. J.-J. Chen.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the main text and the Supplementary Materials of this article.

Acknowledgments

The authors thank Tamkang University and National Yang Ming Chiao Tung University for supporting facilities.

Conflicts of Interest

The authors declare no conflict of interest.

References and Notes

  1. Vogel, H.; Pelletier, J. Curcumin-biological and medicinal properties. J. Pharm. 1815, 2, 24–29. [Google Scholar]
  2. Milobedeska, J.; Kostanecki, S.; Lampe, V. Zur kenntnis des curcumins. Ber. Deut. Chem. Ges. 1910, 43, 2163–2170. [Google Scholar] [CrossRef] [Green Version]
  3. Lampe, V.; Milobedeska, J. Studien über curcumin. Eur. J. Pharm. Biopharm. 1913, 46, 2235–2240. [Google Scholar] [CrossRef]
  4. Hewlings, S.J.; Kalman, D.S. Curcumin: A review of its effects on human health. Foods 2017, 6, 92. [Google Scholar] [CrossRef]
  5. Sharma, O.P. Antioxidant activity of curcumin and related compounds. Biochem. Pharmacol. 1976, 25, 1811–1812. [Google Scholar] [CrossRef]
  6. Singh, S.; Aggarwal, B.B. Activation of transcription factor NF-κB is suppressed by curcumin (diferuloylmethane). J. Biol. Chem. 1995, 270, 24995–25000. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Stanić, Z. Curcumin, a compound from natural sources, a true scientific challenge—A review. Plant Foods Hum. Nutr. 2017, 72, 1–12. [Google Scholar] [CrossRef]
  8. Prasad, D.; Praveen, A.; Mahapatra, S.; Mogurampelly, S.; Chaudhari, S.R. Existence of β-diketone form of curcuminoids revealed by NMR spectroscopy. Food Chem. 2021, 360, 130000. [Google Scholar] [CrossRef]
  9. Noureddin, S.A.; El-Shishtawy, R.M.; Al-Footy, K.O. Curcumin analogues and their hybrid molecules as multifunctional drugs. Euro. J. Med. Chem. 2019, 182, 111631. [Google Scholar] [CrossRef]
  10. Hosseini-Zare, M.S.; Sarhadi, M.; Zarei, M.; Thilagavathi, R.; Selvam, C. Synergistic effects of curcumin and its analogs with other bioactive compounds: A comprehensive review. Euro. J. Med. Chem. 2021, 210, 113072. [Google Scholar] [CrossRef]
  11. Bairwa, K.; Grover, J.; Kania, M.; Jachak, S.M. Recent developments in chemistry and biology of curcumin analogues. RSC Adv. 2014, 4, 13946–13978. [Google Scholar] [CrossRef]
  12. Khor, P.Y.; Aluwi, M.F.F.M.; Rullah, K.; Lam, K.W. Insights on the synthesis of asymmetric curcumin derivatives and their biological activities. Euro. J. Med. Chem. 2019, 183, 111704. [Google Scholar] [CrossRef] [PubMed]
  13. Yang, J.; Cheng, R.; Fu, H.; Yang, J.; Kumar, M.; Lu, J.; Xu, Y.; Liang, S.H.; Cui, M.; Ran, C. Half-curcumin analogues as PET imaging probes for amyloid beta species. Chem. Commun. 2019, 55, 3630–3633. [Google Scholar] [CrossRef] [PubMed]
  14. Okuda, M.; Hijikuro, I.; Fujita, Y.; Teruya, T.; Kawakami, H.; Takahashi, T.; Sugimoto, H. Design and synthesis of curcumin derivatives as tau and amyloid β dual aggregation inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 5024–5028. [Google Scholar] [CrossRef] [PubMed]
  15. Konno, H.; Endo, H.; Ise, S.; Miyazaki, K.; Aoki, H.; Sanjoh, A.; Kobayashi, K.; Hattori, Y.; Akaji, K. Synthesis and evaluation of curcumin derivatives toward an inhibitor of beta-site amyloid precursor protein cleaving enzyme 1. Bioorg. Med. Chem. Lett. 2014, 24, 685–690. [Google Scholar] [CrossRef]
  16. Kim, B.R.; Park, J.-Y.; Jeong, H.J.; Kwon, H.-J.; Park, S.-J.; Lee, I.-C.; Ryu, Y.B.; Lee, W.S. Design, synthesis, and evaluation of curcumin analogues as potential inhibitors of bacterial sialidase J. Enzym. Inhib. Med. Chem. 2018, 33, 1256–1265. [Google Scholar] [CrossRef] [Green Version]
  17. Golonko, A.; Lewandowska, H.; Świsłocka, R.; Jasińska, U.T.; Priebe, W.; Lewandowski, W. Curcumin as tyrosine kinase inhibitor in cancer treatment. Euro. J. Med. Chem. 2019, 181, 111512. [Google Scholar] [CrossRef]
  18. Rodrigues, F.C.; Kumar, N.V.A.; Thakur, G. Developments in the anticancer activity of structurally modified curcumin: An up-to-date review. Euro. J. Med. Chem. 2019, 177, 76–104. [Google Scholar] [CrossRef]
  19. Zhao, S.; Pi, C.; Ye, Y.; Zhao, L.; Wei, Y. Recent advances of analogues of curcumin for treatment of cancer. Eur. J. Med. Chem. 2019, 180, 524–535. [Google Scholar] [CrossRef]
  20. Fang, X.; Fang, L.; Gou, S.; Cheng, L. Design and synthesis of dimethylaminomethyl-substituted curcumin derivatives/analogues: Potent antitumor and antioxidant activity, improved stability and aqueous solubility compared with curcumin. Bioorg. Med. Chem. Lett. 2013, 23, 1297–1301. [Google Scholar] [CrossRef]
  21. Shi, Q.; Wada, K.; Ohkoshi, E.; Lin, L.; Huang, R.; Morris-Natschke, S.L.; Goto, M.; Lee, K.-H. Antitumor agents 290. Design, synthesis, and biological evaluation of new LNCaP and PC-3 cytotoxic curcumin analogs conjugated with anti-androgens. Bioorg. Med. Chem. 2012, 20, 4020–4031. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Wichitnithad, W.; Nimmannit, U.; Wacharasindhu, S.; Rojsitthisak, P. Synthesis, characterization and biological evaluation of succinate prodrugs of curcuminoids for colon cancer treatment. Molecules 2011, 16, 1888–1900. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Lin, L.; Shi, Q.; Nyarko, A.K.; Bastow, K.F.; Wu, C.-C.; Su, C.-Y.; Shih, C.C.-Y.; Lee, K.-H. Antitumor agents. 250. Design and synthesis of new curcumin analogues as potential anti-prostate cancer agents. J. Med. Chem. 2006, 49, 3963–3972. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Chen, T.; Zhu, G.; Meng, X.; Zhang, X. Recent developments of small molecules with anti-inflammatory activities for the treatment of acute lung injury. Euro. J. Med. Chem. 2020, 207, 112660. [Google Scholar] [CrossRef]
  25. Ahmed, S.; Khan, H.; Mirzaei, H. Mechanics insights of curcumin in myocardial ischemia: Where are we standing? Euro. J. Med. Chem. 2019, 183, 111658. [Google Scholar] [CrossRef]
  26. Wal, P.; Saraswat, N.; Pal, R.S.; Wal, A.; Chaubey, M.A. Detailed insight of the anti-inflammatory effects of curcumin with the assessment of parameters, sources of ROS and associated mechanisms. Open Med. J. 2019, 6, 64–76. [Google Scholar] [CrossRef] [Green Version]
  27. Leong, S.W.; Awin, T.; Faudzi, S.M.M.; Maulidiani, M.; Shaari, K.; Abas, F. Synthesis and biological evaluation of asymmetrical diarylpentanoids as antiinflammatory, anti-α-glucosidase, and antioxidant agents. Med. Chem. Res. 2019, 28, 2002–2009. [Google Scholar] [CrossRef]
  28. Sohilait, M.R.; Pranowo, H.D.; Haryadi, W. Synthesis, in vitro and molecular docking studies of 1-(3,4-dimethoxy-phenyl)-5-(4-hydroxy3-methoxy-phenyl)-penta-1,4-dien-3-one as new potential anti-inflammatory. Asian J. Chem. 2018, 30, 1765–1770. [Google Scholar] [CrossRef]
  29. Bandgar, B.P.; Kinkar, S.N.; Chavan, H.V.; Jalde, S.S.; Shaikh, R.U.; Gacche, R.N. Synthesis and biological evaluation of asymmetric indole curcumin analogs as potential anti-inflammatory and antioxidant agents. J. Enzym. Inhib. Med. Chem. 2014, 29, 7–11. [Google Scholar] [CrossRef] [Green Version]
  30. Zhang, Y.; Zhao, L.; Wu, J.; Jiang, X.; Dong, L.; Xu, F.; Zou, P.; Dai, Y.; Shan, X.; Yang, S.; et al. Synthesis and evaluation of a series of novel asymmetrical curcumin analogs for the treatment of inflammation. Molecules 2014, 19, 7287–7307. [Google Scholar] [CrossRef] [Green Version]
  31. Zhang, Y.; Jiang, X.; Peng, K.; Chen, C.; Fu, L.; Wang, Z.; Feng, J.; Liu, Z.; Zhang, H.; Liang, G.; et al. Discovery and evaluation of novel anti-inflammatory derivatives of natural bioactive curcumin. Drug Des. Dev. Ther. 2014, 8, 2161–2171. [Google Scholar]
  32. Salehi, B.; Stojanović-Radić, Z.; Matejić, J.; Sharifi-Rad, M.; Kumar, N.V.A.; Martins, N.; Sharifi-Rad, J. The therapeutic potential of curcumin: A review of clinical trials. Euro. J. Med. Chem. 2019, 163, 527–545. [Google Scholar] [CrossRef] [PubMed]
  33. Nelson, K.M.; Dahlin, J.L.; Bisson, J.; Graham, J.; Pauli, G.F.; Walters, M.A. The essential medicinal chemistry of curcumin. J. Med. Chem. 2017, 60, 1620–1637. [Google Scholar] [CrossRef] [PubMed]
  34. Priyadarsini, K.I. The chemistry of curcumin: From extraction to therapeutic agent. Molecules 2014, 19, 20091–20112. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Anand, P.; Thomas, S.G.; Kunnumakkara, A.B.; Sundaram, C.; Harikumar, K.B.; Sung, B.; Tharakan, S.T.; Misra, K.; Priyadarsini, I.K.; Rajasekharan, K.N.; et al. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem. Pharmacol. 2008, 76, 1590–1611. [Google Scholar] [CrossRef] [PubMed]
  36. Gaafary, M.E.; Lehner, J.; Fouda, A.M.; Hamed, A.; Ulrich, J.; Simmet, T.; Syrovets, T.; El-Agrody, A.M. The AMPA receptor biophysical gating properties and binding site: Focus on novel curcumin-based diazepines as non-competitive antagonists. Bioorg. Chem. 2021, 116, 105406. [Google Scholar]
  37. Her, C.; Venier-Julienne, M.-C.; Roger, E. Improvement of curcumin bioavailability for medical applications. Med. Aromat. Plants 2018, 7, 1000326. [Google Scholar] [CrossRef]
  38. Anand, P.; Kunnumakkara, A.B.; Newman, R.A.; Aggarwal, B.B. Bioavailability of curcumin: Problems and promises. Mol. Pharm. 2007, 4, 807–818. [Google Scholar] [CrossRef]
  39. Pabon, H.J.J. A synthesis of curcumin and related compounds. Recueil 1964, 83, 379–386. [Google Scholar] [CrossRef]
  40. Rao, E.V.; Sudheer, P. Revisiting curcumin chemistry Part I: A new strategy for the synthesis of curcuminoids. Indian J. Pharm. Sci. 2011, 73, 262–270. [Google Scholar]
  41. Hahm, E.-R.; Cheon, G.; Lee, J.; Kim, B.; Parka, C.; Yang, C.-H. New and known symmetrical curcumin derivatives inhibit the formation of Fos-Jun-DNA complex. Cancer Lett. 2002, 184, 89–96. [Google Scholar] [CrossRef]
  42. Nalli, M.; Ortar, G.; Moriello, A.S.; Marzo, V.D.; Petrocellis, L.D. Effects of curcumin and curcumin analogues on TRP channels. Fitoterapia 2017, 122, 126–131. [Google Scholar] [CrossRef] [PubMed]
  43. Shao, W.-Y.; Cao, Y.-N.; Yu, Z.-W.; Pan, W.-J.; Qiu, X.; Bu, X.-Z.; An, L.-K.; Huang, Z.-S.; Gu, L.-Q.; Chan, A.S.C. Facile preparation of new unsymmetrical curcumin derivatives by solid-phase synthesis strategy. Tetrahedron Lett. 2006, 47, 4085–4089. [Google Scholar] [CrossRef]
  44. Park, Y.D.; Kinger, M.; Min, C.; Lee, S.Y.; Byun, Y.; Park, J.W.; Jeon, J. Synthesis and evaluation of curcumin-based near-infrared fluorescent probes for the in vivo optical imaging of amyloid-β plaques. Bioorg. Chem. 2021, 115, 105167. [Google Scholar] [CrossRef]
  45. Wiseman, H.; Halliwell, B. Damage to DNA by reactive oxygen and nitrogen species: Role in inflammatory disease and progression to cancer. Biochem. J. 1996, 313, 17–29. [Google Scholar] [CrossRef] [Green Version]
  46. Bhat, A.H.; Dar, K.B.; Anees, S.; Zargar, M.A.; Masood, A.; Sofi, M.A.; Ganie, S.A. Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed. Pharmacother. 2015, 74, 101–110. [Google Scholar] [CrossRef]
  47. Our explanation to the low-combined yields is due to compounds 7, 9a–l and 10a–l encompassed in the boronic mixture. This polymerized mixture is remained on the top of column chromatography on purification. This phenomenon is alleviated after MS 4Å added.
  48. Hung, S.-J.; Hong, Y.-A.; Lin, K.-Y.; Hua, Y.-W.; Kuo, C.-J.; Hu, A.; Shih, T.-L.; Chen, H.-P. Efficient photodynamic killing of Gram-positive bacteria by synthetic curcuminoids. Int. J. Mol. Sci. 2020, 21, 9024. [Google Scholar] [CrossRef]
  49. Soares, J.R.; Dins, T.C.P.; Cunha, A.P.; Ameida, L.M. Antioxidant activities of some extracts of Thymus zygis. Free Radic. Res. 1997, 26, 469–478. [Google Scholar] [CrossRef]
  50. Re, R.; Pellegrini, N.; Proteggente, A.; Pannala, A.; Yang, M.; Rice-Evans, C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Rad. Biol. Med. 1999, 26, 1231–1237. [Google Scholar] [CrossRef]
  51. Li, C.-W.; Chu, Y.-C.; Huang, C.-Y.; Fu, S.-L.; Chen, J.-J. Evaluation of antioxidant and anti-α-glucosidase activities of various solvent extracts and major bioactive components from the seeds of Myristica fragrans. Molecules 2020, 25, 5198. [Google Scholar] [CrossRef]
Molecules 27 02547 g001 550
Figure 1. The most abundant constituents of natural curcuminoids.
Figure 1. The most abundant constituents of natural curcuminoids.
Molecules 27 02547 g001
Molecules 27 02547 g002 550
Figure 2. Tautomerism of curcumin under different pH values.
Figure 2. Tautomerism of curcumin under different pH values.
Molecules 27 02547 g002
Molecules 27 02547 g003 550
Figure 3. General procedure of Pabon’s method for the synthesis of symmetric and asymmetric curcuminoids.
Figure 3. General procedure of Pabon’s method for the synthesis of symmetric and asymmetric curcuminoids.
Molecules 27 02547 g003
Molecules 27 02547 sch001 550
Scheme 1. Pabon’s method for the synthesis of monosubstituted intermediate 6.
Scheme 1. Pabon’s method for the synthesis of monosubstituted intermediate 6.
Molecules 27 02547 sch001
Molecules 27 02547 sch002 550
Scheme 2. Pabon’s method for the synthesis of asymmetric curcumin analogues 9a–l.
Scheme 2. Pabon’s method for the synthesis of asymmetric curcumin analogues 9a–l.
Molecules 27 02547 sch002
Molecules 27 02547 g004 550
Figure 4. Plausible mechanism of the formation of by-products 7 and compounds 10a–l for the synthesis of asymmetric curcuminoids 9a–l.
Figure 4. Plausible mechanism of the formation of by-products 7 and compounds 10a–l for the synthesis of asymmetric curcuminoids 9a–l.
Molecules 27 02547 g004
Molecules 27 02547 g005 550
Figure 5. Bars show (A) DPPH and (B) ABTS radical scavenging activity at different concentrations (12.5, 25, 50, 100 μM) of compounds 9a–l, curcumin, and BHT. Bars represent mean ± SD of three experiments. Bars marked with different letters are significantly different (a p < 0.05; b p < 0.01; c p < 0.001 compared to control).
Figure 5. Bars show (A) DPPH and (B) ABTS radical scavenging activity at different concentrations (12.5, 25, 50, 100 μM) of compounds 9a–l, curcumin, and BHT. Bars represent mean ± SD of three experiments. Bars marked with different letters are significantly different (a p < 0.05; b p < 0.01; c p < 0.001 compared to control).
Molecules 27 02547 g005
Table
Table 1. Yields of products for the synthesis of asymmetric curcumin analogues 9a–l from compound 6 in condensation with aldehydes 8a–l in Scheme 2.
Table 1. Yields of products for the synthesis of asymmetric curcumin analogues 9a–l from compound 6 in condensation with aldehydes 8a–l in Scheme 2.
EntryAldehydeCompoundYield%CompoundYield%CompoundYield%
18a712 (9.2 a)9a28 (58 a)10a2 (NA a)
28b78 (9.5 a)9b27 (36.7 a)10b3 (NA a)
38c77 (12 a)9c22 (73 a)10c3 (NA a)
48d714.3 (3.8 a)9d12.5 (20 a)10dNA (NA a)
58e78.4 (6 a)9e28.9 (51.6 a)10e3 (NA a)
68f710 (12.7 a)9f34.8 (49.2 a)10f4 (NA a)
78g79.4 (2.5 a)9g31.1 (34 a)10g9 (NA a)
88h710.6 (3.1 a)9h36.8 (44.7 a)10h11 (NA a)
98i711.6 (NA a)9i37.8 (52.1 a)10i9 (NA a)
108j711 (22.2 a)9j20.7 (40.9 a)10j8 (NA a)
118k717.5 (14 a)9k11.2 (48.6 a)10k11 (NA a)
128l718.5 (25.4 a)9l28.8 (39.5 a)10l5 (NA a)
a: Isolated yield by the improved method. NA = Was not obtained from column purification.
Table
Table 2. DPPH and ABTS radical scavenging activity of compounds 9a–l, curcumin and BHT.
Table 2. DPPH and ABTS radical scavenging activity of compounds 9a–l, curcumin and BHT.
CompoundsIC50 (μM) a
DPPH RadicalABTS Radical Cation
9a 37.57 ± 0.89 * 18.79 ± 1.58 *
9b 40.55 ± 6.04 * 22.05 ± 0.51 *
9c 49.22 ± 7.57 * 17.47 ± 1.09 *
9d 54.47 ± 4.08 *46.17 ± 1.62
9e 37.17 ± 1.76 * 19.55 ± 0.08 *
9f 40.74 ± 0.97 ** 17.91 ± 1.21 *
9g 40.47 ± 1.71 ** 14.18 ± 1.44 *
9h 41.81 ± 3.11 * 11.36 ± 0.65 **
9i 48.12 ± 8.70 * 10.91 ± 0.77 **
9j66.67 ± 8.60 22.80 ± 0.26 *
9k 42.18 ± 4.75 *15.05 ± 0.01*
9l 63.77 ± 10.92 * 20.19 ± 1.08 *
curcumin 28.56 ± 4.12 ** 10.14 ± 1.04 **
BHT b122.78 ± 0.96 * 71.94 ± 1.81 *
Results are presented as averages ± SD (n = 3). a Concentration necessary for 50% inhibition (IC50). b Butylated hydroxytoluene (BHT) was used as a positive control. * p < 0.05 compared with the control. ** p < 0.01 compared with the control.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Cheng, Y.-J.; Li, C.-W.; Kuo, C.-L.; Shih, T.-L.; Chen, J.-J. Improved Synthesis of Asymmetric Curcuminoids and Their Assessment as Antioxidants. Molecules 2022, 27, 2547. https://doi.org/10.3390/molecules27082547

AMA Style

Cheng Y-J, Li C-W, Kuo C-L, Shih T-L, Chen J-J. Improved Synthesis of Asymmetric Curcuminoids and Their Assessment as Antioxidants. Molecules. 2022; 27(8):2547. https://doi.org/10.3390/molecules27082547

Chicago/Turabian Style

Cheng, Yang-Je, Cai-Wei Li, Cing-Ling Kuo, Tzenge-Lien Shih, and Jih-Jung Chen. 2022. "Improved Synthesis of Asymmetric Curcuminoids and Their Assessment as Antioxidants" Molecules 27, no. 8: 2547. https://doi.org/10.3390/molecules27082547

Article Metrics

Back to TopTop