Open Access 
Abstract
Introduction: Structure-activity relationship analysis demonstrated that the β-diketone moiety present in curcumin structure is necessary for biological activities. Structural modifications on the pharmacophore can be envisioned as a strategy to afford novel analogues with promising biological activities. Curcumin analgues containing isoxazole ring showed the inhibitory activity against cancer cell lines.
Methods: In this respect, an isoxazole cyclization of the free 1,3-diketone group in the curcuminoids (1-7) bearing -OH/-OCH3/-F in aromatic rings with hydroxylamine hydrochloride was performed in acetic acid as solvent and catalyst to afford isoxazole-containing curcuminoids. NMR and MS measurements were used to interpret the chemical structures of synthesized compounds.
Results: Seven structures (1a-7a) were synthesized in yields of 30-61% and elucidated the chemical structure. Among curcumin-based isoxazole analogues, five new compounds (3a-7a) were reported for the first time.
Conclusion: This work demonstrated the synthesis of five novel isoxazole-containing curcuminoids (3a-7a), along with two known ones (1a, 2a).
INTRODUCTION
Natural products, secondary metabolites derived from natural sources have been demonstrated as a source of potential drug leads 1 , 2 . Curcumin ( 1 ), a major constituent of Curcuma longa L. exhibited several interesting biological activities 3 . Therefore, curcumin has been found to be a natural lead for the development of potentially new drug candidates. However, the clinical application of curcumin has been limited in the body due to its poor solubility and rapid metabolism 4 . Structure-activity relationship (SAR) studies reported that the substituents in the aromatic ring and the β -diketone moiety present in curcumin are responsible for biological responses and kinetic stability. In this respect, several curcumin analogs have been developed from the curcumin skeleton through chemical modifications on the 1,3-diketone group to optimize the curcumin scaffold 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 .
Among numerous curcumin-based analogs, isoxazole curcuminoid constituting a five-membered heterocycle with one nitrogen atom and one oxygen atom at adjacent position exhibited a highly potent multidrug-resistant anti-mycobacterial activity 5 , increased growth inhibitory activity against cancer cell lines, and anti-tumor activity 8 , 9 , 10 , 11 , 12 , 13 , 14 . In the present work, we report the synthesis of isoxazole curcuminoids by converting the β -diketone moiety into its corresponding isoxazole framework ( Figure 1 ).
Scheme 1 . Synthesis of isoxazole-containing curcuminoids ( 1a-7a ) from free 1,3-dicarbonyl curcuminoids ( 1 - 7 ).
MATERIALS AND METHODS
Chemicals
Curcuminoids ( 1 - 7 ) were synthesized according to our previous work, and their NMR/MS data have been described in our early report 7 . The free 1,3-dicarbonyl curcuminoids were used as starting materials for isoxazole cyclization. Hydroxylamine hydrochloride (NH 2 OH.HCl, 99%, ACROS Organics), acetic acid (100%, Merck), dichloromethane (DCM, 99.8%, JTBaker, USA), n -hexane (CH, 98.5%, JTBaker, USA) and ethyl acetate (EA, 98.5%, JTBaker, USA) were used as received without further purification.
General synthetic procedure for isoxazole curcuminoids (1a-7a)
Isoxazole curcuminoids ( 1a - 7a ) were synthesized by following a procedure published in the literature 13 , 14 . Curcuminoid (0.6 mmol) from our previous work and hydroxylamine hydrochloride (1.2 mmol) was transferred into a 50 mL round-bottom flask and dissolved in 10 mL glacial acetic acid. The solution was stirred at 80 o C for 8-24 h. Careful monitoring via thin-layer chromatography (TLC) was necessary to stop the reaction in time. The resulting product was neutralized by 20.0 mL saturated NaHCO 3 and extracted with DCM (3 40 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 . Solvent was removed by using a rotary evaporator. The pure isoxazole curcuminoids were obtained by using flash column chromatography (CC) (SiO 2 , using a gradient of CH/EA = 1:0®7:3).
Analytical method
CC was performed on Merck silica gel (0.040-0.063 mm). TLC was carried out on precoated silica gel 60 F254 plates from Merck (Germany), and sample spots on TLC were detected by UV light at λ = 254 and 365 nm. Melting points (m.p) of pure products were determined by the M5000 melting point meter (Germany) with a heating rate of 2.0 o C/min. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance (500, 600 MHz ( 1 H), 125, 150 MHz ( 13 C)). Mass spectrometry (MS) measurements were performed on an Agilent 1200 series LC-MSD.
RESULTS
The isoxazole cyclization of the -diketone group afforded five new isoxazole-containing curcuminoids ( 3a-7a ), along with two known analogs ( 1a , 2a ) 15 , 16 in a 30-61% yield. Chemical structures of synthesized compounds ( Figure 2 ) were assigned by NMR and MS spectra.
Figure 1 . Chemical structures and synthesis yields of synthesized isoxazole curcuminoids ( 1a - 7a ).
4,4'-((1 E ,1' E )-isoxazole-3,5-diylbis(ethene-2,1-diyl))bis(2-methoxyphenol) (1a): Yield 44% (96.4 mg), white solid, C 21 H 19 NO 5 [365.13 g/mol]; R f = 0.34 (CH/EA = 1:1); m.p. 163.6 o C (lit. 15 162 °C) 1 H-NMR (500 MHz, CDCl 3 , ppm): δ = 3.95 (s, OCH 3 , 3H), 3.96 (s, OCH 3 , 3H), 5.76 (s, Ar-OH, 1H), 5.79 (s, Ar-OH, 1H), 6.41 (s, H 4 , 1H), 6.79 (d, H 6 , 3 J (H,H) = 16.0 Hz, 1H), 6.91 (d, H 5'' , 3 J (H,H) = 8.0 Hz, 1H), 6.92 (d, H 5’ , 3 J (H,H) = 8.0 Hz , 1H), 6.96 (d, H 2 , 3 J (H,H) = 16.5 Hz, 1H), 7.01 (d, H 2'' , 4 J (H,H) = 2.0 Hz, 1H), 7.02 (d, H 2’ , 4 J (H,H) = 2.0 Hz , 1H), 7.06-7.08 (dd, H 6'',6' , 3 J (H,H) = 8.0 Hz, 4 J (H,H) = 2.0 Hz, 2H), 7.08 (d, H 7 , 3 J (H,H) = 16.5 Hz, 1H), 7.26 (d, H 1 , 3 J (H,H) = 16.5 Hz, 1H); 13 C-NMR (125 MHz, CDCl 3 , ppm): δ = 55.9 (OCH 3 ), 55.9 (OCH 3 ), 97.6 (C 4 ), 108.2 (C 2’’ ), 108.8 (C 2’ ), 110.9 (C 5’’ ), 113.8 (C 5’ ), 114.6 (C 6’’ ), 114.8 (C 6’ ), 121.5 (C 2 ), 121.6 (C 6 ), 128.2 (C 1’’ ), 128.5 (C 1’ ), 134.8 (C 1 ), 135.6 (C 7 ), 146.7-147.0 (C 4’,4’’ , C 3’,3’’ , 4C), 162.2 (C 5 ), 168.5 (C 3 ). ESI-MS m/z calc for [M+H] + : 366.14; found: 366.00.
3,5-di(( E )-styryl)isoxazole (2a): Yield 56% (91.7 mg), white solid, C 19 H 15 NO [273.12 g/mol]; R f = 0.43 (CH/EA = 9:1); m.p. 168.3 o C 1 H-NMR (500 MHz, CDCl 3 , ppm): 7.03 (s, H 4 , 1H), 7.23 (d, H 6 , 3 J (H,H) = 16.5 Hz, 1H), 7.26 (d, H 2 , 3 J (H,H) = 16.5 Hz, 2H), 7.30 – 7.38 (m, H 2’ ,2 ’’ , 2H), 7.38 – 7.46 (m, H 1 ,7, 6’ ,6 ’’,4 ’,4 ’’ , 6H), 7.67 (dd, H 3’ ,3 ’’, 5’ ,5 ’’ , 3 J (H,H) = 7.5 Hz, 4H); 13 C-NMR (125 MHz, CDCl 3 , ppm): 99.2 (C 4 ), 113.3 (C 6 ), 115.6 (C 2 ), 127.1 (C 2 ’, 6’ , 2C), 127.2 (C 2’’,6’’ , 2C), 128.8 (C 4’ ), 128.8 (C 4’’ ), 128.9 (C 3’ ,5’ , 2C), 129.1 (C 3’’ ,5’’ , 2C), 134.4 (C 1’ ), 135.3 (C 1’’ ), 135.6 (C 1 ), 136.2 (C 7 ), 161.9 (C 5 ), 168.0 (C 3 ). ESI-MS m/z calc for [M+H] + : 274.13; found: 273.90.
3,5-bis(( E )-4-methoxystyryl)isoxazole (3a): Yield 48% (95.9 mg), yellow solid, C 21 H 19 NO 3 [333.14 g/mol]; R f = 0.28 (CH/EA = 4:1); m.p. 172.2 o C 1 H-NMR (500 MHz, CDCl 3 , ppm): 3.83 (s, OCH 3 , 3H), 3.84 (s, OCH 3 , 3H), 6.41 (s, H 4 , 1H), 6.80 (d, H 6 , 3 J (H,H) = 16.5 Hz, 1H), 6.90 (d, H 3’ ,3’’,5’,5’’ , 3 J (H,H) = 8.0 Hz, 4H), 6.97 (d, H 2 , 3 J (H,H) = 17.0 Hz , 1H), 7.10 (d, H 7 , 3 J (H,H) = 16.5 Hz, 1H), 7.28 (d, H 1 , 3 J (H,H) = 16.0 Hz, 1H), 7.45 (d, H 2’ ,2’’, 6’ ,6’’ , 3 J (H,H) = 9.0 Hz, 4H); 13 C-NMR (125 MHz, CDCl 3 , ppm): 55.3 (OCH 3 ), 55.4 (OCH 3 ), 97.7 (C 4 ), 111.0 (C 6 ), 114.0 (C 2 ), 114.3 (C 3’ ,5’ , 2C), 114.4 (C 3’’ ,5’’ , 2C), 128.3 (C 2 ’, 6’ , 2C), 128.4 (C 1’ ), 128.5 (C 2’’,6’’ , 2C), 128.7 (C 1 ’’ ), 134.4 (C 1 ), 135.2 (C 7 ), 160.2 (C 4’ ), 160.5 (C 4’’ ), 162.2 (C 5 ), 168.6 (C 3 ). ESI-MS m/z calc for [M+H] + : 334.15 found: 333.90.
3,5-bis(( E )-2-fluorostyryl)isoxazole (4a): Yield 61% (113.1 mg), yellow solid, C 19 H 13 F 2 NO [309.10 g/mol]; R f = 0.59 (CH/EA = 9/1); m.p. 120.1 o C 1 H-NMR (500 MHz, CDCl 3 , ppm): 6.57 (s, H 4 , 1H), 7.07 (d, H 6 , 3 J (H,H) = 16.5 Hz, 1H), 7.07-7.12 (m, H 3’ ,3’’ , 2H), 7.15-7.19 (td, H 5’ ,5’ ’ , 3 J (H,H) = 7.5 Hz , 4 J (H,H) = 1.0 Hz, 2H), 7.20 (d, H 2 , 3 J (H,H) = 16.5 Hz, 1H); 7.28-7.32 (m, H 6’ ,6 ’’ , 2H), 7.33 (d, H 7 , 3 J (H,H) = 16.5 Hz, 1H) 7.46 (d, H 1 , 3 J (H,H) = 17.0 Hz, 1H); 7.53-7.63 (td, H 4’,4’’ , 3 J (H,H) = 7.5 Hz, 4 J (H,H) = 1.5 Hz, 2H); 13 C-NMR (125 MHz, CDCl 3 , ppm): 98.9 (C 4 ), 115.5 (C 6 ), 115.9 (C 3’’ ), 116.0 (C 3’ ), 118.3 (C 2 ), 123.5 (C 1’’ , 123.7 (C 1’ ), 124.4 (C 5’ ,5’’ ), 127.4 (C 4’ ), 127.8 (C 1 ), 128.1 (C 7 ), 128.2 (C 4’’ ) , 130.2 (C 6’’ ), 130.4 (C 6’ ), 159.6-161.9 (C 2’ ,2’’ , 2C), 162.1 (C 5 ), 168.3 (C 3 ). ESI-MS m/z calc for [M+H] + : 310.11; found: 309.90.
3,5-bis(( E )-3-fluorostyryl)isoxazole (5a): Yield 57% (105.7 mg), yellow solid, C 19 H 13 F 2 NO [309.10 g/mol]; R f = 0.26 (CH/EA = 9:1); m.p. 157.8 o C 1 H-NMR (500 MHz, CDCl 3 , ppm): 6.50 (s, H 4 , 1H), 6.94 (d, H 6 , 3 J (H,H) = 16.5 Hz, 1H), 7.01 (m, H 4’ ,4’ ’ , 2H), 7.13 (d, H 2 , 3 J (H,H) = 16.5 Hz, 1H), 7.14 (d, H 7 , 3 J (H,H) = 16.5 Hz, 1H), 7.21 (d, H 2’’ , 4 J (H,H) = 1.5 Hz, 1H), 7.23 (d, H 2’ , 4 J (H,H) = 1.5 Hz, 1H), 7.28 (d, H 6’ ,6’’ , 3 J (H,H) = 8.0 Hz, 2H), 7.31 (d, H 1 , 3 J (H,H) = 17.0 Hz, 1H), 7.33 (m, H 5’ ,5’’ , 2H); 13 C-NMR (125 MHz, CDCl 3 , ppm): 99.1 (C 4 ), 113.3 – 113.5 (C 2’ ,2’’ , 2C), 114.1 (C 6 ), 115.7 – 116.1 (C 4’ ,4’ ’ , 2C), 117.4 (C 2 ), 122.8 – 123.2 (C 6’ , 6’’ , 2C), 130.3 – 130.4 (C 5’ ,5’’ , 2C), 133.8 (C 7 ), 134.6 (C 1 ), 138.1 (C 1’ ,1 ’’ , 2C), 161.7 (C 3’’ ), 162.2 (C 3’ ), 164.1 (C 5 ), 167.9 (C 3 ). ESI-MS m/z calc for [M+H] + : 310.11; found: 309.90.
3,5-bis(( E )-3,4-difluorostyryl)isoxazole (6a): Yield 32% (66.3 mg), yellow solid, C 19 H 11 F 4 NO [345.08 g/mol]; R f = 0.45 (CH/EA = 9:1); m.p. 164.7 o C 1 H-NMR (500 MHz, CDCl 3 , ppm): 6.47 (s, H 4 , 1H), 6.85 (d, H 6 , 3 J (H,H) = 16.5 Hz, 1H), 7.01 (d, H 2 , 3 J (H,H) = 16.5 Hz, 1H), 7.08 (d, H 7 , 3 J (H,H) = 16.5 Hz, 1H), 7.17-7.23 (m, H 2’ ,2 ’ ’,5’ ,5 ’ ’ , 4H), 7.29 (d, H 1 , 3 J (H,H) = 15.5 Hz, 1H), 7.32 (m, H 6’ ,6 ’ ’ ,2H); 13 C-NMR (125 MHz, CDCl 3 , ppm): 99.1 (C 4 ), 113.8 (C 6 ), 115.2 – 115.4 (C 6’ ,6 ’’ , 2C), 117.1 (C 2 ), 117.7 – 117.9 (C 2’ ,2 ’ ’ , 2C), 123.3 (C 5’’ ), 123.8 (C 5’ ), 124.8 (C 1’ ,1 ’’ , 2C), 132.8 (C 1 ), 133.6 (C 7 ), 149.6 (C 3’ ,3’’ ), 151.7 (C 4’ ,4 ’’ ), 161.5 (C 5 ), 167.8 (C 3 ). ESI-MS m/z calc for [M+H] + : 346.09; found: 345.80.
4,4'-((1 E ,1' E )-isoxazole-3,5-diylbis(ethene-2,1-diyl))bis(2-fluorophenol) (7a): Yield 30% (61.4 mg), yellow solid, C 19 H 13 F 2 NO 3 [341.09 g/mol]; R f = 0.25 (CH/EA = 7:3); m.p. 214.3 o C 1 H-NMR (600 MHz, CDCl 3 , ppm): 6.37 (s, H 4 , 1H), 6.71 (d, H 6 , 3 J (H,H) = 16.2 Hz, 1H), 6.85 (d, H 2 , 3 J (H,H) = 16.2 Hz, 1H), 6.91 (m, H 2’ ,2 ’ ’ , 2H), 6.99 (d, H 7 , 3 J (H,H) = 16.2 Hz, 1H), 7.07 (d, H 5’ ,5 ’ ’ , 3 J (H,H) = 8.4 Hz, 2H), 7.15 (d, H 1 , 3 J (H,H) = 16.8 Hz, 1H), 7.17 (m, H 6’ ,6 ’ ’ , 2H); 13 C-NMR (150 MHz, CDCl 3 , ppm): 97.9 (C 4 ), 111.3 (C 6 ), 113.9 – 114.0 (C 6’ ,6 ’’ , 2C), 114.2 (C 2 ), 118.1 – 118.2 (C 2’ ,2 ’ ’ , 2C), 123.7 (C 5’’ ), 124.0 (C 5’ ), 128.7-130.9 (C 1’ ,1 ’’ , 2C), 133.9 (C 1 ), 134.7 (C 7 ), 145.8 (C 3’ ,3’’ ), 150.9 (C 4 ’’ ), 152.5 (C 4’ ), 162.0 (C 5 ), 168.3 (C 3 ). ESI-MS m/z calc for [M+H] + : 342.10; found: 341.90.
DISCUSSION
The isoxazole analogs ( 1a - 7a ) were prepared by treatment of free -diketone curcuminoids ( 1 - 7 ) with hydroxylamine hydrochloride in acetic acid at 80 o C. Acetic acid here plays dual roles: as a solvent to dissolve reactants and catalysts for isoxazole cyclization. First, under acidic conditions, an oxime is generated via an acid-catalyzed mechanism, similar to the imine formation between a carbonyl group reacting with a primary amine 6 , 7 . Then, the protonation of the second carbonyl group is occurred rendering it more electrophilic. Then, the oxygen atom is sufficiently nucleophilic to attack a protonated carbonyl group directly to give an isoxazole ring.
The structures of the synthesized compounds were elucidated by 1 H- and 13 C-NMR, MS spectra. The 1 H-NMR spectra of isoxazole curcuminoids ( 1a - 7a ) exhibited a singlet (s, 1H) at ~ 5.8-6.5 ppm, which was assigned to the signal of proton bonded to the central carbon of a three-carbon pattern in isoxazole ring. The doublet signal ( 3 J H-H ~16.0 Hz) at 6.5-7.8 ppm is characteristic of trans -configuration in the seven-carbon chain of isoxazole analogs. Compared to respective mother structures, curcuminoids ( 1 - 7 ), the signal for carbonyl carbon ( ~ 183 ppm) 7 disappeared and the imine bond (>C=N) formation was inferred from an incoming peak at ~ 167 ppm observed at 13 C NMR spectra, which confirmed the presence of isoxazole ring.
CONCLUSIONS
In summary, we reported a synthetic procedure that enables access to isoxazole-containing curcuminoids. Curcuminoids possessing a free 1,3-dicarbonyl group underwent an isoxazole cyclization with hydroxylamine hydrochloride using acetic acid as solvent and catalyst to yield seven isoxazole curcuminoids ( 1a - 7a ). The isolated yields of the isoxazole cyclization are in the range of 30 to 61%. NMR spectra assigned the synthesized structures in combination with ESI-MS measurements. With the results shown above, we could, for the first time, demonstrate the synthesis of five novel isoxazole curcuminoids ( 3a-7a ), along with two known compounds ( 1a , 2a ).
LIST OF ABBREVIATIONS
CC: Column chromatography
CH: n -Hexane
DCM: Dichloromethane
d: Doublet
dd: Doublet-doublet
EA: Ethyl acetate
HSQC: Heteronuclear single quantum correlation
lit: Literature
m: multiplet
m.p: melting point
MS: Mass spectrometry
NMR: Nuclear magnetic resonance
td: Triplet-doublet
TLC: Thin layer chromatography
UV: Ultraviolet
COMPETING INTERESTS
The authors declare that they have no competing interests.
SUPPORTING INFORMATION
Supporting Information contains 1 H, 13 C-NMR, HSQC, and MS spectra of the isoxazole containing curcuminoids ( 1a - 7a ).
ACKNOWLEDGMENT
This work belongs to the project grant No: B2020-SPK-05 funded by the Ministry of Education and Training and hosted by Ho Chi Minh City University of Technology and Education, Vietnam.
AUTHOR CONTRIBUTIONS
Vo Thi Nga: 1 H-, 13 C-NMR and MS analysis, writing-original draft preparation; Le Thanh Huy: laboratory work-up, writing-original draft preparation. Hoang Minh Hao: conceptualization, supervision, writing-review and editing. All authors have read and agreed to the published version of the manuscript.
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