Green approach to semisynthesis of apigenin from naringin isolated from very immature pomelo peels

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The flavanone glycoside naringin, which is abundant in the very immature pomelo peel cultivated in Vietnam, has been demonstrated to have potential use in semisynthesis into other flavonoid compounds, especially apigenin, which exhibits several biological properties and has a greater commercial value. In this study, we carried out an oxidation reaction on flavanone backbone to semisynthesize apigenin with I2 catalyst in some environmentally friendly solvents such as a replacement for the reaction in the pyridine solvent, which is thought to be a non-green solvent.

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Nội dung Text: Green approach to semisynthesis of apigenin from naringin isolated from very immature pomelo peels

Cite this paper: Vietnam J. Chem., 2023, 61(S2), 137-142 Research Article DOI: 10.1002/vjch.202300098 Green approach to semisynthesis of apigenin from naringin isolated from very immature pomelo peels Nguyen Khanh Hung1,2, Nguyen Tuan Thanh1,2, Nguyen Thi Thuy Luyen1,2,4, Nguyen Huy Du1,2,3* 1 Faculty of Chemistry, University of Science, 227 Nguyen Van Cu Road, District 5, Ho Chi Minh City 70000, Viet Nam 2 Vietnam National University of Ho Chi Minh City, Vo Truong Toan Road, Linh Trung Ward, Thu Duc City, Ho Chi Minh City 70000, Viet Nam 3 Central Laboratory of Analysis, University of Science, 227 Nguyen Van Cu Road, District 5, Ho Chi Minh City 70000, Viet Nam 4 Faculty of Geology, University of Science, 227 Nguyen Van Cu Road, District 5, Ho Chi Minh City 70000, Viet Nam Submitted February 22, 2023; Revised April 16, 2023; Accepted May 28, 2023 Abstract The flavanone glycoside naringin, which is abundant in the very immature pomelo peel cultivated in Vietnam, has been demonstrated to have potential use in semisynthesis into other flavonoid compounds, especially apigenin, which exhibits several biological properties and has a greater commercial value. In this study, we carried out an oxidation reaction on flavanone backbone to semisynthesize apigenin with I 2 catalyst in some environmentally friendly solvents such as a replacement for the reaction in the pyridine solvent, which is thought to be a non-green solvent. These solvents which were employed in this investigation included water, DMSO, ethyl acetate, ethanol, ethylene glycol, and vegetable oil. The degree of conversion and the purity of the isolated product were evaluated using the RP-HPLC-DAD method, the yield was calculated according to the mass of the obtained crystals, and the synthetic compounds were confirmed by NMR spectra. The results showed that the solvents of DMSO, DMSO:H 2O gave the total yield of 93% and the purity of apigenin greater than 95% as compared to 74% and 93%, respectively, with the reaction in pyridine. Our findings revealed that using 10% mol of I2 catalyst was more cost-effective than conducting the reaction in pyridine, which required an equivalency of substrate and catalyst of 1:1. The solubility of naringin in the solvent combination should be taken into account, though, since this might result in a low yield and influence the degree of conversion. Keywords. Apigenin, semisynthesis, naringin, iodine oxidation, DMSO. 1. INTRODUCTION (30% in dried weight) and high purity of isolated product, 92.3%.[7] Many studies have shown that the Flavonoids are natural products which exhibit semisynthesis of apigenin from naringin was mainly diversely biological activities, widely applied in through oxidation of the flavanone framework, and pharmaceutical research.[1,2] Apigenin is a flavone subsequent removal of the carbohydrate which is extensively distributed in nature in many substituent.[8-10] Victor et al. (2018) synthesized plant species including chrysanthemum,[3] parsley, apigenin from naringin obtained from ripe grapefruit etc., has a number of biological activities including peel and had a relatively high yield.[8] However, the antioxidant,[4] antiviral,[5] anti-cancer.[6] In an attempt large amount of catalysts and pyridine solvents are to find out natural sources of flavanoids for semi- considered non-green solvents, some hidden health synthesis of the novel analgesics and anticancer effects, and are not suitable for application in agents contain flavone moiety, we were really synthetic reactions used for medicinal chemistry in fascinated by the abundance of naringin in the pomelo terms of safty and toxicity. In this study, we used peel. In our previous study, the very immature greener solvents such DMSO, H2O, ethyl acetate, etc. pomelo peels was demonstrated a potential raw to conduct a semi-synthetic synthesis of apigenin material for conducting semisythesis of other from naringin obtained from young pomelo peels bioactivity flavonoid, which possesses high content collected in Tien Giang province, Viet Nam. 137 Wiley Online Library © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH
25728288, 2023, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300098 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Nguyen Huy Du et al. Figure 1: Schematic diagram of apgenin synthesis from naringin 2. MATERIALS AND METHODS H2SO4. The dark yellow mixture was heated under reflux condition for 3h and cooled down to room 2.1. Apparatus and chemicals temperature. 10 mL of ice water was added to the solution and concentrated sodium bicarbonate was Agilent 1200 series coupled with DAD detector. used to adjust the pH value to 3. The resulting Analysis column Zorbax SB C18 (250 mm4.6 mm precipitate was filtered and washed with distilled ice 0.45 m) obtained from Agilent (USA). Binder water until the pH value of filtrate reached 7. The vacuum drying carbinet (Germany) was used for solid was then re-dissolved in MeOH, dried under drying synthetic products. The nuclear magnetic rotary evoparation and vacuum at 80oC. The light resonance (NMR) spectra (500 MHz for 1H and 125 yellow solid was then characterized by HPLC-DAD MHz for 13C) was recorded by a Bruker Advance III for purity analysis and confirmed by NMR spectra. 500 spectrometer (Bruker BioSpin AG, Thailand). Methanol HPLC Grade (Schalau, Spain) and 2.3. HPLC-UV analysis and characterization of distilled water were used for HPLC analysis; n- isolated synthetic products hexane ACS Grade (Scharlau, Spain), dichloromethane ACS Grade (Scharlau, Spain), ethyl The mixture of standard solution including naringin, acetate ACS Grade (Scharlau, Spain), ethanol naringenin, rhoifolin, and apigenin was used to absolute ACS Grade (VWR Prolabo, UK), pyridine determination of purity of synthetic rhoifolin and ACS Grade (Acros, USA), dimethyl sulfoxide HPLC apigenin products. The crystal was dissolved in Grade (Merck, USA), iodine ACS Grade (Labchem, MeOH solvent to prepare a 500 mg L-1 solution. The USA), sodium thiosulfate (Xilong, China), sodium sample was then purified by loading on SPE-C18 bicarbonate (Xilong, China) were used for catridge, dilutted with MeOH/H2O (2:8, v/v) mixture, semisynthesis; deuterated solvent of acetone-d6 or and filtered through 0.45 m PTFE membrane prior CDCl3 was used for NMR analysis. to subjected to analyze by RP-HPLC-DAD system. The sample was resolved on the HPLC system with 2.2. Synthesis procedure the quantitative wavelength of 290 nm for naringin and naringenin, 345 nm for rhoifolin and apigenin; 2.2.1. Synthesis of rhoifolin the Zorbax SB C18 (250 mm  4.6 mm  0.45 m) at a flow rate of 0.7 mL/min and the mobile phase 0.22 g of iodine (0.85 mmol) was added to the consisting of water (Channel A) and methanol solution of naringin (0.50 g, 0.85 mmol) dissolved in (Channel B). The gradient elution proceeded as 7 mL of dry pyridine. The dark-red mixture was follows: start with 20% B, then increase by 20-80% heated for 5h at 95oC, and was then cooled down to in 10 minutes, then increase 80-100% B within 2 room temperature. 100 mL of ice-water was poured minutes and hold for 5 minutes. into the container and the pH value of mixture was adjust to 3 by using concentrated HCl. The resulting 3. RESULTS AND DISCUSSION light yellow solid was filter and washed with concentrated Na2S2O3 solution and ice water until the 3.1. NMR confirmation and HPLC-UV pH value of filtrate reached 7. The solid was then re- identification of isolated synthetic products dissolved in MeOH, dried under rotary evoparation and vacuum at 80oC. The products after being synthesized were confirmed by NMR spectroscopy. The results of the spectrum 2.2.2. Synthesis of apigenin were compatible with previous studies, it could be concluded that rhoifolin and apigenin have been 0.20 g of rhoifolin (0.346 mmol) was dissolved in 25 successfully synthesized, specifically showing that mL of ethanol acidified by 3 mL of concentrated the signal of 2H at the 3' position of naringin has been © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 138
25728288, 2023, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300098 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Green approach to semisynthesis of apigenin... converted into a singlet signal with a chemical shift at considered a green catalyst with the advantages of 6.67 ppm. In addition, The coupling constants (J = 8.0 being non-toxic, inexpensive, and insensitive to air Hz and 1.1 Hz) of the anomeric protons indicated the β- and α-configurations for glucopyranosyl and rhamnopyranosyl, respectively. This shows that the glycoside substituent retains its configuration after reacting with iodine. Naringin 1H-NMR (CD3OD, 500 MHz): δ7.32 (d, J = 8.5 Hz, 2H), 6.81 (dt, J = 8.5, 2.0 Hz, 2H), 6.17 (dd, J = 10.2, 2.0 Hz, 2H), 5.38 (tt, 1H), 5.24 (dd, J = 5.2, 1.6 Hz, 1H), 5.10 (m, 1H), 3.94-3.33 (m, 10H), 3.17 (m, 1H), 2.78-2.73 (m, 1H), 1.28 (d, J = 7.3, 1.2 Hz, 3H). Rhoifolin 1H-NMR (CD3OD, 500 MHz): δ7.90 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 6.80 (d, J = 2.0 Hz, 1H), 6.67 (s, 1H), 6.47 (d, J = 2.0 Hz, 1H), 5.30 (d, J = 1.5 Hz, 1H), 5.22 (d, J = 7.5 Hz, 1H), 3.96-3.40 (m, 10H), 1.34 (d, 6.5 Hz, 3H). Apigenin 1H-NMR (DMSO-d6, 500 MHz): δ12.91 (s, 1H), 10.84 (s, 1H), 10.36 (s, 1H) 7.92 (d, J = 8.9, 2H), 6.92 (d, J = 8.9, 2H), 6.77 (s, 1H), 6.48 (d, 2.1 Hz, 1H), 6.19 (dd, J = 6.1, 2.1 Hz, 1H). 13 C-NMR (DMSO-d6, 500 MHz): δ94.0, 98.8, 102.8, 103.7, 116.0, 121.2, 128.5, 157.3, 161.2, 161.4, 163.1, 164.1, 181.7. The results of the determination of the purity of the synthetic product monitored by HPLC-DAD were shown in figure 3 revealed that no residual naringin and naringenin was found in the obtained crystals. In addition, rhoifolin was synthesized in pyrindine possessed a high purity. Meanwhile, rhoifolin synthesized in DMSO and DMSO:H2O solvents showed many signals of other substances, indicating that the obtained crystals contain more impurities. However, an interesting point in this investigation, when performing the reaction in DMSO and DMSO:H2O solvent, rhoifolin was hydrolyzed instantly to apigenin (See figures 3D and 3E). This suggests the possibility of simplification of apigenin synthesis in a single step without the need for rhoifolin separation and subsequent hydrolysis. Effect of I2 catalyst amount on the degree of apigenin conversion The synthesis of apigenin from naringin has been performed in previous studies, showing that pyridine was an effective solvent to carry out the iodine- catalyzed -elimination reaction.[[8,10] Iodine equivalent of 1:1 to the substrate was used as a reference to other reaction. According to the findings in table 1, the overall yield of apigenin was 102% Figure 2: Chromatogram of synthetic products. higher when the reaction was carried out in DMSO (A) crude naringin; (B) naringenin standard; solvent with a catalytic amount of 10% mol. (C) Rhoifolin (Pyridine); (D) Rhoifolin Additionally, DMSO is regarded as a green, eco- (DMSO+H2O); (E) Apigenin (Pyridine); friendly solvent[11.12] and molecular iodine is (F) Apigenin (DMSO+H2O) © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 139
25728288, 2023, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300098 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Nguyen Huy Du et al. Figure 3: 1H-NMR spectra of naringin and rhoifolin (Py.) and water.[12] Taken together, I2 and/or I2/DMSO environmentally friendly solvents have been combination with 10% mol of catalytic amount was exploited to conduct the oxidation reaction such as used to investigate further experiments. water, ethanol, ethylene glycol, ethyl acetate, and vegetable oil. The findings of the synthesis yield Table 1: Catalytic amount investigation of demonstrated that the oxidation reaction could only oxidization reaction be carried out by DMSO-containing solvents, including pure DMSO and DMSO diluted in water at Catalyst Solvent Yield (%) ratios of 1:1 and 1:10, respectively. According to our I2 1 eq. Pyridine 74 proposed mechanism based on other mechanisms of I2 1 eq. DMSO 97 chalcone oxidation reaction to synthesis flavone, I2 0.1 eq. DMSO 102 DMSO functions as both a solvent and a catalyst. Additionally, since HI was generated during the beta- 3.2. Effect of solvent on the degree of apigenin cleavage reaction based on the mechanism, it is conversion totally adsorbed when the reaction is conducted in pyridine solvent. In contrast, the amount of catalyst In an attempt to efficiently carry out semi-synthetic was continuously regenerated in DMSO solvent, apigenin processes and use green chemistry, other diminishing the need for molecular iodine. R = Rhamnose-Glucose β-elimination Figure 4: Plausible mechanism of rhoifolin synthesis in DMSO with I2 catalyst from naringin © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 140
25728288, 2023, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300098 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Green approach to semisynthesis of apigenin... Table 2: Investigation of solvent used in the supports in this study. This research is funded by the oxidation reaction University of Science, VNU-HCM under grant Cat. eq m Solvent h% p% number 562-2020-18-7. 1 Pyridine 74 93 0.1 DMSO 97 95 List of abbreviations DMSO:H2O HPLC: High performance liquid chromatography. 0.1 94 96 (1:1, v/v) NMR: Nuclear magnetic resonance. 0.1 DMSO:H2O 28 - DAD: Diode arry detector. (1:10, v/v) DMSO: Dimethyl sulfate. I2 0.50 1.0 EtOAc 0 - PTFE: Polytetrafluoroethylene. EtOAc:EtOH 1.0 0 - (1:1, v/v) Conflict of interest statement. The authors declare Ethylene 1.0 glycol 0 - that they have no competing interests. 1.0 Vegetable oil 0 - REFERENCES In terms of experimental, semisynthesis and product isolation procedure in the DMSO solvent 1. Roy A., Khan A., Ahmad I., Alghamdi S., Rajab BS, were utterly similar to those in the pyridine solvent. Babalghith AO. et al. Flavonoids a Bioactive Additionally, the DMSO:H2O (1:1, v/v) Compound from Medicinal Plants and Its Therapeutic Applications, BioMed Research International, 2022, solvent performed significantly good yield over 93% 2022. and product purity greater than 95% in comparison with pyridine. In conclusion, the following conditions 2. Ullah A., Munir S., Badshah SL., Khan N., Ghani L., were optimal for the semisynthesis of apigenin: The Poulson BG, et al. Important flavonoids and their role as a therapeutic agent, Molecules, 2020, 25(22), 5243. DMSO:H2O (1:1, v/v) solvent is utilized to conduct thorough investigation or to carry out apigenin 3. Caldwell E. The Compound in The Mediterranean production on a larger scale. Diet That Makes Cancer Cell Mortal. Medical Express, 2013. We discovered that HI exhibited strong acidity, which assisted to hydrolyze rhoifolin to its aglycone 4. Kashyap P., Shikha D., Thakur M., Aneja A. when the reaction was conducted in the DMSO Functionality of apigenin as a potent antioxidant with solvent in the presence of water. The fact that emphasis on bioavailability, metabolism, action mechanism and in vitro and in vivo studies: A review. apigenin was found in the rhoifolin crystals after Journal of Food Biochemistry, 2022, 46(4), e13950. being isolated in the first phase serves as proof. Consequently, further advancement will be achieved 5. Khandelwal N., Chander Y., Kumar R., Riyesh T., Dedar RK., Kumar M. et al. Antiviral activity of in forthcoming investigations to synthesize apigenin Apigenin against buffalopox: Novel mechanistic from naringin in just one reaction, including the acid insights and drug-resistance considerations, Antiviral addition or the extension of the reaction period for Research, 2020, 181, 104870. complete hydrolysis. 6. Liu R., Zhang H., Yuan M., Zhou J., Tu Q., Liu J-J, et al. Synthesis and biological evaluation of apigenin 4. CONCLUSION derivatives as antibacterial and antiproliferative agents, Molecules, 2013, 18(9), 11496-511. With high purity, simple product isolation, and good 7. Hung NK, Thanh NHP, Luyen NTT, Lan BTT. yield, we have investigated the ideal conditions for Isolation of (2S)-naringin from very immature pomelo the semi-synthetic reaction of apigenin from naringin. peels cultivated at Chau Thanh district, Tien Giang These findings have encouraged us to province, VNUHCM Journal of Natural Sciences, conduct additional study on the one-step synthesis of 2022, 6(2), 2076-82. apigenin from naringin, which will be used as a 8. Victor MM, David JM, Sakukuma MC, França EL, starting material for the synthesis of apigenin Nunes AV. A simple and efficient process for the derivatives. The abundance of naringin from the extraction of naringin from grapefruit peel waste, very immature pomelo peels in Vietnam makes it a Green Processing and Synthesis, 2018, 7(6), 524-9. desirable for the manufacturing of apigenin. 9. Su L., Jin Z, Liu K, Wang Q. Synthesis of polymethoxyflavonoids from hesperidin and naringin Acknowledgements. We thank all members of and their antiproliferative activity, Chemistry of Central Laboratory of Analysis for their great Heterocyclic Compounds, 2022, 58(2), 100-5. © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 141
25728288, 2023, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300098 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Nguyen Huy Du et al. 10. 10. Victor MM, David JM, Cortez MV, Leite JL, da Investigating the in vitro photothermal effect of green Silva GS. A high-yield process for extraction of synthesized apigenin-coated gold nanoparticle on hesperidin from orange (Citrus sinensis L. osbeck) colorectal carcinoma, IET Nanobiotechnol., 2021, peels waste, and its transformation to diosmetin, A 15(3), 329-337. valuable and bioactive flavonoid. Waste and Biomass 12. J.-Q. Wang, Z.-Y. Zuo, W. He. Recent advances of Valorization, 2021, 12(1), 313-20. green catalytic system I2/DMSO in C–C and C– 11. S. M. Amini, E. Mohammadi, S. Askarian-Amiri, Y. Heteroatom bonds formation, Catalysts, 2022, 12(8), Azizi, A. Shakeri-Zadeh, A. Neshastehriz. 821. Corresponding author: Nguyen Huy Du University of Science, VNU-HCM 227 Nguyen Van Cu, District 5, Ho Chi Minh City 70000, Viet Nam Email: nhdu@hcmus.edu.vn Tel.: +84- 28 73089899. © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 142