Login Register Cart 0
Generic placeholder image

The Natural Products Journal

Editor-in-Chief

ISSN (Print): 2210-3155
ISSN (Online): 2210-3163

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Biological Activities of Flavonoids from the Wood Extract of Artocarpus heterophyllus L. (Jackfruit)

Author(s): Hiroyuki Akazawa*, Takuro Shinozaki, Motohiko Ukiya, Toshihiro Akihisa, Manosroi Jiradej, Harukuni Tokuda and Makoto Fukatsu

Volume 10, Issue 3, 2020

Page: [216 - 225] Pages: 10

DOI: 10.2174/2210315508666181018103353

Price: $65

Abstract

Background: Artocarpus heterophyllus L. (Jackfruit) has been used traditionally as treatment for inflammation and cancer. The aim of this study was to isolate compounds from A. heterophyllus wood extract and evaluate their biological activities such as anti-tumor promoting effect on Epstein-Barr virus early antigen induction, melanogenesis inhibitory activity on the B16 mouse melanoma 4A5 cell line and cytotoxic activity against three human cancer cell lines (HL60, A549, SK-BR-3).

Methods: A. heterophyllus wood was extracted with n-hexane and methanol. The ethyl acetate soluble- fraction separated from the methanol extract was separated and purified with column chromatography to isolate compounds. The structures of isolated compounds were elucidated with spectroscopic methods. These compounds were evaluated for their biological activities.

Results: Thirteen known compounds including four prenylflavonoids were isolated from the wood extracts. Nine flavonoids (2, 3, 5-11) exhibited potent anti-tumor promoting activity with IC50 values of 259-296 molar ratio / 32 pmol TPA. Two flavonoids, Norartocarpetin (6) at concentration of 30 μM and cyanomaclurin (11) at the concentration of 100 μM showed melanin content value of 47.6 % and 80.1 %, respectively. Two prenylflavonoids, cudraflavone B (2) and artocarpin (5), showed cytotoxicity against the human cancer cell lines tested. Cudraflavone B (2) showed cytotoxicity against all three human cancer cell lines whereas artocarpin (5) only exhibited cytotoxicity against two out three cell lines testes. The IC50 values were comparable to or better than cisplatin.

Conclusion: From the view point of structure activity relationships of the flavonoids isolated, side chains such as prenyl and 3-methyl-1-butenyl moiety were key for their potent biological activities.

Keywords: Artocarpus heterophyllus, flavonoid, anti-tumor activity, melanogenesis inhibitory activity, cytotoxicity, wood extract.

Graphical Abstract

[1]
Thomford, N.E.; Senthebane, D.A.; Rowe, A.; Munro, D.; Seele, P.; Maroyi, A.; Dzobo, K. Natural products for drug discovery in the 21st century: Innovations for novel drug discovery. Int. J. Mol. Sci., 2018, 19(6), 1578.
[http://dx.doi.org/10.3390/ijms19061578] [PMID: 29799486]
[2]
Annang, F.; Genilloud, O.; Vicente, F. Contribution of natural products discovery in tropical disease. Drug Discov. Infect. Disease, 2016, 7, 75-104.
[http://dx.doi.org/10.1002/9783527694082.ch3]
[3]
Farha, M.A.; Brown, E.D. Strategies for target identification of antimicrobial natural products. Nat. Prod. Rep., 2016, 33(5), 668-680.
[http://dx.doi.org/10.1039/C5NP00127G] [PMID: 26806527]
[4]
Futamura, Y.; Yamamoto, K.; Osada, H. Phenotypic screening meets natural products in drug discovery. Biosci. Biotechnol. Biochem., 2017, 81(1), 28-31.
[http://dx.doi.org/10.1080/09168451.2016.1248365] [PMID: 27885937]
[5]
DeCorte, B.L. Underexplored opportunities for natural products in drug discovery. J. Med. Chem., 2016, 59(20), 9295-9304.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00473] [PMID: 27331414]
[6]
Aung, T.N.; Qu, Z.; Kortschak, R.D.; Adelson, D.L. Understanding the effectiveness of natural compound mixtures in cancer through their molecular mode of action. Int. J. Mol. Sci., 2017, 18(3), 656.
[http://dx.doi.org/10.3390/ijms18030656] [PMID: 28304343]
[7]
Thomford, N.E.; Dzobo, K.; Chopera, D.; Wonkam, A.; Maroyi, A.; Blackhurst, D.; Dandara, C. In vitro reversible and time-dependent CYP450 inhibition profiles of medicinal herbal plant extracts Newbouldia laevis and Cassia abbreviata: Implications for herb-drug interactions. Molecules, 2016, 21(7), 891.
[http://dx.doi.org/10.3390/molecules21070891] [PMID: 27399660]
[8]
Nicholas, E.T.; Charles, A.; Kevin, D.; Faustina, A.; Denis, C.; Ambroise, W.; Michelle, S.; Dee, B.; Collet, D. Inhibition of CYP2B6 by medicinal plant extracts: Implication for use of Efavirenz and Nevipapine-based highly active anti-retroviral therapy (HAART) in resource-limited settings. Molecules, 2016, 21, 211.
[http://dx.doi.org/10.3390/molecules21020211]
[9]
Qi, J.J.; Yan, Y.M.; Cheng, L.Z.; Liu, B.H.; Qin, F.Y.; Cheng, Y.X. A novel flavonoid glucoside from the fruits of Lycium ruthenicun. Molecules, 2018, 23(2), 325.
[http://dx.doi.org/10.3390/molecules23020325] [PMID: 29401662]
[10]
Posri, P.; Suthiwong, J.; Takomthong, P.; Wongsa, C.; Chuenban, C.; Boonyarat, C.; Yenjai, C. A new flavonoid from the leaves of Atalantia monophylla (L.) DC. Nat. Prod. Res., 2019, 33(8), 1115-1121.
[http://dx.doi.org/10.1080/14786419.2018.1457667] [PMID: 29600742]
[11]
Guo, Z.K.; Wang, R.; Liu, T.M.; Chen, F.X.; Yang, M.Q. A new flavonoid derivative and a new 5-hydroxyanthranilic acid derivative from the sea urchin-derived Streptomyces sp. HDa1. J. Asian Nat. Prod. Res., 2019, 21(10), 992-998.
[http://dx.doi.org/10.1080/10286020.2018.1485663] [PMID: 29972031]
[12]
Jo, B.G.; Park, N.J.; Jegal, J.; Choi, S.; Lee, S.W.; Jin, H.; Kim, S.N.; Yang, M.H. A new flavonoid from Stellera chamaejasme L., stechamone, alleviated 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in a murine model. Int. Immunopharmacol., 2018, 59, 113-119.
[http://dx.doi.org/10.1016/j.intimp.2018.04.008] [PMID: 29653408]
[13]
Ye, C.; Zhang, C.; Huang, H.; Yang, B.; Xiao, G.; Kong, D.; Tian, Q.; Song, Q.; Song, Y.; Tan, H.; Wang, Y.; Zhou, T.; Zi, X.; Sun, Y. The natural compound myricetin effectively represses the malignant progression of prostate cancer by inhibiting PIM1 and disrupting the PIM1/CXCR4 interaction. Cell. Physiol. Biochem., 2018, 48(3), 1230-1244.
[http://dx.doi.org/10.1159/000492009] [PMID: 30045021]
[14]
Akihisa, T.; Tokuda, H.; Hasegawa, D.; Ukiya, M.; Kimura, Y.; Enjo, F.; Suzuki, T.; Nishino, H. Chalcones and other compounds from the exudates of Angelica keiskei and their cancer chemopreventive effects. J. Nat. Prod., 2006, 69(1), 38-42.
[http://dx.doi.org/10.1021/np058080d] [PMID: 16441065]
[15]
Koyama, J.; Morita, I.; Kobayashi, N.; Konoshima, T.; Takasaki, M.; Osakai, T.; Tokuda, H. Correlation between oxidation potentials and inhibitory effects on Epstein-Barr virus activation of flavonoids. Cancer Lett., 2008, 263(1), 61-66.
[http://dx.doi.org/10.1016/j.canlet.2007.12.016] [PMID: 18222035]
[16]
Akazawa, H.; Kohno, H.; Tokuda, H.; Suzuki, N.; Yasukawa, K.; Kimura, Y.; Manosroi, A.; Manosroi, J.; Akihisa, T. Anti-inflammatory and anti-tumor-promoting effects of 5-deprenyllupulonol C and other compounds from Hop (Humulus lupulus L.). Chem. Biodivers., 2012, 9(6), 1045-1054.
[http://dx.doi.org/10.1002/cbdv.201100233] [PMID: 22700224]
[17]
Miyake, Y.; Ito, C.; Tokuda, H.; Suzuki, N.; Itoigawa, M. Evaluation for antitumor-promoting activity of meyerin and 7-methoxy-5-prenyloxy coumarin in meyer lemon. Food Sci. Technol. Res., 2015, 21, 879-882.
[http://dx.doi.org/10.3136/fstr.21.879]
[18]
Iwase, Y.; Takemura, Y.; Ju-ichi, M.; Mukainaka, T.; Ichiishi, E.; Ito, C.; Furukawa, H.; Yano, M.; Tokuda, H.; Nishino, H. Inhibitory effect of flavonoid derivatives on Epstein-Barr virus activation and two-stage carcinogenesis of skin tumors. Cancer Lett., 2001, 173(2), 105-109.
[http://dx.doi.org/10.1016/S0304-3835(01)00615-2] [PMID: 11597783]
[19]
Chen, X.; Gu, N.; Xue, C.; Li, B.R. Plant flavonoid taxifolin inhibits the growth, migration and invasion of human osteosarcoma cells. Mol. Med. Rep., 2018, 17(2), 3239-3245.
[PMID: 29257319]
[20]
Kim, T.W.; Lee, S.Y.; Kim, M.; Cheon, C.; Ko, S.G. Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells. Cell Death Dis., 2018, 9(9), 875.
[http://dx.doi.org/10.1038/s41419-018-0930-1] [PMID: 30158521]
[21]
Kitdamrongtham, W.; Ishii, K.; Ebina, K.; Zhang, J.; Ukiya, M.; Koike, K.; Akazawa, H.; Manosroi, A.; Manosroi, J.; Akihisa, T. Limonoids and flavonoids from the flowers of Azadirachta indica var. siamensis, and their melanogenesis-inhibitory and cytotoxic activities. Chem. Biodivers., 2014, 11(1), 73-84.
[http://dx.doi.org/10.1002/cbdv.201300266] [PMID: 24443427]
[22]
Umesh, B.J.; Shailesh, R.W.; Vinayak, H.L.; Penna, S.; Vishwas, A.B. Preparation and evaluation of antioxidant capacity of Jackfruit (Artocarpus heterophyllus Lam.) wine and its protective role against radiation induced DNA damage. Ind. Crops Prod., 2011, 34, 1595-1601.
[http://dx.doi.org/10.1016/j.indcrop.2011.05.025]
[23]
Zheng, Z.P.; Cheng, K.W.; To, J.T.K.; Li, H.; Wang, M. Isolation of tyrosinase inhibitors from Artocarpus heterophyllus and use of its extract as antibrowning agent. Mol. Nutr. Food Res., 2008, 52(12), 1530-1538.
[http://dx.doi.org/10.1002/mnfr.200700481] [PMID: 18683821]
[24]
Chen, C.C.; Huang, Y.L.; Ou, J.C. Three new prenylflavones from Artocarpus altilis. J. Nat. Prod., 1993, 56, 1594-1597.
[http://dx.doi.org/10.1021/np50099a021]
[25]
Delle Monache, G.; De Rosa, M.C.; Scurria, R.; Vitali, A.; Cuteri, A.; Monacelli, B.; Pasqua, G.; Botta, B. Comparison between metabolite productions in cell culture and in whole plant of Maclura pomifera. Phytochemistry, 1995, 39(3), 575-580.
[http://dx.doi.org/10.1016/0031-9422(94)00971-U] [PMID: 19830921]
[26]
Nguyen, N.T.; Nguyen, M.H.; Nguyen, H.X.; Bui, N.K.; Nguyen, M.T. Tyrosinase inhibitors from the wood of Artocarpus heterophyllus. J. Nat. Prod., 2012, 75(11), 1951-1955.
[http://dx.doi.org/10.1021/np300576w] [PMID: 23113717]
[27]
Septama, A.W.; Panichayupakaranant, P. Antibacterial assay-guided isolation of active compounds from Artocarpus heterophyllus heartwoods. Pharm. Biol., 2015, 53(11), 1608-1613.
[http://dx.doi.org/10.3109/13880209.2014.996819] [PMID: 25856717]
[28]
Panthong, K.; Tohdee, K.; Hutadilok-Towatana, N.; Voravuthikunchai, S.P.; Chusri, S. Prenylated flavone from roots of a hybrid between Artocarpus heterophyllus and Artocarpus integer and its biological activities. J. Braz. Chem. Soc., 2013, 24, 1656-1661.
[29]
Jagtap, U.B.; Panaskar, S.N.; Bapat, V.A. Evaluation of antioxidant capacity and phenol content in jackfruit (Artocarpus heterophyllus Lam.) fruit pulp. Plant Foods Hum. Nutr., 2010, 65(2), 99-104.
[http://dx.doi.org/10.1007/s11130-010-0155-7] [PMID: 20198442]
[30]
Zheng, Z.P.; Chen, S.; Wang, S.; Wang, X.C.; Cheng, K.W.; Wu, J.J.; Yang, D.; Wang, M. Chemical components and tyrosinase inhibitors from the twigs of Artocarpus heterophyllus. J. Agric. Food Chem., 2009, 57(15), 6649-6655.
[http://dx.doi.org/10.1021/jf9014685] [PMID: 19588925]
[31]
Manosroi, J.; Manosroi, A.; Rungruangsri, U. Translation of Lanna medicinal-plant recipes for research and development of modern pharmaceuticals and the understanding of the Lanna Thai cultures/histories. Chiang Mai Univ. J., 2006, 5, 437-441.
[32]
Manosroi, A.; Akazawa, H.; Akihisa, T.; Jantrawut, P.; Kitdamrongtham, W.; Manosroi, W.; Manosroi, J. In vitro anti-proliferative activity on colon cancer cell line (HT-29) of Thai medicinal plants selected from Thai/Lanna medicinal plant recipe database “MANOSROI III”. J. Ethnopharmacol., 2015, 161, 11-17.
[http://dx.doi.org/10.1016/j.jep.2014.11.038] [PMID: 25481081]
[33]
Manosroi, A.; Tangjai, T.; Chankhampan, C.; Manosroi, W.; Najarut, Y.; Kitdamrongtham, W.; Manosroi, J. Potent phosphodi-esterase inhibition and nitric oxide release stimulation of anti-impotence Thai medicinal plant from “MANOSROI III” database. Evid.-Based Complement. Alter. Med.,, 2017.9806979. https://www. hindawi.com/journals/ecam/2017/9806976/ Reference available from:
[34]
Zhang, J.; Zhu, W.F.; Xu, J.; Kitdamrongtham, W.; Manosroi, A.; Manosroi, J.; Tokuda, H.; Abe, M.; Akihisa, T.; Feng, F. Potential cancer chemopreventive and anticancer constituents from the fruits of Ficus hispida L.f. (Moraceae). J. Ethnopharmacol., 2018, 214, 37-46.
[http://dx.doi.org/10.1016/j.jep.2017.11.016] [PMID: 29197545]
[35]
Zhang, J.; Miao, D.; Zhu, W.F.; Xu, J.; Liu, W.Y.; Kitdamrongtham, W.; Manosroi, J.; Abe, M.; Akihisa, T.; Feng, F. Biological activities of phenolics from the fruits of Phyllanthus emblica L. (Euphobiaceae). Chem. Biodivers., 2017, 14 e1700404
[http://dx.doi.org/10.1002/cbdv.201700404]
[36]
Zhang, J.; Zhu, W.F.; Zhu, W.Y.; Yang, P.P.; Xu, J.; Manosroi, J.; Kikuchi, T.; Abe, M.; Akihisa, T.; Feng, F. Melanogenesis-inhibitory and cytotoxic activities of chemical constituents from the leaves of Sauropus androgynus L. Merr. (Euphorbiaceae). Chem. Biodivers., 2018, 15(2) e17800486
[http://dx.doi.org/10.1002/cbdv.201700486] [PMID: 29144597]
[37]
Kikuchi, T.; Akihisa, T.; Tokuda, H.; Ukiya, M.; Watanabe, K.; Nishino, H. Cancer chemopreventive effects of cycloartane-type and related triterpenoids in in vitro and in vivo models. J. Nat. Prod., 2007, 70(6), 918-922.
[http://dx.doi.org/10.1021/np068044u] [PMID: 17503850]
[38]
Takaishi, Y.; Ujita, K.; Tokuda, H.; Nishino, H.; Iwashima, A.; Fujita, T. Inhibitory effects of dihydroagarofuran sesquiterpenes on Epstein-Barr virus activation. Cancer Lett., 1992, 65(1), 19-26.
[http://dx.doi.org/10.1016/0304-3835(92)90208-D] [PMID: 1324784]
[39]
Akihisa, T.; Seino, K.; Kaneko, E.; Watanabe, K.; Tochizawa, S.; Fukatsu, M.; Banno, N.; Metori, K.; Kimura, Y. Melanogenesis inhibitory activities of iridoid-, hemiterpene-, and fatty acid-glycosides from the fruits of Morinda citrifolia (Noni). J. Oleo Sci., 2010, 59(1), 49-57.
[http://dx.doi.org/10.5650/jos.59.49] [PMID: 20032599]
[40]
Kikuchi, T.; Ishii, K.; Ogihara, E.; Zhang, J.; Ukiya, M.; Tokuda, H.; Iida, T.; Tanaka, R.; Akihisa, T. Cytotoxic and apoptosis-inducing activities, and anti-tumor-promoting effects of cyanogenated and oxygenated triterpenes. Chem. Biodivers., 2014, 11(4), 491-504.
[http://dx.doi.org/10.1002/cbdv.201300395] [PMID: 24706621]
[41]
Kikuchi, T.; Ishii, K.; Noto, T.; Takahashi, A.; Tabata, K.; Suzuki, T.; Akihisa, T. Cytotoxic and apoptosis-inducing activities of limonoids from the seeds of Azadirachta indica (neem). J. Nat. Prod., 2011, 74(4), 866-870.
[http://dx.doi.org/10.1021/np100783k] [PMID: 21381696]
[42]
Wang, Y.H.; Hou, A.J.; Chen, L.; Chen, D.F.; Sun, H.D.; Zhao, Q.S.; Bastow, K.F.; Nakanish, Y.; Wang, X.H.; Lee, K.H. New isoprenylated flavones, artochamins A--E, and cytotoxic principles from Artocarpus chama. J. Nat. Prod., 2004, 67(5), 757-761.
[http://dx.doi.org/10.1021/np030467y] [PMID: 15165133]
[43]
Zheng, Z.P.; Zhu, Q.; Fan, C.L.; Tan, H.Y.; Wang, M. Phenolic tyrosinase inhibitors from the stems of Cudrania cochinchinensis. Food Funct., 2011, 2(5), 259-264.
[http://dx.doi.org/10.1039/c1fo10033e] [PMID: 21779564]
[44]
Kojima, H.; Sato, N.; Hatano, A.; Ogura, H. Sterol glucosides from Prunella vulgaris. Phytochemistry, 1990, 29, 2351-2355.
[http://dx.doi.org/10.1016/0031-9422(90)83073-A]
[45]
Seebacher, W.; Simic, N.; Weis, R.; Saf, R.; Kunert, O. Complete assignments of 1H and 13C NMR resonance of oleanolic acid, 18α-oleanolic acid, ursolic acid, and their 11-oxo derivatives. Magn. Reson. Chem., 2002, 41, 636-638.
[http://dx.doi.org/10.1002/mrc.1214]
[46]
Lu, C.M.; Lin, C.N. Flavonoids and 9-hydroxytridecyl docosanoate from Artocarpus heterophyllus. Phytochemistry, 1994, 35, 781-784.
[http://dx.doi.org/10.1016/S0031-9422(00)90605-8]
[47]
Iwatsuki, K.; Akihisa, T.; Tokuda, H.; Ukiya, M.; Higashihara, H.; Mukainaka, T.; Iizuka, M.; Hayashi, Y.; Kimura, Y.; Nishino, H. Sterol ferulates, sterols, and 5-alk(en)ylresorcinols from wheat, rye, and corn bran oils and their inhibitory effects on Epstein-Barr virus activation. J. Agric. Food Chem., 2003, 51(23), 6683-6688.
[http://dx.doi.org/10.1021/jf030371+] [PMID: 14582960]
[48]
Banno, N.; Akihisa, T.; Tokuda, H.; Yasukawa, K.; Higashihara, H.; Ukiya, M.; Watanabe, K.; Kimura, Y.; Hasegawa, J.; Nishino, H. Triterpene acids from the leaves of Perilla frutescens and their anti-inflammatory and antitumor-promoting effects. Biosci. Biotechnol. Biochem., 2004, 68(1), 85-90.
[http://dx.doi.org/10.1271/bbb.68.85] [PMID: 14745168]
[49]
Ko, H.H.; Tsai, Y.T.; Yen, M.H.; Lin, C.C.; Liang, C.J.; Yang, T.H.; Lee, C.W.; Yen, F.L. Norartocarpetin from a folk medicine Artocarpus communis plays a melanogenesis inhibitor without cytotoxicity in B16F10 cell and skin irritation in mice. BMC Complement. Altern. Med., 2013, 13, 348.
[http://dx.doi.org/10.1186/1472-6882-13-348] [PMID: 24325567]
[50]
Anioł, M.; Swiderska, A.; Stompor, M.; Zołnierczyk, A.K. Antiproliferative activity and synthesis of 8-prenylnaringenin derivatives by demethylation of 7-O- and 4′-O-substituted isoxanthohumols. Med. Chem. Res., 2012, 21(12), 4230-4238.
[http://dx.doi.org/10.1007/s00044-011-9967-8] [PMID: 23087590]
[51]
Ren, F.C.; Jiang, X.J.; Wen, S.Z.; Wang, L.X.; Li, X.M.; Wang, F. Prenylated 2-phenoxychromanes and flavonoids from Epimedium brevicorum and revised structures of epimedonins A and B. J. Nat. Prod., 2018, 81(1), 16-21.
[http://dx.doi.org/10.1021/acs.jnatprod.7b00514] [PMID: 29338226]
[52]
Lim, H.J.; Jin, H.G.; Woo, E.R.; Lee, S.K.; Kim, H.P. The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation. J. Ethnopharmacol., 2013, 149(1), 169-175.
[http://dx.doi.org/10.1016/j.jep.2013.06.017] [PMID: 23806866]
[53]
Wei, B.L.; Weng, J.R.; Chiu, P.H.; Hung, C.F.; Wang, J.P.; Lin, C.N. Antiinflammatory flavonoids from Artocarpus heterophyllus and Artocarpus communis. J. Agric. Food Chem., 2005, 53(10), 3867-3871.
[http://dx.doi.org/10.1021/jf047873n] [PMID: 15884809]
[54]
Chung, Y.H.; Kim, D. Enhanced TLR4 expression on colon cancer cells after chemotherapy promotes cell survival and epithelial-mesenchymal transition through phospholylation of GSK3beta. Anticancer Res., 2016, 36(7), 3383-3394.
[PMID: 27354597]

Rights & Permissions Print Cite
Article Metrics
16
1
© 2024 Bentham Science Publishers | Privacy Policy