Prenylated phenols with cytotoxic and antiproliferative activity isolated from Morus alba

Download PDF Česká verze

Authors: Nikol Prausová; Peter Kollár
Published in the journal: Čes. slov. Farm., 2019; 68, 48-68
Category: Přehledy a odborná sdělení

Summary

This review deals with cytotoxic and antiproliferative activity of fifty seven prenylated phenols isolated from Morus alba. Prenyl side chain, which can be variously modified, increases lipophilicity of the substances, thereby improving their penetration through biological membranes and thus results in an increased bioavailability. The objective was to describe the relationship between structure of the prenylated phenols and their cytotoxic effect and to clarify various mechanisms by which cytotoxic prenylated phenols induce apoptosis. The conclusions showed that the cytotoxicity of the substances increases with increasing number of the prenyl side chains and ketal groups. Conversely, modification of the prenyl side chain, such as hydroxylation, reduces cytotoxicity. The cytotoxic activity is also influenced by the presence of prenyl and hydroxyl groups at specific positions.

Keywords:

<i>Morus alba</i> – prenylated phenols – antiproliferative activity – cytotoxicity

Zdroje

1. Chan E., Lye P., Wong S. Review: Phytochemistry, pharmacology, and clinical trials of Morus alba. CJNM 2016; 14(1), 17–30. https://www-sciencedirect-com.katalog.vfu.cz:444/science/article/pii/S187553641630005X

2. Kresánek J. Atlas liečivých rastlín a lesných plodov. 3. vyd. Bratislava: Osveta 1988; 400 s.

3. Natić M., Dabić D., Papetti A., Fotirić Akšić M., Ognjanov V., Ljubojević M., Tešić Ž. Analysis and characterisation of phytochemicals in mulberry (Morus alba L.) fruits grown in Vojvodina, North Serbia. Food Chem. 2015; 171, 128–136. http://linkinghub.elsevier.com/retrieve/pii/S0308814614013260

4. Lim T. Edible Medicinal and Non Medicinal Plants: Volume 3, Fruits. Dordrecht Heidelberg London New York: Springer 2012; 399–429. https://epdf.tips/volume-3-fruits.html

5. Krishna H., Singh D., Singh R., Kumar L., Sharma B., Saroj P. Morphological and antioxidant characteristics of mulberry (Morus spp.) genotypes. Journal of the Saudi Society of Agricultural Sciences 2018. https://linkinghub.elsevier.com/retrieve/pii/S1658077X18302169

6. Yimam M., Jiao P., Hong M., Brownell L., Hyun-Jin Kim, Lee Y., Jia Q. Repeated dose 28-day oral toxicity study of a botanical composition composed of Morus alba and Acacia catechu in rats. Regul. Toxicol. Pharmacol. 2018; 94, 115–123. https://linkinghub.elsevier.com/retrieve/pii/S0273230018300400

7. Kumar V., Chauhan S. Mulberry: Life enhancer. J. Med. Plants Res. 2008; 2(10), 271–278. https://academicjournals.org/article/article1380526584_Kumar %20and %20Chauhan.pdf

8. Šmejkal K. Medicínské využití prenylovaných fenolů. https://docplayer.cz/71015046-Medicinske-vyuziti-prenylovanych-fenolu-karel-smejkal.html (2013)

9. Talhi O. Organic Synthesis of C-Prenylated Phenolic Compounds. Curr. Org. Chem. 2013; 17(10), 1067–1102. https://www.researchgate.net/publication/236854139_Organic_Synthesis_of_C-Prenylated_Phenolic_Compounds

10. Yang X., Jiang Y., Yang J., He J., Sun J., Chen F., Zhang M., Yang B. Prenylated flavonoids, promising nutraceuticals with impressive biological activities. Trends Food Sci. Technol. 2015; 44(1), 93–104. https://linkinghub.elsevier.com/retrieve/pii/S0924224415000710

11. Nomura T., Hano Y., Fukai T. Chemistry and biosynthesis of isoprenylated flavonoids from Japanese mulberry tree. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 2009; 85(9), 391–408. http://joi.jlc.jst.go.jp/JST.JSTAGE/pjab/85.391?from=CrossRef

12. Xia C., Tang G., Guo Y., Xu Y., Huang Z., Yin S. Mulberry Diels-Alder-type adducts from Morus alba as multi-targeted agents for Alzheimer’s disease. Phytochemistry. 2019; 157, 82–91. https://linkinghub.elsevier.com/retrieve/pii/S0031942218306988

13. Nasir S., Tee J., Rahman N., Chee Ch. Flavonoids – from biosynthesis to human health. InTech. 2017; 167–188. http://www.intechopen.com/books/flavonoids-from-biosynthesis-to-human-health/biosynthesis-and-biomimetic-synthesis-of-flavonoid-diels-alder-natural-products

14. Boonyaketgoson S., Rukachaisirikul V., Phongpaichit S., Trisuwan K. Cytotoxic arylbenzofuran and stilbene derivatives from the twigs of Artocarpus heterophyllus. Tetrahedron Lett. 2017; 58(16), 1585–1589. https://linkinghub.elsevier.com/retrieve/pii/S0040403917303167

15. Guo Y., Tang G., Lou L., Li W., Zhang B., Liu B., Yin S. Prenylated flavonoids as potent phosphodiesterase-4 inhibitors from Morus alba: Isolation, modification, and structure-activity relationship study. Eur. J. Med. Chem. 2018; 144, 758–766. https://linkinghub.elsevier.com/retrieve/pii/S0223523417310887

16. Qin J., Fan M., He J., Wu X., Peng L., Su J., Cheng X., Li Y., Kong L., Li R., Zhao Q. New cytotoxic and anti-inflammatory compounds isolated from Morus alba L. Nat. Prod. Res. 2015; 29(18), 1711–1718. http://www.tandfonline.com/doi/full/10.1080/14786419.2014.999333

17. Wätjen W., Weber N., Lou Y., Wang Z., Chovolou Y., Kampkötter A., Kahl R., Proksch P. Prenylation enhances cytotoxicity of apigenin and liquiritigenin in rat H4IIE hepatoma and C6 glioma cells. Food Chem. Toxicol. 2007; 45(1), 119–124. https://linkinghub.elsevier.com/retrieve/pii/S0278691506002213

18. Arung E., Yoshikawa K., Shimizu K., Kondo R. Isoprenoid-substituted flavonoids from wood of Artocarpus heterophyllus on B16 melanoma cells: Cytotoxicity and structural criteria. Fitoterapia. 2010; 81(2), 120–123. https://linkinghub.elsevier.com/retrieve/pii/S0367326X09001749

19. Zhang Y., Luo J., Wan C., Zhou Z., Kong L. Four New Flavonoids with α-Glucosidase Inhibitory Activities from Morus alba var. tatarica. Chem. Biodivers. 2015; 12(11), 1768–1776. https://onlinelibrary-wiley-com.katalog.vfu.cz:444/doi/epdf/10.1002/cbdv.201500005

20. Fomani M., Ngeufa Happi E., Nouga Bisoue A., Ndom J., Kamdem Waffo A., Sewald N., Wansi J. Oxidative burst inhibition, cytotoxicity and antibacterial acriquinoline alkaloids from Citrus reticulate (Blanco). Bioorg. Med. Chem. Lett. 2016; 26(2), 306–309. https://linkinghub.elsevier.com/retrieve/pii/S0960894X15303413

21. Dat N., Binh P., Quynh L., Van Minh C., Huong H., Lee J. Cytotoxic prenylated flavonoids from Morus alba. Fitoterapia. 2010; 81(8), 1224–1227. https://linkinghub.elsevier.com/retrieve/pii/S0367326X10002078

22. Kuete V., Sandjo L., Djeussi D., Zeino M., Kwamou G., Ngadjui B., Efferth T. Cytotoxic flavonoids and isoflavonoids from Erythrina sigmoidea towards multi-factorial drug resistant cancer cells. Invest. New Drugs 2014; 32(6), 1053–1062. http://link.springer.com/10.1007/s10637-014-0137-y

23. Weng J., Bai L., Ko H., Tsai Y. Cyclocommunol induces apoptosis in human oral squamous cell carcinoma partially through a Mcl-1-dependent mechanism. Phytomedicine. 2018; 39, 25–32. https://linkinghub.elsevier.com/retrieve/pii/S0944711317301770

24. Lin W., Lai D., Lee Y., Chen N., Tseng T. Antitumor progression potential of morusin suppressing STAT3 and NFκB in human hepatoma SK-Hep1 cells. Toxicol. Lett. 2015; 232(2), 490–498. http://linkinghub.elsevier.com/retrieve/pii/S0378427414015069

25. Lee J., Won S., Chao C., Wu F., Liu H., Ling P., Lin C., Su C. Morusin induces apoptosis and suppresses NF-κB activity in human colorectal cancer HT-29 cells. Biochem. Biophys. Res. Commun. 2008; 372(1), 236–242. http://linkinghub.elsevier.com/retrieve/pii/S0006291X08009285

26. Kang S., Kim E., Kim S., Lee J., Ahn K., Yun M., Lee S. Morusin induces apoptosis by regulating expression of Bax and Survivin in human breast cancer cells. Oncol. Lett. 2017; 13(6), 4558–4562. https://www.spandidos-publications.com/10.3892/ol.2017.6006

27. Xue J., Li R., Zhao X., Ma C., Lv X., Liu L., Liu P. Morusin induces paraptosis-like cell death through mitochondrial calcium overload and dysfunction in epithelial ovarian cancer. Chem.-Biol. Interact. 2018; 283, 59–74. https://linkinghub.elsevier.com/retrieve/pii/S0009279717311924

28. Park H., Min T., Chi G., Choi Y., Park S. Induction of apoptosis by morusin in human non-small cell lung cancer cells by suppression of EGFR/STAT3 activation. Biochem. Biophys. Res. Commun. 2018; 505(1), 194–200. https://linkinghub.elsevier.com/retrieve/pii/S0006291X18320102

29. Wang L., Guo H., Yang L., Dong L., Lin C., Zhang J., Lin P., Wang X. Morusin inhibits human cervical cancer stem cell growth and migration through attenuation of NF-κB activity and apoptosis induction. Mol. Cell. Biochem. 2013; 379(1–2), 7–18. http://link.springer.com/10.1007/s11010-013-1621-y

30. Lim S., Park S., Kang S., Park D., Kim S., Um J., Jang H., Lee J., Jeong C., Jang J., Ahn K., Lee S. Morusin induces cell death through inactivating STAT3 signaling in prostate cancer cells. Am. J. Cancer Res. 2015; 5(1), 289–300. http://www.ajcr.us/files/ajcr0003469.pdf

31. Kim C., Kim J., Oh E., Nam D., Lee S., Lee J., Kim S., Shim B., Ahn K. Blockage of STAT3 Signaling Pathway by Morusin Induces Apoptosis and Inhibits Invasion in Human Pancreatic Tumor Cells. Pancreas. 2016; 45(3), 409–419. http://Insights.ovid.com/crossref?an=00006676-201603000-00015

32. Park D., Ha I., Park S., Choi M., Lim S., Kim S., Lee J., Ahn K., Yun M., Lee S. Morusin Induces TRAIL Sensitization by Regulating EGFR and DR5 in Human Glioblastoma Cells. J. Nat. Prod. 2016; 79(2), 317–323. http://pubs.acs.org/doi/10.1021/acs.jnatprod.5b00919

33. Guo H., Liu C., Yang L., Dong L., Wang L., Wang Q., Li H., Zhang J., Lin P., Wang X. Morusin inhibits glioblastoma stem cell growth in vitro and in vivo through stemness attenuation, adipocyte transdifferentiation, and apoptosis induction. Mol. Carcinog. 2016; 55(1), 77–89. http://doi.wiley.com/10.1002/mc.22260

34. Wang F., Zhang D., Mao J., Ke X., Zhang R., Yin C., Gao N., Cui H. Morusin inhibits cell proliferation and tumor growth by down-regulating c-Myc in human gastric cancer. Oncotarget. 2017; 8(34), 57187–57200. https://www.researchgate.net/publication/318437337_Morusin_inhibits_cell_proliferation_and_tumor_growth_by_downregulating_c-Myc_in_human_gastric_cancer

35. Wan L., Ma B., Zhang Y. Preparation of morusin from Ramulus mori and its effects on mice with transplanted H 22 hepatocarcinoma. BioFactors 2014; 40(6), 636–645. http://doi.wiley.com/10.1002/biof.1191

36. Ma J., Qiao X., Pan S., Shen H., Zhu G., Hou A. New isoprenylated flavonoids and cytotoxic constituents from Artocarpus tonkinensis. J. Asian Nat. Prod. Res. 2010; 12(7), 586–592. http://www.tandfonline.com/doi/abs/10.1080/10286020.2010.485932

37. Kollár P., Bárta T., Hošek J., Souček K., Závalová V., Artinian S., Talhouk R., Šmejkal K., Suchý P., Hampl A. Prenylated Flavonoids from Morus alba L. Cause Inhibition of G1/S Transition in THP-1 Human Leukemia Cells and Prevent the Lipopolysaccharide-Induced Inflammatory Response. Evid. Based Complementary Alternat. Med. 2013; 2013, 1–13. http://www.hindawi.com/journals/ecam/2013/350519/

38. Lee H., Auh Q., Lee Y., Kang S., Chang S., Lee D., Kim Y., Kim E. Growth inhibition and apoptosis-inducing effects of cudraflavone B in human oral cancer cells via MAPK,
NF-κB, and SIRT1 Signaling Pathway. Planta Medica. 2013; 79(14), 1298–1306. http://www.thieme-connect.de/DOI/DOI?
10.1055/s-0033-1350619

39. Zou Y., Hou A., Zhu G., Chen Y., Sun H., Zhao Q. Cytotoxic isoprenylated xanthones from Cudrania tricuspidata. Bioorg. Med. Chem. 2004; 12(8), 1947–1953. http://linkinghub.elsevier.com/retrieve/pii/S0968089604000641

40. Zhang Q., Tang Y., Chen R., Yu D. Three new cytotoxic Diels-Alder-type adducts from Morus australis. Chemistry 2007; 4(7), 1533–1540. https://onlinelibrary-wiley-com.katalog.vfu.cz:444/doi/epdf/10.1002/cbdv.200790133

41. Oke-Altuntas F., Kapche G., Nantchouang Ouete J., Demirtas I., Koc M., Ngadjui B. Bioactivity evaluation of cudraxanthone I, neocyclomorusin and (9βh)-3β-acetoxylanosta-7,24-diene isolated from Milicia excelsa Welw. C. C. Berg (Moraceae). Med. Chem. Res. 2016; 25(10), 2250–2257. http://link.springer.com/10.1007/s00044-016-1670-3

42. Gryn-Rynko A., Bazylak G., Olszewska-Slonina D. New potential phytotherapeutics obtained from white mulberry (Morus alba L.) leaves. Biomed. Pharmacother. 2016; 84, 628–636. https://linkinghub.elsevier.com/retrieve/pii/S075333221631188

43. Ferlinahayati F., Syah Y., Juliawaty L., Achmad S., Hakim E., Takayama H., Said I., Latip J. Phenolic constituents from the wood of Morus australis with cytotoxic activity. Z. Naturforsch. C. 2008; 63(1–2), 35–39. https://www.degruyter.com/downloadpdf/j/znc.2008.63.issue-1-2/znc-2008-1-207/znc-2008-1-207.pdf

44. Lee C., Yen F., Ko H., Li S., Chiang Y., Lee M., Tsai M., Hsu L. Cudraflavone C induces apoptosis of A375.S2 melanoma cells through mitochondrial ROS production and MAPK activation. Int. J. Mol. Sci. 2017; 18(7), 1508–1520. https://content-ebscohost-com.katalog.vfu.cz:444/ContentServer.asp?T=P&P=AN&K=124367473&S=R&D=a9h&EbscoContent=dGJyMNLr40Sep7A4xNvgOLCmr1GeprFSr6a4S7SWxWXS&ContentCustomer=dGJyMPGut0ivrLZPuePfgeyx43zx

45. Syah Y., Juliawaty L., Achmad S., Hakim E., Ghisalberti E. Cytotoxic prenylated flavones from Artocarpus champeden. J. Nat. Med. 2006; 60(4), 308–312. http://link.springer.com/10.1007/s11418-006-0012-z

46. Soo H., Chung F., Lim K., Yap V., Bradshaw T., Hii L., Tan S., See S., Tan Y., Leong C., Mai C., Castresana J. Cudraflavone C Induces tumor-specific apoptosis in colorectal cancer cells through inhibition of the phosphoinositide 3-kinase (PI3K)-AKT pathway. PLoS One 2017; 12(1), 1–20. https://dx.plos.org/10.1371/journal.pone.0170551

47. Yang Z., Matsuzaki K., Takamatsu S., Kitanaka S. Inhibitory effects of constituents from morus alba var. multicaulis on differentiation of 3T3-L1 cells and nitric oxide production in RAW264.7 cells. Molecules 2011; 16(7), 6010–6022. http://www.mdpi.com/1420-3049/16/7/6010

48. Mihara S., Hara M., Nakamura M., Sakurawi K., Tokura K., Fujimoto M., Fukai T., Nomura T. Non-peptide bombesin receptor antagonists, kuwanon G and H, isolated from mulberry. Biochem. Biophys. Res. Commun. 1995; 213(2), 594–599. http://linkinghub.elsevier.com/retrieve/pii/S0006291X85721730

49. Seiter M., Salcher S., Rupp M., Hagenbuchner J., Kiechl-Kohlendorfer U., Mortier J., Wolber G., Rollinger J., Obexer P., Ausserlechner M. Discovery of Sanggenon G as a natural cell-permeable small-molecular weight inhibitor of X-linked inhibitor of apoptosis protein (XIAP). FEBS Open Bio. 2014; 4(1), 659–671. http://doi.wiley.com/10.1016/j.fob.2014.07.001

50. Wang Z., Li X., Chen M., Liu F., Han C., Kong L., Luo J. A strategy for screening of α-glucosidase inhibitors from Morus alba root bark based on the ligand fishing combined with high-performance liquid chromatography mass spectrometer and molecular docking. Talanta. 2018; 180, 337–345. https://linkinghub.elsevier.com/retrieve/pii/S0039914017312730

51. Wang X., Di X., Shen T., Wang S., Wang X. New phenolic compounds from the leaves of Artocarpus heterophyllus. Chin. Chem. Lett. 2017; 28(1), 37–40. https://linkinghub.elsevier.com/retrieve/pii/S1001841716301838

52. Jung J., Park J., Lee Y., Seo K., Oh E., Lee D., Lim D., Han D., Baek N. Three new isoprenylated flavonoids from the root bark of Morus alba. Molecules 2016; 21(9), 1–10. http://www.mdpi.com/1420-3049/21/9/1112

53. Ferlinahayati F., Syah Y., Juliawaty L., Hakim E. Flavanones from the wood of Morus nigra with cytotoxic activity. Indones. J. Chem. 2013; 13, 205–208. https://www.researchgate.net/publication/286348915_Flavanones_from_the_wood_of_Morus_nigra_with_cytotoxic_activity

54. Kofujita H., Yaguchi M., Doi N., Suzuki K. A novel cytotoxic prenylated flavonoid from the root of Morus alba. J. Insect Biotechnol. Sericology 2004; 73(3), 113–116. https://www.jstage.jst.go.jp/article/jibs/73/3/73_3_113/_pdf/-char/en

55. Šmejkal K. Cytotoxic potential of C-prenylated flavonoids. Phytochem. Rev. 2014; 13(1), 245–275. http://link.springer.com/10.1007/s11101-013-9308-2

56. Cui L., Lee H., Oh W., Ahn J. Inhibition of sanggenon G isolated from Morus alba on the metastasis of cancer cell. Chm. 2011; 3(1), 23–26. http://www.tiprpress.com/chmen/ch/reader/create_pdf.aspx?file_no=CHM20100722001&year_id=2011&quarter_id=1&fal

57. Nam M., Jung D., Seo K., Kim B., Kim J., Kim J., Kim B., Baek N., Kim S. Apoptotic effect of sanggenol L via caspase activation and inhibition of NF-κB signaling in ovarian cancer cells. Phytother. Res. 2016; 30(1), 90–96. http://doi.wiley.com/10.1002/ptr.5505

58. Zhou P., Dong X., Tang P. Sanggenon C induces apoptosis of prostate cancer PC3 cells by activating caspase 3 and caspase 9 pathways. Nan Fang Yi Ke Da Xue Xue Bao 2017; 37(9), 1206–1210. http://www.j-smu.com/Upload/html/2017091206.html

59. Chen L., Liu Z., Zhang L., Yao J., Wang C. Sanggenon C induces apoptosis of colon cancer cells via inhibition of NO production, iNOS expression and ROS activation of the mitochondrial pathway. Oncol. Rep. 2017; 38(4), 2123–2131. https://www.spandidos-publications.com/10.3892/or.2017.5912

60. Dat N., Xuan Binh P., Phuong Quynh L., Huóng H., Van Minh C. Sanggenon C and O inhibit NO production, iNOS expression and NF-κB activation in LPS-induced RAW264.7 cells. Immunopharmacol. Immunotoxicol. 2012; 34(1), 84–88. https://eds-a-ebscohost-com.katalog.vfu.cz:444/eds/pdfviewer/pdfviewer?vid=5&sid=caf51610-430c-4581-952f-c80d8366c0d6 %40sdc-v-sessmgr04

61. Huang H., Liu N., Zhao K., Zhu C., Lu X., Li S., Lian W., Zhou P., Dong X., Zhao C., Guo H., Zhang C., Yang C., Wen G., Lu L., Li X., Guan L., Liu C., Wang X., Dou Q., Liu J. Sanggenon C decreases tumor cell viability associated with proteasome inhibition. Front. Biosci. 2011; 3(4), 1315–1325. https://www.researchgate.net/publication/51174312_Sanggenon_C_decreases_tumor_cell_viability_associated_with_proteasome_inhibition

62. Shi Y., Fukai T., Sakagami H., Chang W., Yang P., Wang F., Nomura T. Cytotoxic Flavonoids with Isoprenoid Groups from Morus mongolica. J. Nat. Prod. 2001; 64(2), 181–188. http://pubs.acs.org/doi/abs/10.1021/np000317c

63. Dat N., Jin X., Lee K., Hong Y., Kim Y., Lee J. Hypoxia-inducible factor-1 inhibitory benzofurans and chalcone-derived Diels-alder adducts from Morus species. J. Nat. Prod. 2009; 72(1), 39–43. http://pubs.acs.org/doi/abs/10.1021/np800491u

64. Wu Y., Kim Y., Kwon T., Tan C., Son K., Kim T. Anti-inflammatory effects of mulberry (Morus alba L.) root bark and its active compounds. Nat. Prod. Res. 2019; 1–4. https://www.tandfonline.com/doi/full/10.1080/14786419.2018.1527832

65. Jing W., Yan R., Wang Y. A practical strategy for chemical profiling of herbal medicines using ultra-high performance liquid chromatography coupled with hybrid triple quadrupole-linear ion trap mass spectrometry: a case study of Mori Cortex. Anal. Methods. 2015; 7(2), 443–457. https://pubs.rsc.org/en/content/getauthorversionpdf/C4AY02196G

66. Liu Y., Li S., Hou J., Liu Y., Wang D., Jiang Y., Ge G., Liang X., Yang L. Identification and characterization of naturally occurring inhibitors against human carboxylesterase 2 in White Mulberry Root-bark. Fitoterapia 2016; 115, 57–63. https://linkinghub.elsevier.com/retrieve/pii/S0367326X16304981

67. Kim S., Son E., Yoon S. Pharmaceutical composition including sanggenol Q for preventing or treating lung cancer. 2017. Republic of Korea. KR101771364B1. Uděleno 19. 7. 2016. Zapsáno 24. 8. 2017. https://patents.google.com/patent/KR101771364B1/en

68. Yang Y., Zhang T., Xiao L., Yang L., Chen R. Two new chalcones from leaves of Morus alba L. Fitoterapia. 2010; 81(6), 614–616. https://linkinghub.elsevier.com/retrieve/pii/S0367326X1000064X

69. Li K., Zheng Q., Chen X., Wang Y., Wang D., Wang J. Isobavachalcone Induces ROS-Mediated Apoptosis via Targeting Thioredoxin Reductase 1 in Human Prostate Cancer PC-3 Cells. Oxid. Med. Cell. Longev. 2018; 2018, 1–13. https://www.hindawi.com/journals/omcl/2018/1915828/

70. Shi Y., Wu W., Huo A., Zhou W., Jin X. Isobavachalcone inhibits the proliferation and invasion of tongue squamous cell carcinoma cells. Oncol. Lett. 2017; 14(3), 2852–2858. https://www.spandidos-publications.com/10.3892/ol.2017.6517

71. Jin X., Shi Y. Isobavachalcone induces the apoptosis of gastric cancer cells via inhibition of the Akt and Erk pathways. Exp. Ther. Med. 2016; 11(2), 403–408. https://www.spandidos-publications.com/10.3892/etm.2015.2904

72. Kuete V., Mbaveng A., Zeino M., Fozing C., Ngameni B., Kapche G., Ngadjui B., Efferth T. Cytotoxicity of three naturally occurring flavonoid derived compounds (artocarpesin, cycloartocarpesin and isobavachalcone) towards multi-factorial drug-resistant cancer cells. Phytomedicine 2015; 22(12), 1096–1102. https://linkinghub.elsevier.com/retrieve/pii/S0944711315002330

73. Szliszka E., Jaworska D., Ksek M., Czuba Z., Król W. Targeting death receptor TRAIL-R2 by chalcones for TRAIL-induced apoptosis in cancer cells. Int. J. Mol. Sci. 2012; 13(12), 15343–15359. http://www.mdpi.com/1422-0067/13/11/15343

74. Zhao S., Ma C., Liu C., Wei W., Sun Y., Yan H., Wu Y. Autophagy inhibition enhances isobavachalcone-induced cell death in multiple myeloma cells. Int. J. Mol. Sci. 2012; 30(4), 939–944. https://www.spandidos-publications.com/10.3892/ijmm.2012.1066

75. Jing H., Zhou X., Dong X., Cao J., Zhu H., Lou J., Hu Y., He Q., Yang B. Abrogation of Akt signaling by Isobavachalcone contributes to its anti-proliferative effects towards human cancer cells. Cancer Lett. 2010; 294(2), 167–177. https://linkinghub.elsevier.com/retrieve/pii/S0304383510000704

76. Nishimura R., Tabata K., Arakawa M., Ito Y., Kimura Y., Akihisa T., Nagai H., Sakuma A., Kohno H., Suzuki T. Isobavachalcone, a chalcone constituent of Angelica keiskei, induces apoptosis in neuroblastoma. Biological. 2007; 30(10), 1878–1883. https://www.jstage.jst.go.jp/article/bpb/30/10/30_10_1878/_pdf

77. Phung T., Tran T., Dan T., Chau V., Hoang T., Nguyen T. Chalcone-derived Diels–Alder adducts as NF-κB inhibitors from Morus alba. J. Asian Nat. Prod. Res. 2012; 14(6), 596–600. https://www.tandfonline.com/doi/abs/10.1080/10286020.2012.670221

78. Kikuchi T., Nihei M., Nagai H., Fukushi H., Tabata K., Suzuki t., Akihisa T. Albanol A from the Root Bark of Morus alba L. Induces Apoptotic Cell Death in HL60 Human Leukemia Cell Line. Chemical 2010; 58(4), 568–571. https://www.jstage.jst.go.jp/article/cpb/58/4/58_4_568/_pdf/-char/en

79. Lee Y., Seo K., Hong E., Kim D., Kim Y., Baek N. Diels-alder type adducts from the fruits of Morus alba L. Appl. Biol. Chem. 2016; 59(2), 91–94. https://www.researchgate.net/publication/304583358_Diels-Alder_type_adducts_from_the_fruits_of_Morus_alba_L

80. Han H., Chou C., Li R., Liu J., Zhang L., Zhu W., Hu J., Yang B., Tian J. Chalcomoracin is a potent anticancer agent acting through triggering Oxidative stress via a mitophagy- and paraptosis-dependent mechanism. Sci. Rep. 2018; 8(1), 1–14. https://www.nature.com/articles/s41598-018-27724-3.pdf

81. Cui X., Wang L., Yan R., Tan Y., Chen R., Yu D. A new Diels-Alder type adduct and two new flavones from the stem bark of Morus yunanensis Koidz. J. Asian Nat. Prod. Res. 2008; 10(4), 315–318. http://www.tandfonline.com/doi/abs/10.1080/10286020701833537

82. Ha M., Seong S., Nguyen T., Cho W., Ah K., Ma J., Woo M., Choi J., Min B. Chalcone derivatives from the root bark of Morus alba L. act as inhibitors of PTP1B and α-glucosidase. Phytochemistry 2018; 155, 114–125. https://linkinghub.elsevier.com/retrieve/pii/S0031942218304254

83. Hu C., Chen Z., Yao R., Xu G. Inhibition of protein kinase C by stilbene derivatives from Morus alba L. Tianran Chanwu Yanjiu Yu Kaifa 1996; 8(2), 13–16. http://en.cnki.com.cn/Article_en/CJFDTOTAL-TRCW199602002.htm

84. Šmejkal K., Svačinová J., Šlapetová T., Schneiderová K., Dall’Acqua S., Innocenti G., Závalová V., Kollár P., Chudík S., Marek R., Julínek O., Urbanová M., Kartal M., Csöllei M., Doležal K. Cytotoxic activities of several geranyl-substituted flavanones. J. Nat. Prod. 2010; 73(4), 568–572. http://pubs.acs.org/doi/abs/10.1021/np900681y