Medicinal Chemistry Research

, Volume 26, Issue 7, pp 1585–1592 | Cite as

Synthesis of Citrus polymethoxyflavonoids and their antiproliferative activities on Hela cells

Review Article


A series of polymethoxyflavonoids (316) were synthesized through dehydrogenation, O-methylation, glycoside hydrolysis, bromination, microwave-assisted aromatic nucleophilic substitution, dimethyldioxirane oxidation and regioselective demethylation, starting from abundant and inexpensive natural sources naringin and hesperidin. All the synthetic compounds were test for antiproliferative activities on human cervical carcinoma Hela cell line by the standard CCK-8 assay, the result showed that most of the target compounds exhibited moderate to potent antiproliferative activities on Hela cells comparable with the positive control cis-Platin. Among them, 5-hydroxypolymethoxy flavonoid 13 showed the strongest activity (IC50 0.791 μM).

Graphical Abstract

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Polymethoxyflavonoids Synthesis Antiproliferative activity Hela cells 



We thank the National “Twelfth Five-year” plan for Science & Technology Support (NO. 2012BAD31B02) and the Hunan Provincial Natural Science Foundation of China (NO. 14JJ2048) for financial support.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.


  1. Adam W, Chan YY, Cremer D, Gauss J, Scheutzow D, Schindler M (1987) Spectral and chemical properties of dimethyldioxirane as determined by experiment and ab initio calculations. J Org Chem 52(13):2800–2803CrossRefGoogle Scholar
  2. Buisson D, Quintin J, Lewin G (2007) Biotransformation of polymethoxylated flavonoids: access to their 4‘-O-demethylated metabolites. J Nat Prod 70:1035–1038CrossRefPubMedGoogle Scholar
  3. Besson T, Ruiz N, Coudert G, Guillaumet G (1995) Synthesis of a benzodioxinic analog of 8-methoxypsoralen. Tetrahedron 51:3197–3204CrossRefGoogle Scholar
  4. Cai SL, Liu S, Liu L, Wang QA (2012) Synthesis of bioactive natural polymethoxyflavones and their vinyl ether derivatives. Chem Res Chinese Universities 28:631–636Google Scholar
  5. Chen KH, Weng MS, Lin JK (2007) Tangeretin suppresses IL-1β-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells. Biochem Pharmacol 73:215–227CrossRefPubMedGoogle Scholar
  6. Lai SC, Li S, Chai CY, Lo CY, Ho CT, Wang YJ, Pan MH (2007) Inhibitory effect of citrus 5-hydroxy-3,6,7,8,3’,4’-hexamethoxyflavone on 12-O-tetradecanoylphorbol 13-acetate-induced skin inflammation and tumor promotion in mice. Carcinogenesis 28(12):2581–2588CrossRefPubMedGoogle Scholar
  7. Lewin G, Maciuk A, Thoret S, Aubert G, Dubois J, Cresteil T (2010) Semisynthesis of natural flavones inhibiting tubulin polymerization from hesperidin. J Nat Prod 73(4):702–706CrossRefPubMedGoogle Scholar
  8. Li L, Xu XY, Cheng D, Yao XL, Pan SY (2012) Structure-activity relationship of Citrus polymethoxylated flavones and their inhibitory effects on Aspergillus niger. J Agric Food Chem 60(17):4336–4341CrossRefGoogle Scholar
  9. Li S, Pan MH, Lai CS, Lo CY, Dushenkov S, Ho CT (2007) Isolation and syntheses of polymethoxyflavones and hydroxylated polymethoxyflavones as inhibitors of HL-60 cell lines. Bioorg Med Chem 15:3381–3389CrossRefPubMedGoogle Scholar
  10. Li Y, Cai SL, He KL, Wang QA (2014) Semisynthesis of polymethoxyflavonoids from naringin and hesperidin. J Chem Res 38:287–290CrossRefGoogle Scholar
  11. Liu JD, Chen L, Cai SL, Wang QA (2012) Semisynthesis of apigenin and acacetin-7-O-β-D-glycosides from naringin and their cytotoxic activity. Carbohydrate Res 357:41–45CrossRefGoogle Scholar
  12. Michelle K, Clark SA, Scott J, Wojtkowiak R, Chirco P, Mathieu J, Reiners J, Raymond R, Mattingly RF, Borch R, Gibbs A (2007) Synthesis, biochemical, and cellular evaluation of farnesyl monophosphate prodrugs as farnesyltransferase inhibitors. J Med Chem 50:3274–3282CrossRefGoogle Scholar
  13. Miyata Y, Oshitari T, Okuyama Y, Shimada A, Takahashi H, Natsugari H, Kosano H (2013) Polymethoxyflavones as agents that prevent formation of cataract: nobiletin congeners show potent growth inhibitory effects in human lens epithelial cells. Bioorg Med Chem Lett 23:183–187CrossRefPubMedGoogle Scholar
  14. Okuno Y, Miyazawa M (2004) Biotransformation of nobiletin by Aspergillus niger and the antimutagenic activity of a metabolite, 4’-hydroxy-5,6,7,8,3’-pentamethoxyflavone. J Nat Prod 67:1876–1878CrossRefPubMedGoogle Scholar
  15. Olga W, Jerzy W, Kamila SP, Aleksandra BP, Maria P, Damuta D, Noelia D, Ferreira MJU, Krystyna M (2012) Multidrug resistance reversal and apoptosis induction in Human colon cancer cells by some flavonoids present in Citrus plants. J Nat Prod 75:1896–1902CrossRefGoogle Scholar
  16. Oshitari T, Okuyama Y, Miyata Y, Kosano H, Takahashi H, Natsugari H (2011) B-Ring-modified and/or 5-demethylated nobiletin congeners: Inhibitory activity against proMMP-9 production. Bioorg Med Chem 19:7085–7092CrossRefPubMedGoogle Scholar
  17. Pan MH, Chen WJ, Lin-Shiau SY, Ho CT, Lin JK (2002) Tangeretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis 23:1677–1684CrossRefPubMedGoogle Scholar
  18. Pan MH, Lai YS, Lai CS, Wang Li YS, Lo CY, Dushenkov S, Ho CT (2007) 5-Hydroxy-3,6,7,8,3’,4’-hexamethoxyflavone induces apoptosis through reactive oxygen species production, growth arrest and DNA damage-inducible gene 153 expression, and caspase activation in human leukemia cells. J Agric Food Chem 55:5081–5091CrossRefPubMedGoogle Scholar
  19. Shan Y, Li GY, Wang QA, Li ZH (2008) Semisynthesis of five bioactive flavonoids from hesperidin. Chin J Org Chem 28(6):1024–1028Google Scholar
  20. Shizuo H, Hiroaki M (1954) Glucoluteolin isolated from the leaves of Sophora angustifolia. J Am Chem Soc 76:5792–5792Google Scholar
  21. Shizuo H, Masami S, Mototake K (1952) Studies on flavanone glycosides. IV. The glycosides of ripe fruit peel and flower petals of Citrus Aurantium L. J Am Chem Soc 74:3614–3615CrossRefGoogle Scholar
  22. Wang QA, Wu Z, Liu L, Zou LH, Luo M (2010) Synthesis of Citrus bioactive polymethoxyflavonoids and flavonoid glucosides. Chin J Org Chem 30(11):1682–1688Google Scholar
  23. Wu Z, Cai SL, Fan WJ, Wang QA (2012) Semisynthesis of bioactive flavonols and aurones from naringin. Chin J Org Chem 32:1296–1301CrossRefGoogle Scholar
  24. Xuan LN, Wang P, Zhang K, Shi YP, Liu YM, Zhu T, Chen BQ (2015) Synthesis and in vitro antiproliferative activity of novel benzisoselenazolone derivatives. Med Chem Res 24:543–552CrossRefGoogle Scholar

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© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.College of Chemistry and Chemical EngineeringHunan UniversityChangshaChina
  2. 2.Technology Faculty of Thanh Hoa CampusIndustrial University of Ho Chi Minh CityHo Chi Minh CityVietnam

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