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Molecular Diversity

, Volume 15, Issue 3, pp 665–675 | Cite as

Design, synthesis and 3D-QSAR study of cytotoxic flavonoid derivatives

  • Lili Ou
  • Shuang Han
  • Wenbo Ding
  • Zhe Chen
  • Ziqi Ye
  • Hongyu Yang
  • Goulin Zhang
  • Yijia Lou
  • Jian-Zhong Chen
  • Yongping Yu
Full-Length Paper

Abstract

Three series of flavonoid derivatives were designed and synthesized. All synthesized compounds were evaluated for cytotoxic activities against five human cancer cell lines, including K562, PC-3, MCF-7, A549, and HO8910. Among the compounds tested, compound 9d exhibited the most potent cytotoxic activity with IC50 values of 2.76–6.98μM. Further comparative molecular field analysis was performed to conduct a 3D quantitative structure–activity relationship study. The generated 3D-QSAR model could be used for further rational design of novel flavonoid analogs as highly potent cytotoxic agents.

Keywords

Flavonoids Cytotoxic activity 3D-QSAR Comparative molecular field analysis CoMFA 

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References

  1. 1.
    Middleton EJ, Kandaswami C, Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 52: 673–751PubMedGoogle Scholar
  2. 2.
    Suresh Babu K, Hari Babu T, Srinivas PV, Kishore KH, Murthy USN, Rao JM (2006) Synthesis and biological evaluation of novel C (7) modified chrysin analogues as antibacterial agents. Bioorg Med Chem Lett 16: 221–224. doi: 10.1016/j.bmcl.2005.09.009 PubMedCrossRefGoogle Scholar
  3. 3.
    Khlebnikov AI, Schepetkin IA, Domina NG, Kirpotina LN, Quinn MT (2007) Improved quantitative structure–activity relationship models to predict antioxidant activity of flavonoids in chemical, enzymatic, and cellular systems. Bioorg Med Chem 15: 1749–1770. doi: 10.1016/j.bmc.2006.11.037 PubMedCrossRefGoogle Scholar
  4. 4.
    Park H, Dao TT, Kim HP (2005) Synthesis and inhibition of PGE2 production of 6,8-disubstituted chrysin derivatives. Eur J Med Chem 40: 943–948. doi: 10.1016/j.ejmech.2005.04.013 PubMedCrossRefGoogle Scholar
  5. 5.
    Nakagawa-Goto K, Bastow KF, Chen TH, Morris-Natschke SL, Lee KH (2008) Antitumor agents 260. new desmosdumotin B analogues with improved in vitro anticancer. J Med Chem 51: 3297–3303. doi: 10.1021/jm701208v PubMedCrossRefGoogle Scholar
  6. 6.
    Cárdenas M, Marder M, Blank VC, Roguin LP (2006) Antitumor activity of some natural flavonoids and synthetic derivatives on various human and murine cancer cell lines. Bioorg Med Chem 14: 2966–2971. doi: 10.1016/j.bmc.2005.12.021 PubMedCrossRefGoogle Scholar
  7. 7.
    Wang CL, Li HQ, Meng WD, Qing FL (2005) Trifluoromethylation of flavonoids and anti-tumor activity of the trifluoromethylated flavonoid derivatives. Bioorg Med Chem Lett 15: 4456–4458. doi: 10.1016/j.bmcl.2005.07.047 PubMedCrossRefGoogle Scholar
  8. 8.
    Tundis R, Deguin B, Loizzo MR, Bonesi M, Statti GA, Tillequinb F. Menichini F, Menichini F (2005) Potential antitumor agents: flavones and their derivatives from Linaria reflexa Desf. Bioorg Med Chem Lett 15: 4757–4760. doi: 10.1016/j.bmcl.2005.07.029 PubMedCrossRefGoogle Scholar
  9. 9.
    Bauvois B, Puiffe ML, Bongui JB, Paillat S, Monneret C, Dauzonne D (2003) Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13. J Med Chem 46: 3900–3913. doi: 10.1021/jm021109f PubMedCrossRefGoogle Scholar
  10. 10.
    Wätjen W, Suckow-Schnitker AK, Rohrig R, Kulawik A, Addae-Kyereme J, Wright CW, Passreiter CM (2008) Prenylated flavonoid derivatives from the bark of Erythrina addisoniae. J Nat Prod 71: 735–738. doi: 10.1021/np070417j PubMedCrossRefGoogle Scholar
  11. 11.
    Yoder BJ, Cao SG, Norris A, Miller JS, Ratovoson F, Razafitsalama J, Andriantsiferana R, Rasamison VE, Kingston DGI (2007) Antiproliferative prenylated stilbenes and flavonoids from macaranga alnifolia from the madagascar rainforest. J Nat Prod 70: 342–346. doi: 10.1021/np060484y PubMedCrossRefGoogle Scholar
  12. 12.
    Wätjen W, Weber N, Lou YJ, Wang ZQ, Chovolou Y, Kampkötter A, Kahl R, Proksch P (2007) Prenylation enhances cytotoxicity of apigenin and liquiritigeninin rat H4IIE hepatoma and C6 glioma cells. Food Chem Toxicol 45: 119–124. doi: 10.1016/j.fct.2006.08.008 PubMedCrossRefGoogle Scholar
  13. 13.
    Roelens F, Heldring N, Dhooge W, Bengtsson M, Comhaire F, Gustafsson JÅ, Treuter E, Keukeleire DD (2006) Subtle side-chain modifications of the hop phytoestrogen 8-prenylnaringenin result in distinct agonist/antagonist activity profiles for estrogen receptors α and β. J Med Chem 49: 7357–7365. doi: 10.1021/jm060692n PubMedCrossRefGoogle Scholar
  14. 14.
    Maitrejea M, Comte G, Barron D, Kirat KE, Conseil G, Pietro AD (2000) The flavanolignan silybin and its hemisynthetic derivatives, a novel series of potential modulators of P-Glycoprotein. Bioorg Med Chem Lett 10: 157–160. doi: 10.1016/S0960-894(99)00636-8 CrossRefGoogle Scholar
  15. 15.
    Lin AS, Nakagawa-Goto K, Chang FR, Yu DL, Morris-Natschke SL, Wu CC, Chen SL, Wu YC, Lee KH (2007) First total synthesis of protoapigenone and its analogues as potent cytotoxic agents. J Med Chem 50: 3921–3927. doi: 10.1021/jm070363a PubMedCrossRefGoogle Scholar
  16. 16.
    Gulati KC, Seth SR, Venkataraman K (1943) Phloroacetophenone. Org Synth 2: 522–523Google Scholar
  17. 17.
    Juntend KYT, Junte TST (1988) Anti-ulcerous agent containing chalcone derivative as effective ingredient and novel chalcone derivatives. Patent EP 292576Google Scholar
  18. 18.
    Bu X, Zhao L, Li Y (1997) A facile synthesis of 6-C-Prenylflavanones. Synthesis 11: 1246–1248. doi: 10.1055/s-1997-1348 CrossRefGoogle Scholar
  19. 19.
    Schwaebe MK, Moran TJ, Whitten JP (2005) Total synthesis of psorospermin. Tetrahedron Lett 46: 827–829. doi: 10.1016/j.tetlet.2004.12.006 CrossRefGoogle Scholar
  20. 20.
    Quintin J, Roullier C, Thoret S, Lewin G (2006) Synthesis and anti-tubulin evaluation of chromone-based analogues of combretastatins. Tetrahedron 62: 4038–4051. doi: 10.1016/j.tet.2006.02.024 CrossRefGoogle Scholar
  21. 21.
    Ho DK, McKenzie AT, Byrn SR, Cassady JM (1987) O5-Methyl-(±)-(2′R, 3′S)-psorospermin. J Org Chem 52: 342–347. doi: 10.1021/jo00379a005 CrossRefGoogle Scholar
  22. 22.
    Meza-Avina ME, Ordonez M, Fernandez-Zertuche M, Rodriguez- Fragoso L, Reyes-Esparza J, de Los Rios-Corsino AA (2005) Synthesis of some monocyclic analogues of mycophenolic acid via the Johnson ortho ester Claisen rearrangement. Bioorg Med Chem 13: 6521–6528. doi: 10.1016/j.bmc.2005.07.013 PubMedCrossRefGoogle Scholar
  23. 23.
    Guo X, Hu W, Cheng S, Wang L, Chang J (2006) Synthesis of novel murrapanine analogues by microwave irradiation. Syn Commun 36: 781–788. doi: 10.1080/00397910500451159 CrossRefGoogle Scholar
  24. 24.
    Solladié G, Gehrold N, Maignan J (1999) Synthesis of (+)-(R)-5-hydroxy-6-hydroxymethyl-7-methoxy-8- methylflavanone. Tetrahedron Asymmetry 10: 2739–2747. doi: 10.1016/S0957-4166(99)00266-9 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Lili Ou
    • 1
  • Shuang Han
    • 1
  • Wenbo Ding
    • 1
  • Zhe Chen
    • 2
  • Ziqi Ye
    • 2
  • Hongyu Yang
    • 2
  • Goulin Zhang
    • 1
  • Yijia Lou
    • 2
  • Jian-Zhong Chen
    • 1
  • Yongping Yu
    • 1
  1. 1.Institute of Materia MedicaCollege of Pharmaceutical Sciences, Zhejiang UniversityHangzhouPeople’s Republic of China
  2. 2.Institute of Pharmacology and Toxicology and Biochemical PharmaceuticsCollege of Pharmaceutical Sciences, Zhejiang UniversityHangzhouPeople’s Republic of China

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