In vitro cytotoxic activity of novel protoflavone analogs - Selectivity towards a multidrug resistant cancer cell line

B. Danko, A. Martins, D. W. Chuang, H. C. Wang, L. Amaral, J. Molnár, F. R. Chang, Yang Chang Wu, A. Hunyadi

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Protoapigenone (PA), a natural flavonoid possessing an unusual p-quinol moiety on its B ring, is a prospective novel lead compound against cancer currently in development, together with WYC0209, a potent synthetic PA analog. Structure activity relationships (SAR) concerning different 1′-O-alkyl side-chains were also studied on two sets of derivatives. Materials and Methods: Fifteen 1′-O-alkyl protoflavone derivatives were synthesized from genkwanin or 4′-hydroxy-6-methylflavone, thirteen of which are new compounds. All compounds were tested for their cytotoxic effect on four human cancer cell lines, such as HepG2 and Hep3B (hepatic), A549 (lung) and MDA-MB-231 (breast) cell lines, with doxorubicin as a positive control. All compounds, as well as PA, WYC0209 and fourteen of their previously reported analogs were also tested on a multidrug-resistant (MDR) sub-cell line of L5178 mouse T-cell lymphoma and on its parental counterpart (PAR). Results: In general, derivatives bearing a free hydroxyl group at C-1′ exerted the strongest activities, while C-1′-substituted compounds were found to be much weaker. Derivatives of 6-methylflavone exhibited mild, but statistically significant selectivity towards the MDR cell line. Conclusion: The results are in agreement with our previous findings for fundamental SAR of protoflavones. 6-Methylated protoflavones may serve as valuable leads for developing selective compounds against MDR cancer. Identical activity of other derivatives on the PAR and MDR cell lines suggests that cancer cells cannot exhibit resistance to protoflavones by ABCB1 efflux pump overexpression.

Original languageEnglish
Pages (from-to)2863-2869
Number of pages7
JournalAnticancer Research
Volume32
Issue number7
Publication statusPublished - Jul 2012

Fingerprint

Cell Line
Structure-Activity Relationship
Neoplasms
Hydroquinones
T-Cell Lymphoma
Flavonoids
Hydroxyl Radical
Doxorubicin
Breast
In Vitro Techniques
Lung
Liver
protoapigenone
6-methylflavone

Keywords

  • 6-methylflavone
  • ABCB1
  • MDR
  • P-glycoprotein
  • P-gp
  • Protoapigenone
  • Protoflavone
  • Selective cytotoxicity
  • WYC0209

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Danko, B., Martins, A., Chuang, D. W., Wang, H. C., Amaral, L., Molnár, J., ... Hunyadi, A. (2012). In vitro cytotoxic activity of novel protoflavone analogs - Selectivity towards a multidrug resistant cancer cell line. Anticancer Research, 32(7), 2863-2869.

In vitro cytotoxic activity of novel protoflavone analogs - Selectivity towards a multidrug resistant cancer cell line. / Danko, B.; Martins, A.; Chuang, D. W.; Wang, H. C.; Amaral, L.; Molnár, J.; Chang, F. R.; Wu, Yang Chang; Hunyadi, A.

In: Anticancer Research, Vol. 32, No. 7, 07.2012, p. 2863-2869.

Research output: Contribution to journalArticle

Danko, B, Martins, A, Chuang, DW, Wang, HC, Amaral, L, Molnár, J, Chang, FR, Wu, YC & Hunyadi, A 2012, 'In vitro cytotoxic activity of novel protoflavone analogs - Selectivity towards a multidrug resistant cancer cell line', Anticancer Research, vol. 32, no. 7, pp. 2863-2869.
Danko, B. ; Martins, A. ; Chuang, D. W. ; Wang, H. C. ; Amaral, L. ; Molnár, J. ; Chang, F. R. ; Wu, Yang Chang ; Hunyadi, A. / In vitro cytotoxic activity of novel protoflavone analogs - Selectivity towards a multidrug resistant cancer cell line. In: Anticancer Research. 2012 ; Vol. 32, No. 7. pp. 2863-2869.
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AU - Martins, A.

AU - Chuang, D. W.

AU - Wang, H. C.

AU - Amaral, L.

AU - Molnár, J.

AU - Chang, F. R.

AU - Wu, Yang Chang

AU - Hunyadi, A.

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N2 - Background: Protoapigenone (PA), a natural flavonoid possessing an unusual p-quinol moiety on its B ring, is a prospective novel lead compound against cancer currently in development, together with WYC0209, a potent synthetic PA analog. Structure activity relationships (SAR) concerning different 1′-O-alkyl side-chains were also studied on two sets of derivatives. Materials and Methods: Fifteen 1′-O-alkyl protoflavone derivatives were synthesized from genkwanin or 4′-hydroxy-6-methylflavone, thirteen of which are new compounds. All compounds were tested for their cytotoxic effect on four human cancer cell lines, such as HepG2 and Hep3B (hepatic), A549 (lung) and MDA-MB-231 (breast) cell lines, with doxorubicin as a positive control. All compounds, as well as PA, WYC0209 and fourteen of their previously reported analogs were also tested on a multidrug-resistant (MDR) sub-cell line of L5178 mouse T-cell lymphoma and on its parental counterpart (PAR). Results: In general, derivatives bearing a free hydroxyl group at C-1′ exerted the strongest activities, while C-1′-substituted compounds were found to be much weaker. Derivatives of 6-methylflavone exhibited mild, but statistically significant selectivity towards the MDR cell line. Conclusion: The results are in agreement with our previous findings for fundamental SAR of protoflavones. 6-Methylated protoflavones may serve as valuable leads for developing selective compounds against MDR cancer. Identical activity of other derivatives on the PAR and MDR cell lines suggests that cancer cells cannot exhibit resistance to protoflavones by ABCB1 efflux pump overexpression.

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