Flavonoids: structural requirements for antiproliferative activity on breast cancer cells

doi:10.1016/S0960-894X(01)00617-5

Bioorganic & Medicinal Chemistry Letters

Volume 11, Issue 24, 17 December 2001, Pages 3095-3097

https://doi.org/10.1016/S0960-894X(01)00617-5 Get rights and content

Abstract

Several classes of flavonoids (flavones, flavanones, 2′-hydroxychalcones and flavan-4-ols) having a variety of substituents on A ring were investigated for their antiproliferative activity against MCF-7 human breast cancer cells. Structure–activity relationships of these compounds were discussed. 2′-hydroxychalcones and methoxylated flavanones were found to be potent inhibitors of MCF-7 cells growth whereas flavones and flavan-4-ols appeared to be weak inhibitory agents except 7,8-dihydroxyflavone.

Introduction

Many clinically successful anticancer drugs are themselves either natural products or have been developed from naturally occurring lead compounds. Great interest is currently being paid to flavonoids—one of the major classes of natural products with widespread distribution in fruits, vegetables, spices, tea and soy-based foodstuff¹—for their interesting pharmacological activities.2, 3 The antiproliferative effects against breast cancer cells,⁴ anti-aromatase activity5, 6 and binding affinities for the estrogen receptor⁷ of these compounds have drawn attention due to their role as potential anti-breast cancer agents.

In our attempt to design flavonoid-related compounds having a balance between the above activities, we undertook a screening relating to several classes of flavonoids and we recently described the aromatase inhibitory effects of some flavones, flavanones⁸ and chalcones.⁹ The aim of the present study was to explore thoroughly the structural requirements on A-ring of chalcones, flavanones and flavones for inhibition of MCF-7 breast cancer cells growth, both to identify an optimal candidate among currently available compounds, as well as to ascertain potential directions for synthetic lead-optimization studies.

Finally, a previous study about anticancer activity of cis- and trans-4′,7-dihydroxyisoflavan-4-ols,¹⁰ two proposed metabolites of daidzein (4′,7-dihydroxyisoflavone) prompted us to investigate for the first time the antiproliferative activity against MCF-7 cells of synthetic flavan-4-ols,¹¹ which are of a rare occurrence in nature.

Section snippets

Chemistry

For this study, we synthesized a set of flavonoid derivatives, increased by commercially available compounds (flavanones 1a and 1d–1i, chalcones 2a and 2c and flavones 3a–3e), all of which bearing either hydrogen, hydroxyl and/or methoxy substituents on the A-ring (Table 1).

2′,4′-dihydroxychalcone 2b was synthesized as previously described¹² (yield 36%). Flavanones 1d–1h were treated by a methanolic KOH solution to afford 2′-hydroxychalcones 2d–2h respectively (yield 50–60%) while flavanones 1b

Proliferation assay

The growth inhibitory activity of the compounds was determined in the MCF-7 human breast cancer cell line using the MTT assay as described by Mosman et al.¹³ Results were represented as % of inhibition compared to control absorbance. The IC₅₀ concentration was calculated graphically and represents the concentration which results in a 50% decrease in cell growth after 6 days incubation. The given values are mean values of three experiments. The deviations were within ±5%.

Results and discussion

The antiproliferative effects of flavanones and flavones on MCF-7 cells are reported in Figure 1 while results from testing 2′-hydroxychalcones are summarized in Table 2.

Some structure–activity relationships for cytotoxicity are apparent from these results. First, the unsubstituted flavanone 1a appeared to be a weak inhibitor of MCF-7 cells growth as well as flavanones with hydroxyl groups like compounds 1b, 1c, 1g and 1i. In contrast, the substitution by a methoxy group at position 7 and/or 5

Acknowledgements

The authors are grateful to the Region Limousin for its financial support and Y. Champavier for running the NMR spectra.

References (15)

J. Peterson et al.
Nutrition Res.
(1998)
G. Di Carlo et al.
Life Sci.
(1999)
F.V. So et al.
Cancer Lett.
(1997)
A.R. Ibrahim et al.
J. Steroid Biochem. Mol. Biol.
(1990)
J.C. Le Bail et al.
Cancer Lett.
(1998)
J.C. Le Bail et al.
Life Sci.
(2001)
C. Pouget et al.
Tetrahedron
(2000)

There are more references available in the full text version of this article.

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Flavonoids: structural requirements for antiproliferative activity on breast cancer cells

Abstract

Introduction

Section snippets

Chemistry

Proliferation assay

Results and discussion

Acknowledgements

Nutrition Res.

Life Sci.

Cancer Lett.

J. Steroid Biochem. Mol. Biol.

Cancer Lett.

Life Sci.

Tetrahedron