Ragini Sinha, Urmila J. Joshi, Akshada Joshi, Girjesh Govil


Objective: Flavones and flavonols are an important class of naturally occurring flavonoids. They are well known for their pharmacological activity. This activity is associated with the ability of flavones and flavonols to influence membrane–dependent processes. In this paper, we have reported localization, orientation and interaction, of four synthesized flavone/flavonols with 1, 2–dipalmitoyl–sn–glycero–3–phosphocholine (DPPC) bilayers. These are compared with standard flavone; chrysin (CHY) and flavonol Quercetin (QUE).

Methods: The molecules studied are 4ʹ–methoxy flavone (MF), 3ʹ,4ʹ–dimethoxyflavone (DMF), 4ʹ–methoxyflavonol (MF–ol) and 3ʹ,4ʹ–dimethoxyflavonol (DMF–ol). The techniques used are Differential Scanning Calorimetry (DSC) and multi–nuclear NMR.

Results: Highest binding to lipid bilayers is shown by DMF, followed by QUE. Based on DSC studies it is seen, that maximum interaction of MF and DMF, takes place with the hydrophobic core of lipid bilayers. DMF–ol shows formation of a heterogeneous system at higher concentrations. The 1H NMR spectra of unilamellar vesicles of DPPC, incorporated with MF, DMF and MF–ol shows significant interaction of these compounds with the alkyl chain of the hydrophobic core. MF, DMF and MF–ol acquire parallel orientation in bilayers with the B–ring pointing towards hydrophobic core, while DMF–ol acquire mixed orientation. This may be ascribed to the presence of two methoxy and one hydroxyl group on the B–ring of DMF–ol which hinders its partitioning inside the hydrophobic core of lipid bilayer. Multi–lamellar vesicles (MLV) of DPPC incorporated with flavones, show maximum increase in Chemical Shift Anisotropy in 31P spectrum of DMF. This is followed by MF. DSC.

Conclusion: NMR and binding studies indicate that DMF is partitioned deeply inside the hydrophobic core, while MF, MF–ol and DMF–ol are mostly located in the vicinity of sn–glycero region. Therefore, we conclude that DMF which penetrates deepest inside the hydrophobic core also shows the highest anti–proliferative activity against K562 and MCF–7 cancer cell lines. Its activity is also better than CHY.


Flavones, Flavonols, DPPC, DSC, NMR, Chemical shifts, CSA

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Kandaswami C, Perkins E, Soloniuk DS, Drzewieki G, Middleton E. Antiproliferative effects of citrus flavonoids on a human squamous cell carcinoma in vitro. Cancer Lett 1991;56:147–52.

Middleton EJ, Kandaswami C, Theoharides TC. The effect of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev 2000;52:673–571.

Pervaiz S. Resveratrol: from grapevines to mammalian biology. J FASEB 2003;17:1975–85.

Goldberg DM, Yan J, Soleas GJ. Absorption of three wine related polyphenols in three different matrices by healthy subjects. Clin Biochem 2003;36:79–87.

Kanoo M, Takayanagi T, Harada K, Sawada S, Ishikawa F. Bioavailability of isoflavones after ingestion of soy beverages in healthy adults. J Nutr 2006;136:2291–6.

Manach C, Scabert A, Morand C, Remesy C, Jiminez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004;79:727–47.

Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J Nutr 2000;130:2073–85.

Cai H, Sali S, Schmid R, Britton RG, Brown K, Steward WP, et al. Flavones as colorectal cancer chemopreventive agents–phenol–O–methylation enhances efficiency. Can Prev Res 2009;2:743–50.

Wen X, Walle T. Methylated flavonoids have greatly improved intestinal absorption and metabolic stability. Drug Metab Disposition 2006;34:1786–92.

Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (caco–2) cells. Biochem Biophys Res Comm 1991;175:880–5.

Mizuno M, Iinuma M, Ohara M, Tanaka T, Iwamasa M. Chemotaxonomy of the genus citrus based on polymethoxy flavones. Chem Pharm Bull 1991;39:945–9.

Jaipetch T, Reutrakul V, Tuntiwachwuttikul P, Santisuk T. Flavonoids in the black rhizomes of boesenbergia pandurate. Phytochem 1983;22:625–6.

Britton RG, Horner–Glister E, Pomenya OA, Smith EE, Denton R, Jenkins PR, et al. Synthesis and biological evaluation of novel flavonols as potential anti–prostrate cancer agents. Eur J Med Chem 2012;54:952–8.

During A, Larondelle Y. The O–methylation of chrysin markedly improves its intestinal anti–inflammatory properties: structure–activity relationships of flavones. Biochem Pharmcol 2013;86:1739–46.

Saad S, Howells LM, Britton RG, Steward WP, Gescher A, Brown K. Sale S, 3ʹ, 4ʹ, 5ʹ–trimethoxyflavonol (TMFol), a novel putative prostrate cancer chemopreventive agent; in–vitro and in–vivo preclinical activity. Can Prev Res 2010;3:A104.

Pouget C, Lauthier F, Simon A, Fagnere C, Basly JP, Delage C. Flavonoids structural requirements for antiproliferative activity on breast cancer cells. Bioorg Med Chem Lett 2001;11:3095–7.

Manthey JA, Guthrie N. Antiproliferative activities of citrus flavonoids against six human cancer cell lines. J Agric Food Chem 2002;50:5837–43.

Howells LM, Britton RG, Mazzoletti M, Greaves P, Broggini M, Brown K, Steward WP, Gescher AJ, Sale S. Preclinical colorectal cancer chemopreventive efficacy and p 53–modulating activity of 3ʹ, 4ʹ, 5ʹ–trimethoxyflavonol, a quercetin analogue, Can Prev Res 2010;3:929–39.

Tsuchiya H. Structure–dependent membrane interaction of flavonoids associated with their bioactivity. Food Chem 2010;120:1089–96.

Aue WP, Bartholdi E, Ernst R. Two dimensional spectroscopy. Application to nuclear magnetic resonance. J Chem Phys 1976;64:2229–46.

Anet FAL, Bourn AJR. Nuclear magnetic resonance spectral assignments from nuclear overhauser effects. J Am Chem Soc 1965;87:5250–1.

Sinha R, Gadhwal MK, Joshi UJ, Srivastava S, Govil G. Interaction of quercetin with DPPC model membrane: Molecular dynamic simulation, DSC and multinuclear NMR studies. J Indian Chem Soc 2011;88:1203.

Kornberg RD, McConnel HM. Inside–outside transitions of phospholipids in vesicle membranes. Biochemistry 1971;10:1111–20.

Cheng HY, Randall CS. Carvedilol–liposome interaction: evidence for strong association with the hydrophobic region of the lipid bilayers. BBA–Biomembranes 1996;1284:20–8.

Molyneux P. The use of the stable free radical diphenylpicrylhydrazyl (DPPH) for estimating antioxidant activity. J Sci Technol 2004;2:211–9.

Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protocols 2006;1:1112–6.

Lambros MP, Sheu E, Lin JS, Pereira HA. Interaction of a synthetic peptide based on the neutrophil–derived antimicrobial protein CAP37 with dipalmitoyl–phosphatidylcholine membranes. BBA–Biomembranes 1997;1329:285–90.

Sinha R, Gadhwal MK, Joshi A, Joshi UJ, Srivastava S, Govil G. Structure–dependent interaction of hydroxy flavones with DPPC model membrane. Eur J Med Chem 2014;80:285–94.

Sinha R, Gadhwal MK, Joshi A, Joshi UJ, Srivastava S, Govil G. Localization and interaction of hydroxy flavones with lipid bilayer model membranes: a study using DSC and multinuclear NMR. Eur J Med Chem 2014;80:285–94.

Gardikis K, Hatziantoniou S, Viras K, Demetzos C. Effect of a bioactive curcumin derivative on DPPC membrane: a DSC and raman spectroscopy study. Thermochim Acta 2006;447:1–4.

Bassolino–Klimas D, Alper HE, Stouch TR. Mechanism of solute diffusion through lipid bilayer membranes by molecular dynamics simulation. J Am Chem Soc 1995;117:4118–29.

Kachel K, Asuncion–Punzalan E, London E. Anchoring of tryptophan and tyrosine analogs at the hydrocarbon–polar boundary in model membrane vesicles. Biochemistry 1995;34:15475–9.

Kimura T, Cheng K, Rice KC, Gawrisch K. Location, structure, and dynamics of the synthetic cannabinoid ligand CP–55,940 in lipid bilayers. Biophys J 2009;96:4916–24.

Stamm H, Jaeckel H. Relative ring current effects based on a new model for aromatic–solvent–induced shift. J Am Chem Soc 1989;111:6544–50.

Levine YK, Partington P, Roberts GCK, Birdstall NMJ, Metcalfe JC. 13C nuclear magnetic relaxation times and models for chain molecules in lecithin vesicles. FEBS Lett 1972;23:203–7.

Srivastava S, Phadke RS, Govil G. Role of tryptophan in inducing polymorphic phase formation in lipid dispersions. Indian J Biochem Biophys 1988;25:283.

Cullis PR, Hope MJ, Tilcock CPS. Lipid polymorphism and the role of lipids in membranes. Chem Phys Lipids 1986;40:127–44.

Frenzel J, Arnold K, Nuhn P. Calorimetric, 13C NMR and 31P NMR studies on the interaction of some phenothiazine derivatives with dipalmitoyl phosphatidylcholine model membranes. Biochem Biophys Acta 1978;507:185–97.

Brand–Williams W, Cuvelier ME, Berset C. Use of a free radical method to evaluate antioxidant activity. Lebensm Wiss Technol 1995;28:25–30.

Van–Acker SABE, de Groot MJ. A quantum chemical explanation of the antioxidant activity of flavonoids. Chem Res Toxicol 1996;9:1305–12.

Walle T, Ta N, Kawamori T, Wen X, Tsuji PA, Walle UK. Cancer chemopreventive properties of orally bioavailable flavonoids–ethylated versus unmethylated flavones. Biochem Pharmaco 2007;73:1288–96.

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Flavones, Flavonols, DPPC, DSC, NMR, Chemical shifts, CSA





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International Journal of Current Pharmaceutical Research
Vol 10, Issue 2 (Mar-Apr), 2018 Page: 60-67

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Authors & Affiliations

Ragini Sinha
National Facility for High Field NMR, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai 400005, India.

Urmila J. Joshi
Principal K M Kundnani College of Pharmacy, Cuffe Parade, Mumbai 400005, India

Akshada Joshi
Principal K M Kundnani College of Pharmacy, Cuffe Parade, Mumbai 400005, India

Girjesh Govil
Principal K M Kundnani College of Pharmacy, Cuffe Parade, Mumbai 400005, India


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