EFFECT OF METHYL SUBSTITUTION IN FLAVONES ON ITS LOCALIZATION AND INTERACTION WITH DPPC MODEL MEMBRANE: IMPLICATIONS FOR ANTI-PROLIFERATIVE ACTIVITY
Keywords:
Flavones, DPPC, Anti-proliferative activity, Anti-oxidant effect, DSC, NMRAbstract
Objective: Flavones are an important class of naturally occurring molecules possessing multiple pharmacological activities. The anti-proliferative activity is associated with the ability of flavones to influence membrane–dependent processes. We have investigated the localization and interaction of the synthesized flavones: 4΄–methylflavone (4MF) and 4΄–methyl–7–hydroxy flavone (4M7HF) with 1,2–dipalmitoyl–sn–glycero–3–phosphocholine (DPPC) model membrane.
Methods: Diferential Scanning Calorimetry (DSC) and multi nuclear NMR were used to study the interactions with DPPC model membrane. The extent of interaction of these compounds has been compared with the parent molecules: flavone (FLV) and 7–hydroxy flavone (7HF).
Results: Results of DSC and NMR indicate that FLV partitions deepest inside the hydrophobic core and 7HF is localized mostly at the lipid/water interface. 4MF and 4M7HF lying in between the hydrophilic and hydrophobic core. All four molecules assume a mixed orientation with respect to the bilayer normal as indicated by chemical shifts of the lipid protons in NMR. Interaction with the membrane follows the order FLV>4MF>4M7HF>7HF. Radical scavenging activity parallels the presence of hydroxyl groups. Although FLV interacts highest with the membrane, it does not show highest antiproliferative activity. Interaction of the compounds with protons 3, 5a and 7 of DPPC is improved by the methyl substitution on the B-ring, so is the antiproliferative activity.
Conclusion: That's antiproliferative activity of the compounds is at least partially related to the interaction of these molecules with the lipid water interface region.
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E Middleton, C Kandaswami, TC Theoharides. The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease and cancer. Pharm Rev 2002;52:103–8.
GK Harris, Y Qian, SS Leonard, DC Sbarra, X Shi. Luteolin and chrysin differentially inhibit cyclooxygenase-2 expression and scavenge reactive oxygen species but similarly inhibit prostaglandin-E2 formation in RAW 264.7 cells. J Nutr 2006;136:1517–21.
V Cody, E Middleton, JB Harborne, A Beretz. Plant Flavonoids in biology and medicine II. Biochemical, pharmacological and structure-activity relationships. A. R. Liss: New York; 1987.
HA Scheidt, A Pampel, L Nissler, R Gebhardt, D Huster. Investigation of the membrane localization and distribution of flavonoids by high-resolution magic angle spinning NMR Spectroscopy. Biochem Biophys Acta 2004;1664:97–107.
G Pushpavalli, P Kalaiarasi, C Veeramani, KV Pugalendi. Effect of chrysin on hepatoprotective and antioxidant status in D-galactosamine-induced hepatitis in rats. Eur J Pharmacol 2010;631:36–41.
PI Oteiza, AG Erlejman, SV Verstraeten, CL Keen, CG Fraga. Flavonoid–membrane interactions: A protective role of flavonoids at the membrane surface? Clin Dev Immun 2005;12:19–25.
S Chaudhari, B Pahari, PK Sengupta. Ground and excited state proton transfer and antioxidant activity of 7–hydroxyflavone in model membranes: Absorption and fluorescence spectroscopic studies. Biophys Chem 2009;139:29–36.
T Zhang, X Chen, L Qu, J Wu, R Cui, Y Zhao. Chrysin and its phosphate ester inhibit cell proliferation and induce apoptosis in Hela cells. Bioorg Med Chem 2004;12:6097–105.
Ragini Sinha, Manoj K Gadhwal, Akshada Joshi, Urmila J Joshi, Sudha Srivastava andGirjesh Govil. Localization and interaction of hydroxy flavones with lipid bilayer model membrane. Eur J Med Chem 2014;80:285–94.
HY Cheng, CS Randall. Carvedilol–liposome interaction: evidence for strong association with the hydrophobic region of the lipid bilayers. BBA–Biomembranes 1996;1284:20–8.
WP Aue, E Bartholdi, R Ernst. Two dimensional spectroscopy. Application to nuclear magnetic resonance. J Chem Phys 1976;64:2229–46.
FAL Anet, AJR Bourn. Nuclear magnetic resonance spectral assignments from nuclear overhauser effects. J Am Chem Soc 1965;87:5250–1.
R Sinha, MK Gadhwal, UJ Joshi, S Srivastava, G Govil. Interaction of quercetin with DPPC model membrane: Molecular dynamic simulation, DSC and multinuclear NMR studies. J Indian Chem Soc 2011;88:1203.
RD Kornberg, HM McConnel. Inside–outside transitions of phospholipids in vesicle membranes. Biochem 1971;10:1111–20.
P Molyneux. The use of the stable free radical diphenylpicrylhydrazyl (DPPH) for estimating antioxidant activity. J Sci Technol 2004;2:211–9.
V Vichai, K Kirtikara. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 2006;1:1112–6.
M Polikandritou Lambros, E Sheu, JS Lin, HA Pereira. Interaction of a synthetic peptide based on the neutrophil–derived antimicrobial protein CAP37 with dipalmitoyl–phosphatidylcholine membranes. BBA–Biomembranes 1997;1329:285–90.
RF Epand, A Ramamoorthy, RM Epand. Membrane lipid composition and the interaction of pardaxin: The role of cholesterol. Prot Pept Lett 2006;13:1–5.
D Bassolino-Klimas, HE Alper, TR Stouch. Mechanism of solute diffusion through lipid bilayer membranes by molecular dynamics simulation. J Am Chem Soc 1995;117:4118–29.
K Kachel, E Asuncion–Punzalan, E London. Anchoring of tryptophan and tyrosine analogs at the hydrocarbon–polar boundary in model membrane vesicles. Biochem 1995;34:15475–9.
T Kimura, K Cheng, KC Rice, K Gawrisch. Location, structure, and dynamics of the synthetic cannabinoid ligand CP–55, 940 in lipid bilayers. Biophys J 2009;96:4916–24.
H 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.
YK Levine, P Partington, GCK Roberts, NMJ Birdstall, JC Metcalfe. 13C Nuclear Magnetic relaxation times and models for chain molecules in Lecithin vesicles. FEBS Lett 1972;23:203–7.
S Srivastava, RS Phadke, G Govil. Role of tryptophan in inducing polymorphic phase formation in lipid dispersions. Indian J Biochem Biophys 1988;25:283.
PR Cullis, MJ Hope, CPS Tilcock. Lipid polymorphism and the role of lipids in membranes. Chem Phys Lipids 1986;40:127–44.
J Frenzel, K Arnold, P Nuhn. 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.
W Brand–Williams, ME Cuvelier, C Berset. Use of a free radical method to evaluate antioxidant activity. Lebensm Wiss Technol 1995;28:25–30.
SABE van Acker, MJ de Groot. A quantum chemical explanation of the antioxidant activity of flavonoids. Chem Res Toxicol 1996;9:1305–12.
Ragini Sinha, Urmila J Joshi, Sudha Srivastava, Girjesh Govil. Interaction of chrysin and some novel flavones with DPPC model membrane: study based on MD Simulation, DSC And NMR. Int J Pharm Biosci 2014;5(1):364-81.