Emergence of high aqueous solubility for some flavone glycosides by disruption of molecular planarity
G. Lewin, Alexandre Maciuk, Aurélien Moncomble, J.P. Cornard · Planta Medica · 2012
Balance between aqueous solubility and hydrophobicity is an important parameter for drug design. Improvement of aqueous solubility by introducing hydrophilic groups often results in a decrease of oral bioavailability. At the same time, poor hydrosolubility can be observed for polar compounds like flavones. For these compounds, molecular planarity, symmetry and subsequent molecular associations play a significant role 1 . Therefore an alternative strategy to increase aqueous solubility consists of disrupting molecular planarity. The phlebotropic drug diosmin, a flavone glycoside, is known to be greatly insoluble in water. We describe the dramatic 10 5 -fold increase of aqueous solubility concomitant with increase of lipophilicity by the introduction of a single halogen substituent at the C-3 position. Computed optimized structures show that the value of the twist angle between the chromone moiety and the B ring is closely related to the aqueous solubility. Also, steric hindrance in position 3 is more important than electronic factors to increase aqueous solubility. 1 Ishikawa & al., J. Med Chem 2011, 54, 1539.