Emergence of high aqueous solubility for some flavone glycosides by disruption of molecular planarity
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 role1. 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 105-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.
1Ishikawa & al., J. Med Chem 2011, 54, 1539.