Prodrugs of quercetin and resveratrol: a strategy under development.

The biochemical activities of plant flavonoids and stilbenoids point to many health-related applications, hampered however by a low bioavailability associated with rapid metabolic modification. A possible approach to overcome this obstacle is the development of prodrugs. In this review we provide some background information and summarize the efforts made so far to obtain suitable precursors of the two best known model polyphenols belonging to the classes just mentioned, quercetin and resveratrol. Prodrug design needs to take into account two key aspects: the nature of the chemical bond linking the core molecule to the protecting substituent, and the substituent itself, which can impart desirable physico-chemical properties. Only recently a systematic study of the several possible combinations has begun. Most bond systems tested so far appear to be either too stable or too unstable under physiological conditions. A range of substituent moieties is available, allowing the modulation of properties such as water solubility and the ability to permeate biomembranes. Work so far has been largely performed in vitro, and more in vivo experiments are definitely needed for a reliable assessment of the potentialities of the classes of prodrugs produced so far and of those still awaiting creation.