Jeffrey Joseph Ares

Synthesis and biological evaluation of flavonoids and related compounds as gastroprotective agents

Abstract Several analogs of the gastroprotective molecule flavone have been synthesized and evaluated for gastroprotective activity. A C2–C3 double bond and an intact C ring appear necessary for optimum activity. Activity can be retained by replacing the 2-phenyl substituent with other groups but is eliminated when this ring is moved from the 2- to the 3-position.

Flavonoid-induced gastroprotection in rats: role of blood flow and leukocyte adherence.

To elucidate the mechanisms of flavonoid-induced protection against nonsteroidal anti-inflammatory drug (indomethacin)-induced acute gastric damage, the effects of 5-methoxyflavone and 5-methoxyflavanone on the gastric vasculature were compared both in vivo (using laser Doppler flowmetry in anesthetized rats) and in vitro on rat superior mesenteric arteries. The effects of the compounds on indomethacin-induced leukocyte adherence to mesenteric venules were investigated by intravital videomicroscopy. Oral 5-methoxyflavone reduced indomethacin-induced macroscopic damage by 38 to 99% (ED50 = 5.5 mg/kg). Damage was not significantly reduced by 5-methoxyflavanone. Light microscopy studies also demonstrated a reduction in damage severity. 5-Methoxyflavone, but not 5-methoxyflavanone, increased the gastric conductance significantly. The effects on isolated mesenteric arteries correlated with the effects on in vivo conductance. Finally, indomethacin-induced leukocyte adherence was inhibited to a greater extent by 5-methoxyflavone than by 5-methoxyflavanone. In conclusion, the flavonoid 5-methoxyflavone provides gastroprotection against nonsteroidal anti-inflammatory drug-induced gastric damage. A structurally similar compound, 5-methoxyflavanone, demonstrated minimal gastroprotective activity, suggesting that the double bond of 5-methoxyflavone is required for biological activity. The finding that 5-methoxyflavone (but not 5-methoxyflavanone) significantly increased gastric vascular perfusion and reduced leukocyte adherence to mesenteric venules suggests that these mechanisms may contribute to the flavonoids gastroprotective activity.