Vanillin, a food additive, covalently binds with sickle haemoglobin (Hb S), inhibits cell sickling and shifts the oxygen equilibrium curve towards the left. These effects would potentially benefit patients with sickle cell disease (SCD). However, vanillin has no therapeutic effect if given orally because orally administered vanillin is rapidly decomposed in the upper digestive tract. To overcome this problem, a vanillin prodrug, MX-1520, which is biotransformed to vanillin in vivo, was synthesized. Studies using transgenic sickle mice, which nearly exclusively develop pulmonary sequestration upon exposure to hypoxia, showed that oral administration of MX-1520 prior to hypoxia exposure significantly reduced the percentage of sickled cells in the blood. The survival time under severe hypoxic conditions was prolonged from 6.6 +/- 0.8 min in untreated animals to 28.8 +/- 12 min (P < 0.05) and 31 +/- 7.5 min (P < 0.05) for doses of 137.5 and 275 mg/kg respectively. Intraperitoneal injection of MX-1520 to bypass possible degradation in the digestive tract showed that doses as low as 7 mg/kg prolonged the survival time and reduced the percentage of sickled cells during hypoxia exposure. These results demonstrate the potential for MX-1520 to be a new and safe anti-sickling agent for patients with SCD.