Study On The Synthetic Of Curcumine Prodrug FM0807 And Its Antitumor Inflammatory Effect

Introduction: Curcumin is a natural phenolic compound isolated from turmeric(Curcuma longa L.). Curcumin has a wide range of pharmacological effects, such as anti-ancer,anti-inflanlrnatory, anti-oxidation, anti-gallstones, lipid-lowering, improve immunity ,and so on. Adequate source of curcumin, is a great development prospect of the natural compoun.However, there are some problems to Curcumin .Such as its water insolubility ,its aqueous solution at neutral to alkaline pH conditions of instability, first-pass elimination of the phenomenon of apparent and low bioavailability in vivo.And there is also no better stability of drug dosage forms, its metabolic inactivation to be absorbed into the blood circulation in small quantities.All of these become a limiting factor in its clinical application and industrialization of the major bottlenecks in. In order to find more active comPounds with improved pharmacokinetics properties,we have designed and synthesized a novel curcumin prodrug FM0807.In the present study we further investigated the antitumor and its inflammatory effect in vitro and in vivo.Objective: To evaluate the pharmacokinetics and the antitumor,anti-inflammatory effect of curcumine prodrug FM0807 in vitro and in vivo.Methods :(1) Prodrug mtabolism was studied in homogenized liver and rat plasma by the reversed-phase high performance liquid chromatography(RP-HPLC); (2)Prodrug pharmacokinetics was studied after oral and intravenous in mice by the reversed-phase high performance liquid chromatography(RP-HPLC) ; (3)The MTT assay was used to examine the inhibition of a variety of tumor cells induced by FM0807 ; (4)The MTT assay was used to examine the inhibition of a variety of tumor cells induced by FM0807 metabolites; (5)The H22 murine xenog-raft models were established and antitumor effect of FM0807 in vivo was analyzed; (6)The K562 murine xenog-raft models were established and antitumor effect of FM0807 in vivo was analyzed; (7) The Inflammation models were established by xylene-induced mouse ear edema, carrageenan-induced claw foot swelling, cotton-induced granuloma , and anti-inflammatory effect of FM0807 in vivo was analyzed.Results:(1)FM0807 was susceptible to hydrolysis by homogenized liver and blood plasma; (2)FM0807 can remarkably inhibit the proliferation of tumor cell lines,and we found that the Serum containing metabolites had significant antiproliferative effects in cancer cells at dose of 200mg/kg, but its IC50 is far greater than the Cur; (3)The area under the concentration-time curve for plasma Cur of FM0807were 5- and 20-fold higher than those of Cur, respectively; (4)FM0807 has a good pharmacokinetic characteristics ,it can release high concentrations of curcumin . HPLC analysis showed that the t1/2 to FM0807 in vivo was significantly prolonged. Intravenous administration in vivo release higher concentrations of curcumin than oral administration at the same doses of FM0807, and the AUC is about 9 times as oral administration ;(5)FM0807 showed significant inhibitory effect on H22 mice xenograft models,the inhibitory rates at dose of 100-400mg/kg were 40-70%,there were significantly higher than the same dose of curcumin group ; (6)FM0807 showed significant inhibitory effect on K562 nude mice xenograft model, the inhibitory rates at dose of 50-200mg/kg were to 60%; (7) FM0807 showed significant inhibitory effect on xylene-induced mouse ear edema, carrageenan-induced claw foot swelling, cotton-induced granuloma .Conclusion: The characteristics of metabolism of FM0807 results in a longer retaining time of Cur in the body.It was able to inhibit the growth of the tumor cells and inhibit inflammation in vivo. FM0807 increases anti-cancer and anti-inflammatory activities, suggesting its promise for clinical utility as a Cur prodrug.