Diarylpentadienone Derivatives Of Synthesis, Anti-inflammatory And Pharmacokinetics In Rats

Curcumin,a naturally occurring phytochemical derived from the rootstalk of the turmeric plant, has been extensively investigated for centuries in a variety of pharmaceutical applications. Previous studies reveal that curcumin,and its derivatives have various pharmacological activities such as anti-inflammatory,antioxidant and anti-HIV.However, due to its relatively low bioavailability, the potential utility of curcumin is limited.In order to develop the molecules with enhances properties and stability,number of curcumin analogs /derivatives have been designed and synthesized. Among them, a lot of results suggested that the unsymmetrical form of demethoxycurcumin derivative might possess greater biological profile compared to the symmetrical form of bisdemethoxcurcumin. Motivated by the afore-mentioned findings, we aim in this study was to find new, potent anti-inflammatory agents with higher efficacy and better safety profiles, herein, we have synthesized a series of unsymmetrical diarylpentadienone.In this study,we determined the substructure of compound 3(a-k) by using the X-ray crystallography and measured the hydrogen spectrum data. In the screening assay studies,all the compounds were evaluated for preliminary anti-inflammatory activity characterized by evaluating their inhibition against LPS-induced IL-6 release in mouse macrophage cell with LPS. Among them, compound 3i showed the highest anti-inflammatory activity , so compound 3i was chosen for further study. In order to study the effects of LPS-induced the NF-?B signaling pathway, p65,p-p65,iNOS and COX-2 protein were detected by Western Blot.The results showed that compound 3i showed the highest anti-inflammatory activity.The immunofluorescence assay alos showed that 3i could inhibit the immune function.Because compound 3i has exhibited strong anti-inflammatory activity, in order to study the interaction between 3i and the organism,the rats were used to study in pharmacokinetics, and a convenient and feasible method for the determination of 3i was established,after used a single dose 5mg/kg intragastric administration at different time points from the rat inner canthus blood. Acetonitrile precipitation protein,take supernatat after centrifugal and test by HPLC,it conforms to one compartment model. Main pharmacokinetic datas:t1/2=0.508h,AUC0-t=1.253mg·h/L,AUC0-?=1.566mg·h/L,CL=3.988L/(h·kg).