Design, Synthetic And Evaluation Of Novel Trehalose Derivatives As Antitumor Agent

Objective: Structure-activity relationship of asymmetrical trehalose derivatives was primarily analyzed and provided a basis for design and synthesis of trehalose derivatives with structural diversity and evaluation of their anti-tumor invasion and migration.Methods: Using brartemicin as a leading compound, twenty five novel trehalose derivatives were designed and synthesized, and the structures were determined by MS,1H NMR and 13 C NMR. As a positive control with brartemicin, inhibitory effects of the target compounds on the proliferation of A549, Hep G2 and HUVEC cells were performed by MTT assay. The abilities of adhesion, invasion, migration,MMP-9 and MMP-2 expression of A549 and Hep G2 cells inhibited by the synthesized compounds were evaluated through Matrigel experiment, Transwell assay and Western blot.Results: The results showed that, the target compounds had no significantly cytotoxicity(P > 0.05) to A549, Hep G2 and HUVEC cells at the dose range of 1 μM~32 μM. At the above dose range, the inhibitory effects of A549 cells adhesion, invasion and migration and Hep G2 cells adhesion and invasion by compounds 129 and 132 were better than brartemicin; Compounds 129 and 132 concentration-dependently inhibited the expression of MMP-9 and MMP-2(P < 0.05).Conclusion: Preliminary structure-activity relationship indicates that, the bigger contributors to improve the abilities of anti-tumor adhesion, invasion and migration were substituent effects of target compounds with 2 position, 2 and 3 position introduced electron-donating methoxy. Their anti-tumor invasion activities might be related to down-regulation of MMP-9 and MMP-2. In addition, simultaneously present diester was not necessary structure of anti-tumor activity.