Design And Synthesis Of Lenalidomide Derivatives As Tumor Of Angiogenesis Inhibitor

With the development of molecular biology, molecular targeted therapy for cancer has become the fourth treatment in addition to the operation, radiotherapy and chemotherapy. It has been widely used for clinical treatment of malignant tumor. The angiogenesis is closely related to the tumor growth, invasion and metastasis. The tumor angiogenesis has become one of new target for anticancer therapies.Lenalidomide is a novel type of immunomodulatory agent with anti-tumor activity, which is mainly expressed in the angiogenesis. In this paper, a series of Lenalidomide derivatives were designed by the virtual screening of the molecular targets of anti-tumor angiogenesis. In optimization to the synthesis of Lenalidomide, the Lenalidomide derivatives were obtained and their anti-cancer activity were carried out. The results will provide theoretical and experimental basis for the antiangiogenic developments of the Lenalidomide and the new molecular targeted drugs.Firstly, the molecular targets of tumor angiogenesis of Lenalidomide were virtual screened and the structures of Lenalidomide derivatives were designed. Lenalidomide, 3-(4-Amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione was used as the initial structure to screening the angiogenesis molecular targets on Auto-Dock 4.0 by using reverse docking method. The six target proteins, such as Vascular endothelial growth factor receptor(VEGFR-2), Epidermal growth factor receptor(erb B-3), Fibroblast growth factor receptor(FGFR-4), BCR-ABL tyrosine kinase(ABL), p38 Mitogen activated protein kinase(p38MAPK) and Metal protein kinase(MMP-3) were chosen as the targets. The docking results show that the angiogenesis molecular target of Lenalidomide is innitialy FGFR-4. The docking study on the designed 54 Lenalidomide derivatives was carried out with FGFR-4. And the intended 30 structures of Lenalidomide derivatives were identified as the alkylation, acylation and sulfonylation of Lenalidomide.Secondly, the synthesis of Lenalidomide and its derivatives was studied on the review of Lenalidomide and its intermediates. Lenalidomide was used as raw material and synthesized by the known method. The 30 Lenalidomide derivatives were obtained by the alkylation, acylation and sulfonylation of Lenalidomide. The reaction conditions were determined by the optimization on the effects of solvent, temperature, catalyst, condensation agent and acid. All synthesized compounds were verified by the 1H-NMR, 13C-NMR and MS. The 28 Lenalidomide derivatives were new and have not been reported.Finally, the anti-tumor activity of Lenalidomide and its derivatives. CCK-8 was used to detect the inhibitory activity in the esophageal carcinoma cell line EC9706. The results indicate that the inhibitory activity IC50 of Lenalidomide was 340.3 μg/m L(ΔG=-7.05 kcal/mol) and the inhibitory activity IC50 of its derivatives 1-4,1-18 and 1-40 were 261.8 μg/m L(ΔG=-7.18 kcal/mol), 309.5 μg/m L(ΔG=-7.39 kcal/mol) and 225.2 μg/m L(ΔG=-8.40 kcal/mol), it show that the Lenalidomide derivatives have better inhibitory activity than Lenalidomide. The consistent of anti-tumor activity on EC9706 with that of molecular docking, show that the angiogenesis docking is feasible and the FGFR-4 is the potential target for Lenalidomide derivatives.