Targeting matrix metalloproteinases with novel diazepine substituted cinnamic acid derivatives: design, synthesis, in vitro and in silico studies

Abstract

Lung cancer is the notable cause of cancer associated deaths worldwide. Recent studies revealed that the expression of matrix metalloproteinases (MMPs) is extremely high in lung tumors compared with non-malignant lung tissue. MMPs (-2 and -9) play an important part in tumor development and angiogenesis, which suggests that creating potent MMP-2 and -9 inhibitors, should be an important goal in lung cancer therapy. In the present study, an effort has been made to develop new anti-metastatic and anti-invasive agents, wherein a series of novel diazepine substituted cinnamic acid derivatives were designed, synthesized and assayed for their inhibitory activities on MMP-2 and MMP-9. These derivatives were prepared via microwave assisted reaction of tert-butyl (3-cinnamamidopropyl)carbamate derivatives mixed with 2,3-dibromopropanoic acid and potassium carbonate was added to obtain 4-(tert-butoxycarbonyl)-1-cinnamoyl-1,4-diazepane-2-carboxylic acid derivatives. The newly synthesized compounds were characterized by IR, NMR and mass spectroscopy. All the tested compounds showed good to excellent cytotoxic potential against A549 human lung cancer cells. The active compounds displaying good activity were further examined for the inhibitory activity against MMPs (-2 and -9). In addition, the structure and anticancer activity relationship were further supported by in silico docking studies of the active compounds against MMP-2 and MMP-9.