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Oxazepine Derivative as an Antitumor Agent and Snail1 Inhibitor against Human Colorectal Adenocarcinoma

Dhanya Sunil , Ranjitha C , Rama M , KSR Pai

Colorectal cancer is the third most common malignancy in man, with significant morbidity and mortality. Metastasis, the major cause of cancer-associated deaths occurs as a multistep process, where cancer cells detach from the primary tumor, intravasate circulation to disseminate and invade surrounding tissues to form the secondary tumors. The effectiveness of many anticancer drugs is limited by their toxicity to normal rapidly growing cells. Four oxazepines were synthesized by the cycloaddition reaction between schiff bases and maleic anhydride, which were characterized by CHN analysis and advanced spectral techniques. The cytotoxicity of oxazepines against HCT116 (human colon cancer) cell lines were studied using Sulphorhodamine-B (SRB) assay, and their antimigratory properties using wound healing assay. 1-[2-(2,3-dihydro-1H-indol-3-yl)-4,7-dioxo-4,7-dihydro-1,3-oxazepin-3(2H)- yl]thiourea (2b) exhibited very low IC50 in SRB assay with good antimigratory activity as observed in wound healing assay. Snail 1, a transcription regulator of E-cadherin induces epithelial-to mesenchymal transition, reduces intercellular adhesion and increases cell motility, endows epithelial cancer cells with migration and invasive properties. Snail1 is upregulated in several human cancers and is frequently associated with apoptotic resistance, invasiveness, metastases and poor prognosis and it can act as a molecular target in cancer treatment. The docking studies of 2b with the active site of snail1 suggest it to be a potent chemotherapeutic agent in the treatment of colorectal cancer