Discovery of tetracyclic 1,2,4-triazoline-fused dibenzo[b,f][1,4]oxazepine as a potent anti-colorectal cancer agent with good efficacy and low toxicity.

A series of tetracyclic 1,2,4-triazoline-fused dibenzo[b,f][1,4]oxazepines were evaluated as novel anti-tumor agents. MTT assay conducted in four human cancer cell lines (SW620, A549, MCF-7, HepG2) showed that 1,2,4-triazoline-fused dibenzo[b,f][1,4]oxazepine decorated by a methyl group on the benzene ring of 1,2,4-triazoline moiety exhibited a superior antiproliferative activity against SW620 cells with a IC50 value of 0.86 μM. The above compound was thus chosen for further investigation on its anti-colorectal cancer (CRC) effect, and displayed inhibitory effects on the proliferation of HCT116 and CT26 cells with IC50 values of 0.96 μM and 1.71 μM, respectively. Furthermore, this compound could effectively suppress colony formation and induce cell cycle arrest and apoptosis in SW620 cells. Western blot analysis demonstrated that it exerted the anti-tumor activity through blocking the PI3K-AKT signaling pathway. Next, we examined its in vivo anti-tumor activity by establishing a subcutaneous CT26 xenograft model, and found that it significantly reduced the tumor sizes with limited toxicity. Collectively, these findings suggest that this compound could be utilized as a promising candidate against CRC.