Identification and biological evaluation of glycol diaryl ethers as novel anti-cancer agents through structure-based optimization of crizotinib.

Crizotinib, a drug for anaplastic lymphoma kinase (ALK) positive and c-ros oncogene 1 receptor tyrosine kinase (ROS1) positive non-small cell lung cancer (NSCLC), was structurally optimized via a strategy of structure-based fragment replacing. Computational study showed it was beneficial for interaction of crizotinib and ALK to increase the distance between pyridyl ring and phenyl ring in crizotinib, and thus, a series of novel glycol diaryl ethers were synthesized. The in vitro anti-tumor activity of synthesized compounds was studied in NSCLC cell line H2228 and neurobalstoma cell line SH-SY5Y. Among the synthesized compounds, 9e exhibits stronger anti-cancer activity than crizotinib toward H2228 cell line with an IC50 value of 0.22 μM. Molecular docking indicated that a longer chain between pyridyl ring and phenyl ring enabled molecule to have new interaction with a neighboring small hydrophobic pocket.