Design and synthesis of novel benzoxazole analogs as Aurora B kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2016-07, Vol.26 (13), p.3067-3072
• Main Authors: An, Ying, Lee, Eun, Yu, Yeongji, Yun, Jieun, Lee, Myeong Youl, Kang, Jong Soon, Kim, Woo-Young, Jeon, Raok
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferation; Aurora B kinase; Aurora Kinase B - antagonists & inhibitors; Aurora Kinase B - metabolism; Benzoxazole analogs; Benzoxazoles - chemical synthesis; Benzoxazoles - chemistry; Benzoxazoles - pharmacology; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Humans; Mice; Mice, Nude; Models, Molecular; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.05.017

[Display omitted] A novel series of benzoxazole analogs was designed and synthesized, and their inhibitory activities against Aurora kinases were evaluated. Some of the tested compounds exhibited a promising activity with respect to the inhibition of Aurora B kinase. A structure–activity relationship study indicated that linker length, regiochemistry, and halogen substitution play important roles in kinase inhibitory potency. The binding modes between representative compounds and Aurora kinases were interpreted through a molecular docking study to explain the inhibitory activity and selectivity for Aurora A and B kinases. Compounds 13l and 13q also show an antiproliferative effect on the human tumor cell lines in a dose-dependent manner. The most potent 13q demonstrated good efficacy in the prostate cancer PC-3 tumor xenograft model.