Design, synthesis and preliminary bioactivity studies of indomethacin derivatives as Bcl-2/Mcl-1 dual inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 27; no. 13; pp. 2771 - 2783
• Main Authors: Chen, Chen, Nie, Yiming, Xu, Guangsen, Yang, Xinying, Fang, Hao, Hou, Xuben
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.07.2019; Elsevier
• Subjects: Anticancer; Apoptosis; Bcl-2/Mcl-1 dual inhibitor; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Indomethacin derivatives; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Indomethacin derivatives; Anticancer; Bcl-2/Mcl-1 dual inhibitor; Apoptosis; BCL-2; RESISTANCE; MCL-1 INHIBITORS; PROTEINS; CELL; ABT-199
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.05.003

[Display omitted] Bcl-2 family proteins, which divides into pro-apoptosis proteins and anti-apoptosis proteins, are involved in cell apoptosis progression. As numerous studies illustrated, targeting Bcl-2 family proteins is more and more attractive and practicable to cancer treatment. In this work, we designed and synthesized a series of indomethacin derivatives as new inhibitors for Bcl-2 family proteins. Our results of binding assay to Bcl-2 proteins, MTT assay and apoptotic assay indicated that some compounds had potent binding affinity to Bcl-2/Mcl-1 but not Bcl-XL. Furthermore, compound 8j showed improved anti-proliferative activity than known Bcl-2 inhibitor WL-276.