Synthesis and evaluation of novel 2, 4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibition agents. (15th September 2021)

• Record Type: Journal Article
• Authors: Wu, Feng; Yao, Han; Li, Wei; Zhang, Niuniu; Fan, Yangyang; Chan, Albert S.C.; Li, Xingshu; An, Baijiao
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 48(2021)
• Publication Date: 2021-09-15
• Subjects: Anaplastic lymphoma kinase inhibitors -- Antiproliferative activity -- Mechanism -- Sulfoxide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128253
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. Here we synthesized and evaluated sixteen new 2, 4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibitors. The optimal compound 9e exhibited excellent antiproliferative activity against non-small cell lung cancer NCI-H2228 cells, which is better than that of Brigatinib and similar to Ceritinib. Mechanism study revealed that the optimal compound 9e decreased the mitochondrial membrane potential and arrested NCI-H2228 cells in the G0/G1 phase, finally resulting in cellular apoptosis. It is interesting that 9e could effectively inhibit the migration of NCI-H2228 cells and may be a promising leading compound for chemotherapy of metastatic cancer.