2. Academic Validation
  3. Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibition agents

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

  • Bioorg Med Chem Lett. 2021 Sep 15:48:128253. doi: 10.1016/j.bmcl.2021.128253.
Feng Wu 1,  Han Yao 1,  Wei Li 1,  Niuniu Zhang 2,  Yangyang Fan 3,  Albert S C Chan 1,  Xingshu Li 4,  Baijiao An 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
  • 2 School of Pharmaceutical Sciences, Guilin Medical University, Guilin 541199, PR China.
  • 3 School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong Province 264003, PR China.
  • 4 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China. Electronic address: lixsh@mail.sysu.edu.cn.
  • 5 School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong Province 264003, PR China. Electronic address: Anbj3@bzmc.edu.cn.
PMID: 34245852 DOI: 10.1016/j.bmcl.2021.128253
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.

Keywords

Anaplastic lymphoma kinase inhibitors; Antiproliferative activity; Mechanism; Sulfoxide.

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