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

Feng Wu; Han Yao; Wei Li; Niuniu Zhang; Yangyang Fan; Albert S C Chan; Xingshu Li; Baijiao An

doi:10.1016/j.bmcl.2021.128253

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. Epub 2021 Jul 8.

Authors

Feng Wu¹, Han Yao¹, Wei Li¹, Niuniu Zhang², Yangyang Fan³, Albert S C Chan¹, Xingshu Li⁴, Baijiao An⁵

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase / antagonists & inhibitors*
Anaplastic Lymphoma Kinase / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Membrane Potential, Mitochondrial / drug effects
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Safrole / analogs & derivatives*
Safrole / chemistry
Safrole / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
2,4-diaminopyrimidine
ALK protein, human
Anaplastic Lymphoma Kinase
Safrole
sulfoxide