2. Academic Validation
  3. Synthesis, cytotoxic evaluation and target identification of thieno[2,3-d]pyrimidine derivatives with a dithiocarbamate side chain at C2 position

Synthesis, cytotoxic evaluation and target identification of thieno[2,3-d]pyrimidine derivatives with a dithiocarbamate side chain at C2 position

  • Eur J Med Chem. 2018 Jun 25:154:324-340. doi: 10.1016/j.ejmech.2018.05.028.
Chao-Rui Yang 1,  Bin Peng 2,  Sheng-Li Cao 3,  Ting-Ting Ren 1,  Wei Jiang 1,  Fu-Cheng Wang 1,  You-Shan Li 1,  Guo Wang 1,  Zheng Li 4,  Shibin Xu 5,  Ji Liao 4,  Hailong Wang 5,  Jing Li 5,  Xingzhi Xu 6
Affiliations

Affiliations

  • 1 Department of Chemistry and Beijing Key Laboratory of DNA Damage Response, Capital Normal University, Beijing, 100048, PR China.
  • 2 Shenzhen University School of Medicine and Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen, Guangdong, 518060, PR China.
  • 3 Department of Chemistry and Beijing Key Laboratory of DNA Damage Response, Capital Normal University, Beijing, 100048, PR China. Electronic address: slcao@cnu.edu.cn.
  • 4 Shenzhen University School of Medicine and Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen, Guangdong, 518060, PR China; College of Life Science and Beijing Key Laboratory of DNA Damage Response, Capital Normal University, Beijing, 100048, PR China.
  • 5 College of Life Science and Beijing Key Laboratory of DNA Damage Response, Capital Normal University, Beijing, 100048, PR China.
  • 6 Shenzhen University School of Medicine and Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen, Guangdong, 518060, PR China. Electronic address: xingzhi.xu@szu.edu.cn.
PMID: 29843103 DOI: 10.1016/j.ejmech.2018.05.028
Abstract

Two series of thieno[2,3-d]pyrimidine derivatives bearing a dithiocarbamate side chain at the C2 position were synthesized and evaluated for cytotoxic activity in human lung Cancer A549 and colon Cancer HCT-116 cell lines. Compound 3n exhibited the most cytotoxic effect on A549 cells with an IC50 value of 4.87 μM, inducing a cell cycle arrest at G2/M phase and activating the spindle assembly checkpoint (SAC). To identify the target protein(s) of 3n, we incorporated biotin with 3n through a three-carbon chain and an amide bond to synthesize probe 10. The targeted proteins were pulled down from the A549 total cell lysate by biotin-streptavidin affinity purification and analyzed by mass spectrometry. Tubulin was the only protein identified, which is related to the SAC and directly binds to probe 10 both in vivo and in vitro. Furthermore, compound 3n inhibited tubulin polymerization in vitro in a dose-dependent manner, competed with taxol in binding to tubulin, exerting cytotoxic activity toward taxol-resistant A549 cells. These results demonstrate that thieno[2,3-d]pyrimidine derivative 3n exhibits cytotoxicity in Cancer cells by targeting tubulin to activate the SAC and potentially acts as a therapeutic lead compound for taxol-resistant cancers.

Keywords

Cytotoxicity; Dithiocarbamate; Probe; Target identification; Thieno[2,3-d]pyrimidine; Tubulin.

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