2. Academic Validation
  3. Design and biological features of platinum (II) complexes with 3-hydroxy-3-(Trifluoromethyl)cyclobutane-1,1-Dicarboxylate as a leaving ligand

Design and biological features of platinum (II) complexes with 3-hydroxy-3-(Trifluoromethyl)cyclobutane-1,1-Dicarboxylate as a leaving ligand

  • Eur J Med Chem. 2022 Nov 15;242:114673. doi: 10.1016/j.ejmech.2022.114673.
Fengfan Liu 1,  Chen Yang 2,  Shaoguang Li 2,  Xiaoqi Wu 2,  Keming Xue 2,  Yibo Zhou 2,  Xiaobing Liang 2,  Xiang Cheng 2,  Qiwen Shi 3,  Weike Su 4
Affiliations

Affiliations

  • 1 National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: liufengfan@zjut.edu.cn.
  • 2 National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, China.
  • 3 National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: qshi@zjut.edu.cn.
  • 4 National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: pharmlab@zjut.edu.cn.
PMID: 36049275 DOI: 10.1016/j.ejmech.2022.114673
Abstract

A series of platinum compounds 2a-5a and 2b-5b with fluoro-functional groups are designed and synthesized. Among them, complex 2b is the most effective agent with 3-hydroxy-3-(trifluoromethyl)cyclobutane-1,1-dicarboxylate as a leaving ligand, which showed better cytotoxic activity than compounds containing only CF3 or OH group at 3-position of cyclobutane-1,1-dicarboxylate. The water solubility of 2a is better than that of carboplatin (32 mg/mL vs. 16 mg/mL), and its antitumor activity on A549 is 4.6-fold higher than that of carboplatin. The IC50 value of 2b on A549 cells is 4.73 ± 0.64 μM, which is comparable to that of oxaliplatin and higher than that of carboplatin. Meanwhile, 2a and 2b are less toxic than oxaliplatin and cisplatin toward BEAS-2B cells. Moreover, 2a and 2b induce cell Apoptosis in vitro by the Bax-Bcl-2-caspase-3 pathway and Ferroptosis through inhibiting GPx-4 and elevating COX2. Results from in vivo experiment show that the inhibition rate of A549 xenograft tumor is cisplatin > 2b > oxaliplatin > 2a > carboplatin.

Keywords

3-Hydroxy-3-(trifluoromethyl)cyclobutane-1,1-dicarboxylic acid; Cytotoxicity; platinum (II) complexes.

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