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

Fengfan Liu; Chen Yang; Shaoguang Li; Xiaoqi Wu; Keming Xue; Yibo Zhou; Xiaobing Liang; Xiang Cheng; Qiwen Shi; Weike Su

doi:10.1016/j.ejmech.2022.114673

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. Epub 2022 Aug 17.

Authors

Fengfan Liu¹, Chen Yang², Shaoguang Li², Xiaoqi Wu², Keming Xue², Yibo Zhou², Xiaobing Liang², Xiang Cheng², Qiwen Shi³, Weike Su⁴

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.

MeSH terms

Antineoplastic Agents* / pharmacology
Carboplatin / pharmacology
Caspase 3
Cisplatin / pharmacology
Cyclobutanes* / pharmacology
Cyclooxygenase 2
Drug Screening Assays, Antitumor
Humans
Ligands
Organoplatinum Compounds / pharmacology
Oxaliplatin
Platinum
Water
bcl-2-Associated X Protein

Substances

Antineoplastic Agents
Cyclobutanes
Ligands
Organoplatinum Compounds
bcl-2-Associated X Protein
Oxaliplatin
Water
Platinum
Carboplatin
Cyclooxygenase 2
Caspase 3
Cisplatin