Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 242, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114673
Keywords
platinum (II) complexes; 3-Hydroxy-3-(trifluoromethyl)cyclobutane-1,1-dicarboxylic acid; Cytotoxicity
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Funding
- National Natural Science Foundation of China [21808205]
- Zhejiang Provincial Key RD Project [2020C03006, 2019-ZJ-JS-03]
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A series of platinum compounds with fluoro-functional groups were designed and synthesized, and specific compounds were found to exhibit better cytotoxic activity in antitumor activity.
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 mu M, 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.
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