Synthesis, Characterization, and Cytotoxicity of a Reactive Platinum(IV) Monotrifluoromethyl Complex

• Published in: European journal of inorganic chemistry 2023-01, Vol.26 (3), p.n/a
• Main Authors: Liu, Yanpeng, Yao, Houzong, Tse, Man‐Kit, Chen, Shu, Yiu, Shek‐Man, Zhu, Guangyu
• Format: Article
• Language: English
• Subjects: Anticancer properties; Drugs; Inorganic chemistry; Ligands; Nonclassical Pt(IV) complex; Nucleophiles; Nucleophilic substitution; Nucleotides; Organometallic Pt(IV) complex; Platinum; Reaction mechanisms; Substitution reactions; Substrates; Toxicity; Trans effect
• ISSN: 1434-1948; 1099-0682
• DOI: 10.1002/ejic.202200438

Platinum‐based complexes are among the most widely utilized cancer therapeutics. Current Pt(II) drugs face some challenges including toxicity and drug resistance. To solve these issues, great efforts have been devoted to developing nonclassical platinum complexes, such as Pt(IV) prodrugs, that act via mechanisms distinct from those of the approved drugs. Compared with active Pt(II) counterparts, Pt(IV) complexes are relatively inert. Although direct interactions between Pt(IV) complexes and nucleotides have been reported, the reaction is slow due to the kinetic inertness of Pt(IV) complexes. Herein, we design and synthesize a Pt(IV) monotrifluoromethyl complex, in which the chloride ligand that is trans to trifluoromethyl ligand is reactive. The Pt(IV) monotrifluoromethyl complex is very stable in water but displays high reactivity towards various substrates including buffer components and 5’‐dGMP. The study of reaction mechanism reveals that this Pt(IV) complex reacts with phosphate via SN2 nucleophilic substitution pathway, which is different from Pt(II) drugs. The Pt(IV) monotrifluoromethyl complex is cytotoxic in human ovarian cancer cells. Our work reports an example of a reactive organometallic Pt(IV) complex that can directly interact with nucleophiles and implies its potential as an anticancer agent. A Pt(IV) monotrifluoromethyl complex containing a reactive chloride ligand trans to the trifluoromethyl ligand is reported. This Pt(IV) complex is very stable in water but displays high reactivity towards various substrates including buffer components and 5’‐dGMP, and the complex is cytotoxic in human ovarian cancer cells.