Synthesis, Characterization, and Cytotoxicity of Platinum(IV) Carbamate Complexes

Abstract

The synthesis, characterization, and cytotoxicity of eight new platinum(IV) complexes having the general formula, c,c,t-[Pt(NH3)2Cl2(O2CNHR)2], are reported, where R = tert-butyl (4), cyclopentyl (5), cyclohexyl (6), phenyl (7), p-tolyl (8), p-anisole (9), 4-fluorophenyl (10), or 1-naphthyl (11). These compounds were synthesized by reacting organic isocyanates with the platinum(IV) complex, c,c,t-[Pt(NH3)2Cl2(OH)2]. The electrochemistry of the compounds was investigated by cyclic voltammetry. The aryl carbamate complexes 7 – 11 exhibit reduction peak potentials near −720 mV vs. Ag/AgCl, whereas the alkyl carbamate complexes display reduction peak potentials between −820 and −850 mV vs. Ag/AgCl. The cyclic voltammograms of c,c,t-[Pt(NH3)2Cl2(O2CCH3)2] (1), c,c,t-[Pt(NH3)2Cl2(O2CCF3)2] (2), and cis-[Pt(NH3)2Cl4] (3) were measured for comparison. Density functional theory (DFT) studies were undertaken to investigate the electronic structures of 1 – 11 and to determine their adiabatic electron affinities. A linear correlation (R2 = 0.887) between computed adiabatic electron affinities and measured reduction peak potential was discovered. The biological activity of 4 – 11 and, for comparison, cisplatin was evaluated in human lung cancer A549 and normal MRC-5 cells by the MTT assay. The compounds exhibit comparable or slightly better activity than cisplatin against the A549 cells. In MRC-5 cells, all are equally or slightly less cytotoxic than cisplatin, except for 4 and 5, which are more toxic.

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

“…305 The relative cathodic peak potentials of structurally related complexes are, however, typically correlated to the relative facility with which the metal center is reduced and have been correlated with reduction rates in solution. 306 Early quantitative SAR studies showed that the nature of the axial ligands has a stronger influence on reduction rates than the equatorial ligands. 307 Within the cis -[Pt(en)Cl 2 X 2 ] series where X is an anionic axial ligand, the chloride species (E p = −4 mV) is much more susceptible to reduction than the carboxylate (E p = −250–350 mV) or hydroxide (E p = −664 mV) derivatives.…”

Monofunctional and Higher-Valent Platinum Anticancer Agents

“…106,114,115 The products of such reactions are platinum(IV) carboxylates, carbamates, or carbonates. Another reaction of importance is that of platinum(IV) hydroxides with cyclic anhydrides.…”

Oxidative halogenation of cisplatin and carboplatin: synthesis, spectroscopy, and crystal and molecular structures of Pt(iv) prodrugs

“…11 Similar nucleophilic attack of other substrates can afford Pt(IV) carbonates and carbamates. 12,13 Treatment with hydrochloric acid results in substitution of the hydroxide ligands for chloride, presumably through an intermediate bearing aqua ligands. 14 Pt(IV) prodrugs with chloride axial ligands can also be obtained by direct oxidation with chlorine gas.…”