The formation of unusual seven-membered, sterically overloaded chelates [Pt(en)(L/L´)](NO3)2 (4a/4b) from the corresponding potent hybrid antitumor agents [PtCl(en)(LH/L´H)](NO3)2 (3a/3b) is described, where en is ethane-1,2-diamine and L(H) and L´(H) are (protonated) N-(2-(acridin-9-ylamino)ethyl)-N-methylpropionimidamide and N-(2-(acridin-9-ylamino)ethyl)-N-methylacetimidamide, respectively. Compounds 3a and 3b inhibit H460 lung cancer cell proliferation with IC50 values of 12 ± 2 nM and 2.8 ± 0.3 nM, respectively. The new derivative 3b proves to be not only the most cytotoxic platinum–acridine hybrid of this kind, but also one of the most potent platinum-based anticancer agents described to date. The chelates 4a and 4b do not undergo ligand substitution reactions with nucleobase nitrogen and cysteine sulfur and do not intercalate into DNA. Despite their inertness, the two chelates appear to maintain micromolar activity in H460 cells. The results are discussed in the context of potential DNA-mediated and DNA-independent cell kill mechanisms and the potential use of the chelates as prodrugs.

The synthesis of platinum–acridine hybrid agents containing carboxylic acid ester groups is described. The most active derivatives and the unmodified parent compounds showed up to 6-fold higher activity in ovarian cancer (OVCAR-3) and breast cancer (MCF-7, MDA-MB-23) cell lines than cisplatin. Inhibition of cell proliferation at nanomolar concentrations was observed in pancreatic (PANC-1) and non-small cell lung cancer cells (NSCLC, NCI-H460) of 80- and 150-fold, respectively. Introduction of the ester groups did not affect the cytotoxic properties of the hybrids, which form the same monofunctional–intercalative DNA adducts as the parent compounds, as demonstrated in a plasmid unwinding assay. In-line high-performance liquid chromatography and electrospray mass spectrometry (LC-ESMS) shows that the ester moieties undergo platinum-mediated hydrolysis in a chloride concentration-dependent manner to form carboxylate chelates. Potential applications of the chloride-sensitive ester hydrolysis as a self-immolative release mechanism for tumor-selective delivery of platinum–acridines are discussed.

Me-lexpy/py, an adenine-N3-selective alkylating agent, and the reversible minor-groove binder netropsin were used to probe the formation of unusual minor-groove adducts by the cytotoxic hybrid agent PT-ACRAMTU ([PtCl(en)(ACRAMTU)](NO3)2; en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea). PT-ACRAMTU was found by chemical footprinting to inhibit specific Me-lex-mediated DNA cleavage at several adenine sites, but not at nonspecific guanine, which is consistent with platination of adenine-N3. In a cell proliferation assay, a significant decrease in cytotoxicity was observed for PT-ACRAMTU, when cancer cells were pretreated with netropsin, suggesting that minor-groove adducts in cellular DNA contribute to the biological activity of the hybrid agent.