Trans-[bis(benzimidazol-2-ylidene)dichlorido]platinum(II) complexes with peculiar modes of action and activity against cisplatin-resistant cancer cells.

Three series of cis- and trans-[bis(benzimidazol-2-ylidene)dichlorido]platinum(II) and cis-[(benzimidazol-2-ylidene)(DMSO)dichlorido]platinum(II) complexes were synthesised and screened for cytotoxicity against six human cancer cell lines. Depending on their N-alkyl and 5-alkoxycarbonyl substituents, two-digit nanomolar to single-digit micromolar IC50 values against cancer cell lines intrinsically resistant to or ill-responding to cisplatin were reached by both cis- and trans-configured complexes. The stability of the complexes under aqueous biotest conditions was shown via 1H and 195Pt NMR monitoring to be dependent on their configuration and their N-substituents. Localisation studies employing click reactions with 1-alkyne- or cyclopropene-tagged derivatives revealed that the cis-complexes accumulated in the cell nuclei and the trans-complexes in the mitochondria. While the most active cis-complexes showed modes of action akin to those of cisplatin, the most active trans-complexes differed from cisplatin by much lower rates of cellular uptake and ROS production, and by their non-interaction with the cell cycle and the DNA of cancer cells. Thus, we identified structural key elements for the synthesis of optimised trans-configured NHC platinum(II) complexes with high activity also against cisplatin-refractory cancer cells.

Synthesis and Bioactivity of a Macrocidin B Stereoisomer.

A stereoisomer of macrocidin B, a presumed metabolite of the fungus Phoma macrostoma, was synthesized in 18 steps and 2.7% yield from protected l-tyrosine that was N-ß-ketoacylated with a fully functionalized octanoyl Meldrum's acid. Dieckmann condensation gave a 3-acyltetramic acid, which was macrocyclized via Williamson etherification between the phenol and epi-bromohydrin termini. This macrocidin B stereoisomer showed a weaker herbicidal effect than macrocidin A and no similar inhibitory effect on biofilms of Staphylococcus aureus.