Here we present the preparation of 14 pairs of cis- and trans-diammine monochlorido
platinum(II) complexes, coordinated to heterocycles (i.e.,
imidazole, 2-methylimidazole and
pyrazole) and linked to various acylhydrazones, which were designed as potential inhibitors of the
selenium-dependent
enzymes glutathione peroxidase 1 (GPx-1) and
thioredoxin reductase 1 (TrxR-1). However, no inhibition of bovine GPx-1 and only weak inhibition of murine TrxR-1 was observed in in vitro assays. Nonetheless, the cis configured diammine monochlorido Pt(II) complexes exhibited cytotoxic and apoptotic properties on various human
cancer cell lines, whereas the trans configured complexes generally showed weaker potency with a few exceptions. On the other hand, the trans complexes were generally more likely to lack cross-resistance to
cisplatin than the cis analogues.
Platinum was found bound to the nuclear
DNA of
cancer cells treated with representative Pt complexes, suggesting that
DNA might be a possible target. Thus, detailed in vitro binding experiments with
DNA were conducted. Interactions of the compounds with
calf thymus DNA were investigated, including Pt binding kinetics, circular dichroism (CD) spectral changes, changes in DNA melting temperatures, unwinding of supercoiled plasmids and
ethidium bromide displacement in
DNA. The CD results indicate that the most active cis configured
pyrazole-derived complex causes unique structural changes in the
DNA compared to the other complexes as well as to those caused by
cisplatin, suggesting a denaturation of the
DNA structure. This may be important for the antiproliferative activity of this compound in the
cancer cells.