Synthesis, Biophysical Studies, and Antiproliferative Activity of Platinum(II) Complexes Having 1,2-Bis(aminomethyl)carbobicyclic Ligands

Abstract

A selected chemical library of six platinum(II) complexes having 1,2-bis(aminomethyl)carbobicyclic ligands were synthesized after a rational design in order to evaluate their antiproliferative activity and the structure-activity relationships. The cytotoxicity studies were performed using cancer cell lines sensitive (A2780) and resistant (A2780R) to cisplatin. Excellent cytotoxicity was observed for most of complexes, which presented better resistance factors than cisplatin against the A2780R cell line. The interaction of these complexes with DNA, as the target biomolecule, was evaluated by several methods: DNA-platinum binding kinetics, changes in the DNA melting temperature, evaluation of the unwinding angle of supercoiled DNA, evaluation of the interstrand cross-links, and replication mapping. The kinetics of the interaction with glutathione was also investigated to better understand the resistant factors observed for the new complexes.

Synthesis, biological evaluation and SAR studies of novel bicyclic antitumor platinum(IV) complexes

“…The synthesis of ligands 1e3 was performed by following a synthetic pathway developed by our research group [13,14] and other authors [15] (Fig. 4).…”

“…The synthesis of these ligands [13] was accomplished following the synthetic route illustrated in Fig. 5.…”

“…In a previous research work [13] we synthesized and biologically evaluated cis-platinum (II) complexes with ligands containing a carbobicyclic framework and two methylamino substituents in 1,2 positions in order to have a 1,4-diaminobutane-like substructure ( Fig. 2) with moderated steric hindrance and interesting stereo-differentiating properties.…”

Rational design, synthesis and characterization of amide functionalized pyridine and benzimidazole transition metal complexes.

“…Of the thousands of platinum compounds synthesized, only a few have reached clinical trials and still fewer have received approval for clinical use. Newer derivatives have attempted to exploit steric hinderance of associated bulky ligands in retarding thiol coordination; a process believed to playa central role in the deactivation of Pt drugs [45,[63][64][65]. Other studies have focused on developing orally active Pt compounds containing Pt (IV), which is more inert to ligand substitution compare to Pt (II).…”

“…The various combinations of solvents were reached based on the solubility of the reactants . It should be noted that other tests have been designed to monitor the binding of platinated species to GSH including assays that have phosphate buffers and NADPH coupled reactions [64,165]. Additionally, this study is aimed at finding the effects of solvent on the reactivity of thiols and the platinated complexes of this series.…”