A comparative computational mechanistic study on derivatives of pyriplatin, modified with the –CH2Ph3P+ group, as anticancer complexes targeting mitochondria

Abstract

Chemoresistance of Pt(II) based therapy is related to the extensive repair of modified DNA in the nucleus as a consequence of the nucleotide excision repair mechanism. Delivering Pt(II) complexes to the mitochondria to attack mitochondrial genome lacking repair machinery can lead to a rationally designed therapy for chemoresistant cancers and might overcome the problems associated with conventional cisplatin and its derivatives treatment. Here the outcomes of a computational investigation on the behavior of three monofunctional Pt(II) complexes synthesized starting from the monofunctional drug pyriplatin is reported. Owing to the introduction of the -CH2Ph3P+ group in ortho, meta and para positions of the pyridine ligand of pyriplatin, the newly prepared complexes exhibited significant in vitro and in vivo antitumor efficacy and demonstrated to be able to penetrate mitochondria and accumulate in the mitochondrial matrix. Aquation reaction, DNA attack, modeled by the interaction with the guanine nucleobase, as well as reaction with N-acetyl methionine and imidazole as a model for proteins such as histidine- and methionine-rich compounds, have been computationally investigated for the three complexes and compared with analogous interactions of intact pyriplatin and cisplatin.