trans-Dichloro(triphenylarsino)(N,N-dialkylamino)platinum(II) Complexes: In Search of New Scaffolds to Circumvent Cisplatin Resistance

Abstract

The high incidence of the resistance phenomenon represents one of the most important limitations to the clinical usefulness of cisplatin as an anticancer drug. Notwithstanding the considerable efforts to solve this problem, the circumvention of cisplatin resistance remains a challenge in the treatment of cancer. In this work, the synthesis and characterization of two trans-dichloro(triphenylarsino)(N,N-dialkylamino)platinum(II) complexes (1 and 2) were described. The trypan blue exclusion assay demonstrated an interesting antiproliferative effect for complex 1 in ovarian carcinoma-resistant cells, A2780cis. Quantitative analysis performed by ICP-AES demonstrated a scarce ability to platinate DNA, and a significant intracellular accumulation. The investigation of the mechanism of action highlighted the ability of 1 to inhibit the relaxation of supercoiled plasmid DNA mediated by topoisomerase II and to stabilize the cleavable complex. Cytofluorimetric analyses indicated the activation of the apoptotic pathway and the mitochondrial membrane depolarization. Therefore, topoisomerase II and mitochondria could represent possible intracellular targets. The biological properties of 1 and 2 were compared to those of the related trans-dichloro(triphenylphosphino)(N,N-dialkylamino)platinum(II) complexes in order to draw structure–activity relationships useful to face the resistance phenotype.

The Challenging Treatment of Cisplatin-Resistant Tumors: State of the Art and Future Perspectives

“…Complexes with bromocatechol (32)(33)(34) showed good cytotoxic activity against MDA-MB-231 cells, which were independent of the cyclometalated ligand's nature. Complexes 29-31, possessing alizarine as a ligand, were studied as a mixture of the two isomers, showing a different form of cytotoxic activity that depends on a different CˆN ligand.…”

“…Analogously to complexes 1a-e, trans-Pt(II) complexes with triphenylphosphine ligands have also been synthesized, and in particular, complexes 3 and 4 have been evaluated for their promising anticancer activities (Figure 4) [32]. Indeed, several analogs have been studied, starting with complexes 3 and 4, where a triphenylphosphine ligand was substituted with a triphenylarsine ligand (complexes 5 and 6) with the same dialkylamino ligand preserved, in addition to the two chloride ligands.…”

Dibromo–Isonitrile and N-acyclic Carbene Complexes of Platinum(II): Synthesis and Reactivity

“…In the context of our studies about platinum complexes with antiproliferative properties [1][2][3][4][5][6], we have been searching for new scaffolds to outline compounds capable of circumventing platinum resistance phenomena [7,8]. Among the complexes prepared, those bearing a triphenylphosphino ligand proved capable of affecting mitochondria, and their modes of action often proved effective on cisplatin resistant cell lines.…”

Dibromo- and Dichlorotriphenylphosphino N-Acyclic Carbene Complexes of Platinum(II)—Synthesis and Cytotoxicity

“…In recent years, we focused on the synthesis and biological studies of many platinumbased complexes endowed with antiproliferative properties [34][35][36][37][38][39][40][41][42]. Such investigations allowed us to conclude that the presence of a triphenylphosphine ligand can promote cell uptake and, in many cases, provide modes of action against cisplatin-resistant cancer cells.…”

“…Such investigations allowed us to conclude that the presence of a triphenylphosphine ligand can promote cell uptake and, in many cases, provide modes of action against cisplatin-resistant cancer cells. The trans-[PtCl 2 (PPh 3 )(L)] (L = N,N-dialkylamine) [36,42] and [PtCl(PPh 3 )(L∧L )] 2 of 11 (L∧L = chelating oxime ligand) [38,41] represent interesting examples of such complexes. More in detail, the mechanism of action of trans-[PtCl 2 (PPh 3 )(L)] (L = N,N-dialkylamine) was investigated [42] and the ability to interfere with the catalytic activity of topoisomerase II was evidenced.…”