New trans dichloro (triphenylphosphine)platinum(II) complexes containing N -(butyl), N -(arylmethyl)amino ligands: Synthesis, cytotoxicity and mechanism of action

Abstract

Some new platinum(II) complexes have been prepared, of general formula trans-[PtCl2(PPh3){NH(Bu)CH2Ar}], where the dimension of the Ar residue in the secondary amines has been varied from small phenyl to large pyrenyl group. The obtained complexes, tested in vitro towards a panel of human tumor cell lines showed an interesting antiproliferative effect on both cisplatin-sensitive and -resistant cells. For the most cytotoxic derivative 2a the investigation on the mechanism of action highlighted the ability to induce apoptosis on resistant cells and interestingly, to inhibit the catalytic activity of topoisomerase II.

Pentafluorophenyl Platinum(II) Complexes of PTA and Its N-Allyl and N-Benzyl Derivatives: Synthesis, Characterization and Biological Activity

“…Platinum(II) complexes with trans geometry have proved to be interesting candidates to replace the commonly used cisplatin in view of its known adverse effects (mainly its toxicity) and to overcome acquired resistance (due to DME, drug-metabolizing enzymes or genetic variation) [74,75,76,77]. Trans-bisphosphino Pt(II) complexes have shown antiproliferative activity, being able to generate reactive oxygen species, targeting both mitochondria and genomic DNA [78], but also showed affinity toward protein models comparable or higher than cisplatin [79].…”

New Platinum(II) Complexes Affecting Different Biomolecular Targets in Resistant Ovarian Carcinoma Cells

“…Both complexes were characterized spectroscopically (for NMR spectra, see Figures S1–S8 in the Supporting Information) and showed features in good agreement with their chlorinated counterparts, [15,17] except for 195 Pt NMR signals, which were shifted downfield (ca. −4000 ppm), due to the presence of two bromide substituents, as expected [21] .…”

“…The reaction is guided by the strong trans effect exerted by triphenylphosphine and affords the trans products in generally good yields. Complexes 1 and 2 are structural analogues of the corresponding chlorinated derivatives, for which interesting antiproliferative properties had been previously described [15,17] …”

“…Trans‐[Pt(μ‐Br)Br(PPh 3 )] 2 [20] was prepared according to a reported procedure. A sample of benzylbutylamine (BzBuNH) was prepared according to a reported procedure [17] and purified by distillation. A sample of dibenzylamine (Aldrich™) was passed over a short package of dry Al 2 O 3 immediately before use.…”

“…In this scenario, we moved our interest toward new transplatinum complexes containing the triphenylphosphino moiety and indeed, in our previous papers, we reported for some new complexes the ability to exert an interesting antiproliferative activity on human tumor cell lines and to affect mitochondrial functions, leading to apoptosis [15,16] . More recently, we synthesized analogues carrying N ‐(butyl), N ‐(arylmethyl)amino ligands that demonstrated the capacity to overcome cisplatin resistance in ovarian cancer cells [17] …”