Biological evaluation of transdichloridoplatinum( II) complexes with 3- and 4-acetylpyridine in comparison to cisplatin

Abstract

BackgroundIn our previous study we reported the synthesis and cytotoxicity of two trans-platinum(II) complexes: trans-[PtCl2(3-acetylpyridine)2] (1) and trans-[PtCl2(4-acetylpyridine)2] (2), revealing significant cytotoxic potential of 2. In order to evaluate the mechanism underlying biological activity of both trans-Pt(II) isomers, comparative studies versus cisplatin were performed in HeLa, MRC-5 and MS1 cells.Materials and methods.The cytotoxic activity of the investigated complexes was determined using SRB assay. The colagenolytic activity was determined using gelatin zymography, while the effect of platinum complexes on matrix metalloproteinases 2 and 9 mRNA expression was evaluated by quantitative real-time PCR. Apoptotic potential and cell cycle alterations were determined by FACS analyses. Western blot analysis was used to evaluate the effect on expression of DNA-repair enzyme ERCC1, and quantitative real-time PCR was used for the ERCC1 mRNA expression analysis. In vitro antiangiogenic potential was determined by tube formation assay. Platinum content in intracellular DNA and proteins was determined by inductively coupled plasma-optical emission spectrometry.ResultsCompound 2 displayed an apparent cytoselective profile, and flow cytometry analysis in HeLa cells indicated that 2 exerted antiproliferative effect through apoptosis induction, while 1 induced both apoptosis and necrosis. Action of 1 and 2, as analyzed by quantitative real-time PCR and Western blot, was associated with down-regulation of ERCC1. Both trans-complexes inhibited MMP-9 mRNA expression in HeLa, while 2 significantly abrogated in vitro tubulogenesis in MS1 cells.ConclusionsThe ability of 2 to induce multiple and selective in vitro cytotoxic effects encourages further investigations of trans-platinum(II) complexes with substituted pyridines.

Synthesis of Platinum(II) Complexes with Some 1-Methylnitropyrazoles and In Vitro Research on Their Cytotoxic Activity

“…Thus, typical platinum anticancer complexes have the general formula cis-[Pt(NHR1R2)2X2], in which R1 and R2 are organic moieties and X is a leaving group, usually a monovalent and biologically acceptable ion such as chlorido, nitrato or carboxylato ligands [7]. Although these findings can still be useful in the development of new platinum complexes with anticancer properties, starting in the early 1990s, numerous compounds have broken the rules mentioned above and have been synthesized and biologically tested with promising results [1,[8][9][10][11][12]. Several classes of such non-classical (or non-conventional) platinum It is well known that tumor hypoxia provides a crucial difference between cancer cells and normal cells, offering a reductive environment for bio reducible prodrug activation.…”

“…Pharmaceuticals 2020, 13, x FOR PEER REVIEW 3 of 23 drugs can be distinguished, including trans platinum(II) analogs [11][12][13][14][15][16][17][18][19][20], Pt(IV) derivatives [21,22] polynuclear Pt complexes [23,24], Pt complexes with N-heterocyclic ligands [25], N-heterocyclic carbenes and cyclometallated Pt complexes [8], Pt(II) compounds with sulfur and phosphorus donors [26], compounds with leaving groups other than chlorido ligands [27]. However, it is necessary to emphasize that none of the trans Pt(II) and Pt(IV) complexes have been officially registered as anticancer drugs so far.…”

“…Thus, typical platinum anticancer complexes have the general formula cis -[Pt(NHR 1 R 2 ) 2 X 2 ], in which R 1 and R 2 are organic moieties and X is a leaving group, usually a monovalent and biologically acceptable ion such as chlorido, nitrato or carboxylato ligands [ 7 ]. Although these findings can still be useful in the development of new platinum complexes with anticancer properties, starting in the early 1990s, numerous compounds have broken the rules mentioned above and have been synthesized and biologically tested with promising results [ 1 , 8 , 9 , 10 , 11 , 12 ]. Several classes of such non-classical (or non-conventional) platinum drugs can be distinguished, including trans platinum(II) analogs [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], Pt(IV) derivatives [ 21 , 22 ] polynuclear Pt complexes [ 23 , 24 ], Pt complexes with N -heterocyclic ligands [ 25 ], N -heterocyclic carbenes and cyclometallated Pt complexes [ 8 ], Pt(II) compounds with sulfur and phosphorus donors [ 26 ], compounds with leaving groups other than chlorido ligands [ 27 ].…”

Synthesis and Characterization of Pt(II) Complexes with Pyridyl Ligands: Elongated Octahedral Ion Pairs and Other Factors Influencing1H NMR Spectra

“…9,11,12,18 We propose that, whereas bulky ligands have been reported to decrease activity of cis bifunctional Pt(II) agents, bulky ligands are needed to allow trans bifunctional as well as monofunctional Pt(II) agents to form DNA adducts in which the DNA structure is distorted in such a way as to lead to cancer cell cytotoxicity. 19−22 Because evidence exists that trans-[PtL 2 Cl 2 ] complexes with L = 4-substituted pyridyl ligands (4-Xpy) exhibit cancer cell cytotoxicity, 16,17 we believe that 4-Xpy ligands have sufficient bulk to cause DNA distortions necessary for anticancer activity. Thus, we initiated an investigation of the preparation of trans-[Pt II (4-Xpy) 2 Cl 2 ] complexes containing strongly coordinating pyridyl ligands such as 4-piperidinopyridine (4-(CH 2 ) 5 Npy, Figure 1).…”

“…Cisplatin, cis -[Pt­(NH 3 ) 2 Cl 2 ], is one of the most effective chemotherapeutic agents being used in clinical therapy. , Many closely related cis bifunctional analogues of cisplatin also show good anticancer activity. ,− In contrast, the inactivity of the trans -[Pt­(NH 3 ) 2 Cl 2 ] isomer has led to a presumption that trans compounds are inactive. − Historically, trans -[PtL 2 Cl 2 ] complexes have been neglected. In recent years, however, several types of platinum compounds with trans geometry have shown promising in vitro activity against several cancer cell lines, including some that are resistant to cisplatin. − ,− Among the recently studied trans platinum complexes, the iminoether complex trans -[Pt­( E -HNC­(OCH 3 )­CH 3 ) 2 Cl 2 ] has been studied most intensively and has demonstrated significant activity against several cisplatin-resistant tumor cell lines. ,,, We propose that, whereas bulky ligands have been reported to decrease activity of cis bifunctional Pt­(II) agents, bulky ligands are needed to allow trans bifunctional as well as monofunctional Pt­(II) agents to form DNA adducts in which the DNA structure is distorted in such a way as to lead to cancer cell cytotoxicity. − …”