Platinum(II) Iodido Complexes of 7-Azaindoles with Significant Antiproliferative Effects: An Old Story Revisited with Unexpected Outcomes

Abstract

A series of platinum(II) diiodido complexes containing 7-azaindole derivatives, having the general formula cis-[PtI2(naza)2] (1–8), has been prepared and thoroughly characterized, including X-ray structure analysis of cis-[PtI2(2Me4Claza)2]∙DMF (8∙DMF; 2Me4Claza = 2-methyl-4-chloro-7-azaindole). Complexes showed high in vitro cytotoxicity against nine human cancer cell lines (IC50 ranging from 0.4 to 12.8 μM), including the cisplatin-resistant ovarian cancer cell line (A2780R; IC50 = 1.0–3.5 μM). The results of in vivo testing, using the L1210 lymphocytic leukaemia model, at the equimolar doses of Pt with cisplatin (2 mg/kg) confirmed the activity of complex 8 comparable to cisplatin. From the mechanistic point of view, evaluated ex vivo by Western blot analyses on the samples of isolated tumour tissues, the treatment of the animals with complex 8, contrary to cisplatin, decreased the levels of tumour suppressor p53 and increased significantly the amount of intracellular anti-apoptotic protein MCL-1L (37 kDa). Additionally, the active form of caspase 3 was significantly elevated in the sample of tumour tissues treated with complex 8, indicating that the activation of p53-independent cell-death pathway was initiated. The light and electron microscopy observations of the cancerous tissues revealed necrosis as a dominant mechanism of cell death, followed by scarce signs of apoptosis. The additional results (e.g. in vitro interaction experiments with selected biomolecules, cell cycle perturbations, gel electrophoretic studies on pUC19 plasmid DNA) supported the hypothesis that the complexes might be involved in the mechanism of action quite different from cisplatin.

New Findings in the Signaling Pathways of cis and trans Platinum Iodido Complexes’ Interaction with DNA of Cancer Cells

“…4 Another example is the work performed by Dvořák et al., varying the amine ligand and substituting for bulkier azaindoles. 5 They studied the cytotoxic activity of iodide azaindole complexes and looked at the molecular level mechanism to find a decrease of tumor suppressor p53 amount, which can agree with our previous observations with the aliphatic amine iodido compounds. 6…”

Novel cis‐Pt(II) Complexes with Alkylpyrazole Ligands: Synthesis, Characterization, and Unusual Mode of Anticancer Action

“…Cis-Pt(II) iodido complexes have long been predominantly used as intermediates in synthesizing target platinum chlorides and carboxylates, particularly by the Dhara method or its modifications [17,18]. However, later several studies have shown that the iodido ligand may have unique chemical, physical, and biological properties, with a mechanism of action different from that of Pt(II) chlorido analogs [19][20][21][22]. For example, cis-Pt(II) diiodides containing 7-azaindole and its derivatives were significantly more active than cisplatin in several cancer cell lines [19].…”

“…However, later several studies have shown that the iodido ligand may have unique chemical, physical, and biological properties, with a mechanism of action different from that of Pt(II) chlorido analogs [19][20][21][22]. For example, cis-Pt(II) diiodides containing 7-azaindole and its derivatives were significantly more active than cisplatin in several cancer cell lines [19].…”

Synthesis, Reactivity Studies, and Cytotoxicity of Two trans-Iodidoplatinum(II) Complexes. Does Photoactivation Work?

“…Morevoer, these last trans series seemed to be affected by the size of the amine ligands showing differences in their reactivity versus S-donor models and in their cytotoxicity [6]. The reconsideration of these iodido derivatives have shown a great impact in the field, and the trend and behavior of these complexes is being reevaluated [7].…”