The synthesis, spectroscopic, X-ray characterization and in vitro cytotoxic testing results of activity of five new trans-platinum(IV) complexes with functionalized pyridines

Abstract

Platinum(IV) complexes with general formulas [Pt(L¹⁻²)₂Cl₄], where L¹⁻² are 3-acetylpyridine (1) and 4-acetylpyridine (2) respectively, and [Pt(HL³⁻⁵)₂Cl₂], where H₂L³⁻⁵ are 2,3-pyridinedicarboxylic acid (3), 2,4-pyridinedicarboxylic acid (4) and 2,5-pyridinedicarboxylic acid (5) respectively, were prepared by the reaction of K₂[PtCl₆] with the corresponding ligand in 1:2 M ratio in water. The complexes were characterized by elemental analysis and IR and NMR spectroscopy. The structures of complexes 2 and 5 were determined by X-ray crystallography, which revealed the trans orientation of chloride anions around platinum(IV) in the case of both complexes. The antiproliferative activity was investigated in six tumor cell lines (human cervical carcinoma cells (HeLa), murine melanoma cells (B16), human breast carcinoma cells (MDA-MB-453), human colon carcinoma cells (LS-174), transformed human umbilical vein endothelial cells (EA.hy 926) and murine endothelial cells (MS1)) and in one non-tumor cell line-human fetal lung fibroblast cells (MRC-5). Cytotoxicity studies indicated that Pt(IV) complexes with acetyl-substituted pyridine ligands exhibit significantly higher in vitro antiproliferative activity than the complexes with carboxylato-substituted pyridines. Complexes 1 and 2 showed antiproliferative activity in all tested tumor cell lines, with the highest potential in human endothelial cells EA.hy 926, since they had IC₅₀ values of 13.8 ± 5.8 μM and 23.4 ± 3.3 μM, respectively and were more active than cisplatin. Complexes 1 and 2 exhibited lower toxicity against the non-tumor human lung fibroblast cell line (MRC-5) than against most of the tested tumor cell lines.

Introduction

The platinum-based anticancer complexes play a major role in the medical treatment of cancer, since approximately 50% of all anticancer treatments are based on platinum compounds [1], [2], [3]. Unfortunately, treating patients with platinum chemotherapy causes some clinical inconveniences such as severe side effects, acquired or intrinsic resistance of cancer cells and limited therapeutic potential against widespread tumors [3], [4]. Platinum(IV) complexes [5], [6] qualify as very promising candidates among other potential inorganic chemotherapeutics. One of them is satraplatin, an orally active platinum(IV) complex which has recently been abandoned in advanced phase III of clinical trials for the treatment of hormone-refractory prostate cancer [7]. Nevertheless, the main advantages of platinum(IV) over platinum(II) are the octahedral geometry which introduces two axial ligand sites and kinetic inertness which lowers reactivity and offers the possibility of functionalization of peripheral groups. In addition, trans-platinum complexes were not given much attention for many years, since cis geometry was considered to be a necessary requirement for antitumor activity [8], [9]. Interestingly, a significant number of trans-complexes which demonstrated similar cytotoxicity as the corresponding cis-complexes disproved that previously accepted opinion [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22].

There are several pyridine derivatives which have various pharmacological activities. 2,4-pyridinedicarboxylic acid has immuno-suppressive and fibro-suppressive properties [23] and is capable of protecting certain enzymes from heat inactivation [24], [25]. A literature survey showed that, depending on the position of the substituent, 2,4- and 2,5-pyridinedicarboxylic acids were found to inhibit or activate some metalloenzymes [26]. Since the role of pyridinedicarboxylic acids in these processes is not well-understood, the study of their coordination chemistry toward biologically relevant metal ions is of particular interest.

Prompted by these reports and continuing our search for bioactive metal drugs [27], [28], [29], it seemed worthwhile to synthesize novel Pt(IV) complexes with functionalized pyridines. We herein report the synthesis, spectroscopic, X-ray characterization and in vitro cytotoxic testing results of [Pt(L¹⁻²)₂Cl₄], where L¹⁻² are 3-acetylpyridine (1) and 4-acetylpyridine (2) respectively, and [Pt(HL³⁻⁵)₂Cl₂], where H₂L³⁻⁵ are 2,3-pyridinedicarboxylic acid (3), 2,4-pyridinedicarboxylic acid (4) and 2,5-pyridinedicarboxylic acid (5) respectively.