Elsevier

Journal of Inorganic Biochemistry

Volume 138, September 2014, Pages 89-98
Journal of Inorganic Biochemistry

Mono and dinuclear phosphinegold(I) sulfanylcarboxylates: Influence of nuclearity and substitution of PPh3 for PEt3 on cytotoxicity

https://doi.org/10.1016/j.jinorgbio.2014.05.010Get rights and content

Abstract

Gold complexes of the type [Au(PEt3)(Hxspa)] were prepared by reacting triethylphosphinegold(I) chloride in ethanol/water (8:1) with the 3-(aryl)-2-sulfanylpropenoic acids H2xspa [x = p = 3-phenyl-; f = 3-(2-furyl)-; t = 3-(2-thienyl)-; py = 3-(2-pyridyl); Clp = 3-(2-Chlorophenyl)-; -o-mp = 3-(2-methoxyphenyl)-; -p-mp = 3-(4-methoxyphenyl)-; -o-hp = 3-(2-hydroxyphenyl)-; -p-hp = 3-(4-hydroxyphenyl)-; -diBr-o-hp = 3-(3,5-dibromo-2-hidroxyphenyl-); spa = 2-sulfanylpropenoato] or 2-cyclopentylidene-2-sulfanylacetic acid (H2cpa) and KOH in a 1:1:1 mole ratio. The compounds were characterized by IR spectroscopy and FAB mass spectrometry and by 1H, 13C and 31P NMR spectroscopy. The in vitro antitumor activity of these and of the previously described dinuclear [(AuPEt3)2(xspa)] complexes against the HeLa-229, A2780 and A2780cis cell lines was determined and compared with those of the analogous PPh3 complexes. The results show that the substitution of the PPh3 ligand by PEt3 is particularly effective in increasing the cytotoxicity of the dinuclear [(AuPR3)2(xspa)] complexes, giving rise to compounds that are significantly more active than cisplatin against the aforementioned cell lines. In addition, and as a preliminary test for nephrotoxicity, the cytotoxicity of the most active compounds against the normal renal LCC-PK1 cell line was evaluated and compared with that of cisplatin.

Graphical abstract

Mono and dinuclear phosphinegold(I) sulfanylcarboxylates: influence of nuclearity and substitution of PPh3 for PEt3 on cytotoxicity.

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Introduction

A considerable number of new metal-based therapeutic agents, including antitumoral ones, are being prepared and biologically tested [1]; the search for effective alternatives to the widely used platinum-based anticancer drugs [2], [3], [4] is a particularly interesting and active field [5]. Recent examples of homo- [6], [7] and heteronuclear [8], [9] compounds are indicative of this activity.

Another metal with a great deal of potential included in this field is gold, which has been present in medicine since ancient history [10]. Interest has been considerably focused on Au(III) compounds [11], [12], [13] due to its structural and electronic similarity to the widely used cisplatin and cisplatin-related antitumor drugs. On the other hand, Au(I) complexes also exhibit cytotoxic activity against cells from several tumor cell lines, some of which are resistant to cisplatin, [12], [13]. This ability can be due to the different electronic/structural properties of these complexes, which lead them to interact with other biological targets such as proteins [14], [15], [16], and the thioredoxin reductase is now considered to be the most relevant [17], [18], [19], [20], [21], [22], [23].

Auranofin, triethylphosphine(2,3,4,6-tetra-o-acetyl-β,1-D-thiopyranosato-S)gold(I) is a well known antiarthritic drug that also shows significant cytotoxic activity [13], [24]; it is an interesting example of a group of Au(I) thiolate compounds, which contain the S–Au–P fragment and have also attracted interest as potential antitumor agents [12], [13]. The replacement of the thiolate ligand by other biological ligands is presumed to modulate the biological activity of these compounds, [10], [25] and consequently it is attractive to explore the activity of members of this family in which the S–Au bond has been stabilized. This stabilization can be achieved by endowing the thiolate ligand with other groups that are also capable of binding to the metal.

On this basis we have drawn up a concise compilation in which structural modifications could be related to changes in the in vitro antitumoral activity; thus, we have selected a number of sulfanylcarboxylic acids, R-CH-C(SH)-COOH, H2xspa, and 2-cyclopentylidene-2-sulfanylacetic acid (H2cpa) in order to prepare gold(I) complexes which could also contain a phosphine ligand. The sulfanylcarboxylic ligands (Scheme 1) present a wide spectrum of R groups which can modulate the hydrophilicity/lipophilicity of the complexes, a property of great importance for drug action [10], [25], [26]. The possibility of intra/intermolecular interactions and their associated structural effects is yet another point of interest for the selection of these groups. We initially prepared compounds of the type [Au(PPh3)(Hxspa)] [27], which included an S–Au–P fragment, and maintained the COOH group protonated. These compounds were subsequently structurally modified by deprotonating this group; this was achieved by reacting them either with diisopropylamine or triethylamine, which affords compounds of the type [HQ][Au(PPh3)(xspa)] and [HP][Au(PPh3)(xspa)] (HQ = diisopropylammonium; HP = triethylammonium) [28] or with Au(PPh3)Cl, thus including a new AuPPh3 group to give dinuclear [(AuPPh3)2(xspa)] compounds [29]. In addition, we have incorporated the AgPPh3 fragment, thus preparing heteronuclear complexes containing Ag(I) and Au(I) centers [30], [31].

We now initiate the study of the effect that the substitution of the PPh3 phosphine can have on the cytotoxicity of the complexes. This paper describes the synthesis, characterization and the study of the cytotoxic activity of complexes of the type [Au(PEt3)(Hxspa)] against the human cervical carcinoma cell line HeLa-229 and the ovarian carcinoma cell line A2780 and its cisplatin-resistant mutant A2780cis. The activity of the previously described [(AuPEt3)2(xspa)] complexes [32] was also investigated and the results obtained for both types of complexes were comparatively analyzed and contrasted with those of the equivalent PPh3 complexes.

In an attempt to get information about possible adverse effects limiting the potential therapeutic utility of these compounds, a preliminary study of toxicity on normal cells was also carried out. Thus, some of the compounds showing the best activity against the A2780cis cell line were selected to be tested on the normal epithelial renal LLC-PK1 cell line.

Section snippets

Materials and methods

2-Chlorobenzaldehyde, 2-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 3,5-dibromo-2-hydroxybenzaldehyde, 2-furancarboxaldehyde, 2-thiophenecarboxaldehyde, 2-pyridinecarboxaldehyde, cyclopentanone (all from Aldrich), benzaldehyde (Probus), rhodanine (Aldrich) and triethylphosphinegold(I) chloride (Aldrich) were used as supplied. The 3-(aryl)-2-sulfanylpropenoic acids H2xspa [x = f = 3-(2-furyl)-; t = 3-(2-thienyl)-; p = 3-phenyl-; Clp = 3-(2-Chlorophenyl)-; -o-mp

Synthesis and characterization

The complexes of the type [Au(PEt3)(Hxspa)] (111) were prepared by adding Au(PEt3)Cl to a solution of the appropriate sulfanyl carboxylic acid and KOH (1:1:1 molar ratio) in ethanol/water. This solution was stirred for 1 h; after this time the solvent was evaporated and the resulting oil was dissolved in chloroform. Complexes 8, 9 and 10 were obtained as solids but in the other cases the evaporation of the chloroform again afforded oily products in high yields. These oils were also obtained in

Conclusions

In conclusion, the screening of the cytotoxic activity of the triethylphosphine complexes against the HeLa-229, A2780 and A2780cis cell lines reveals that the [(AuPEt3)2(xspa)] compounds are highly effective, particularly against the A2780cis line, showing a high ability to circumvent cellular resistance to cisplatin. These compounds are the most active of a series of gold(I) complexes prepared to correlate structure and activity. The series was initiated with compounds of the type R-CH-C(SAuPPh

Acknowledgments

We wish to thank the Dirección Xeral de I + D, Xunta de Galicia, Spain, for financial support (IN845B-2010/121) and the Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia, Spain, for a postdoctoral fellowship (I2C plan) to E.B.

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