Syntheses, crystal structure and cytotoxicity of diamine platinum(II) complexes containing maltol

doi:10.1016/j.jinorgbio.2005.06.003

Journal of Inorganic Biochemistry

Volume 99, Issue 8, August 2005, Pages 1738-1743

https://doi.org/10.1016/j.jinorgbio.2005.06.003 Get rights and content

Abstract

The cationic complexes (1,2-diaminoethane)(maltolato)platinum(II) ([Pt(en)(ma)]⁺) and (1R,2R-1,2-diaminocyclohexane)(maltolato)platinum(II) ([Pt(R,R-DACH)(ma)]⁺) have been prepared and the structure of [Pt(R,R-DACH)(ma)]NO₃ has been determined by single crystal X-ray diffraction. The geometry of the metal in [Pt(R,R-DACH)(ma)]NO₃ is essentially square planar and the maltolate ligand has a geometry similar to other chelate complexes involving this ligand. The cytotoxicities of the compounds have been assessed in the human cell lines HeLa and K562 and the IC₅₀ values are approximately 32 μM in HeLa cells and 26 μM in K562 cells. In these cell lines the cytotoxicity of cisplatin is higher than the maltolate complexes by a factor of 2 to 3 whereas the cytotoxicity of carboplatin is lower than the maltolate complexes.

Introduction

In a series of recent reports [1], [2] we have described the chemistry and biological properties of a set of DNA targeted platinum complexes 1 (Fig. 1) in which the (1,2-diaminoethane)platinum(II) moiety is tethered to the acridine-4-carboxamide chromophore. These complexes have emerged as clear candidates for further development because they show promising activity against cisplatin resistant cell lines and most significantly a different DNA sequence specificity [3] to that of cisplatin. These compounds are of limited aqueous solubility and overcoming this deficiency is an important practical objective if these compounds are to be exploited as useful drugs. One way of doing this is to adopt the widely used approach of replacing the chloride leaving groups with chelating oxygen donors. This strategy has, for example, led to the development of the neutral compounds such carboplatin 2, oxaliplatin 3, nedaplatin 4 and the cationic complex TRK-710 5 [4]. A further suitable ligand for use as an oxygen-based chelate would be 3-hydroxy-2-methyl-4-pyrone (Maltol) 6. The maltolato anion has been shown to function as a bidentate chelate with a wide range of metal ions and the bis(maltolato)oxovanadium(IV) complex BMOV shows promise as a therapeutic agent for the treatment of type 2 diabetes mellitus [5].

As a prelude to incorporation of the maltolate anion in the acridine systems 1 we were motivated to carry out model studies with simpler diamine platinum complexes. If the maltolate anion is to be useful as the leaving group in the acridine complexes 1 it first needs to be established that: (i) the synthesis of maltolato platinum(II) complexes may be carried out in a straightforward manner, (ii) maltolato complexes are far more soluble than their dichloro analogues, and, (iii) mixed ligand platinum(II) diamine maltolato complexes are cytotoxic. There has been one report in the patent literature [6] on a cytotoxic compound formulated as [Pt(trans-1,2-diaminocyclohexane)maltolato)]OH although in this case little detail was provided on the synthesis and characterisation of the material.

With these objectives in mind we describe in this report the synthesis and spectral characterisation of the cationic complexes (1,2-diaminoethane)(maltolato)platinum(II) ([Pt(en)(ma)]⁺) (7) and (1R,2R-1,2-diaminocyclohexane)(maltolato)platinum(II) ([Pt(R,R-DACH)(ma)]⁺) (8) and the crystal structure of [Pt(R,R-DACH)(ma)]NO₃. As well, we present the results of our cytotoxicity studies on these complexes and compare their behaviour with that of cisplatin and carboplatin.

Section snippets

Chemistry

Electrospray ionization-mass spectrometry (ESI-MS) spectra were recorded on a quadrupole ion trap Finnigan-MAT LCQ mass spectrometer equipped with electrospray ionisazation (ESI). Infra-red spectra were recorded on a BIO-RAD FT-IR spectrometer. NMR spectra were obtained on a Varian Unityplus 400 spectrometer at 400 MHz for ¹H spectra and 85 MHz for ¹⁹⁵Pt spectra. Sodium trimethylsilylpropanesulfonate was used as the standard for ¹H NMR in D₂O. ¹⁹⁵Pt spectra were externally referenced to potassium

Chemistry

The complexes 7 and 8 were prepared by starting with the complexes Pt(en)I₂ and Pt(R,R-DACH)I₂, respectively, then removing the halogen as AgI to yield the corresponding diaqua complexes. The water ligands were then substituted by the maltolate anion, the formation of which was facilitated by the addition of about one equivalent of base along with maltol to the reaction mixture. Both complexes were isolated as nitrate salts. In the case of the DACH complex, sodium hydroxide was used as the

Conclusions

The information we have collected indicates that the synthesis of mixed ligand diamine maltolato platinum (II) complexes is relatively straightforward. The complexes 7 and 8 show good aqueous solubility and in the cell lines we have examined their cytotoxicities lie between cisplatin and carboplatin. As a result, the maltolate anion is an excellent candidate for incorporation as the leaving group in DNA targeted complexes such as the acridrine systems 1. The targeted acridine complexes 1 [3]

Acknowledgement

Support of this work by The National Health and Medical Research Council (W.D. Mc F., V.M., W.A.D.) is gratefully acknowledged.

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Syntheses, crystal structure and cytotoxicity of diamine platinum(II) complexes containing maltol

Abstract

Introduction

Section snippets

Chemistry

Chemistry

Conclusions

Acknowledgement

J. Inorg. Biochem.

J. Inorg. Biochem.

J. Inorg. Biochem.

Inorg. Chim. Acta

Polyhedron

Anti-Cancer Drug Des.

Biochemistry

Chem. Rev.