Elsevier

Inorganica Chimica Acta

Volume 339, 15 November 2002, Pages 525-531
Inorganica Chimica Acta

Synthesis and characterization of new cis-[PtCl2(isopropylamine)(amine′)] compounds: cytotoxic activity and reactions with 5′-GMP compared with their trans-platinum isomers

In honor of the 65th birthday of Professor Helmut Sigel
https://doi.org/10.1016/S0020-1693(02)01050-2Get rights and content

Abstract

The synthesis and characterization of four new cis-platinum compounds of structural formula cis-[PtCl2(NH2CH(CH3)2)(amine′)] (amine′=methylamine, dimethylamine, propylamine and butylamine) (2a2d) are described. Cytotoxicity tests in tumor cell lines sensitive to cisplatin (CH1 and Pam 212) and resistant to cisplatin (CH1cisR, and Pam 212-ras) indicate that only compound 2a possesses cytotoxic activity in the cisplatin-sensitive cell line CH1, albeit much less than cis-DDP and also less than corresponding trans-platinum compounds with mixed aliphatic amines. The interactions of cis- (2a2d) and trans- (3a3d) [PtCl2(NH2CH(CH3)2)(amine′)] compounds with 5′-GMP in dilute NaClO4 (10 mM) were investigated by 1H NMR spectroscopy, and the progress of the reactions was followed overnight. In all cases two product peaks are observed in the cis-complexes, because the compounds are not symmetric. Temperature-dependent studies have been performed, but no significant variation in product structure is observed.

A comparison of cis-, and trans-[PtCl2(isopropylamine)(amine′)] compounds, where amine′ is an aliphatic amine, is made in this paper. The results of cytotoxicity tests in tumor cell lines sensitive to and resistant to cisplatin, show that trans-Pt(II) complexes are more cytotoxic than their cis isomers. The interaction of the compounds with 5′-GMP was studied by 1H NMR spectroscopy.

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Introduction

cis-Diamminedichloroplatinum(II), generally referred to as cisplatin, or cis-DDP, was chemically described as early as 1844 by Peyrone [1], but the anticancer properties of cis-DDP were discovered only 35 years ago by Rosenberg [2]. Early structure–activity studies showed that a cis configuration of the two leaving groups is essential for antitumor activity of simple Pt(II) derivatives and has later been confirmed for several groups of compounds [3], [4]. Thus, cis-DDP is endowed with cytotoxic properties, while its trans analogue (trans-DDP) does not show activity [5], [6].

However, several classes of Pt(II) complexes, that violate this structure–activity rule, have been reported in the last decade, examples being: (i) trans-PtCl2(L)(L′) with L and L′ are planar heterocyclic ligands [7], [8], (ii) dinuclear compounds of the type [trans-{PtCl(NH3)2}2{μ-NH2-(CH2)n-NH2}]2+ (with n=2–6), or trinuclear complexes containing two trans-PtCl(NH3)2 units linked by a NH2(CH2)6NH2-(trans-Pt(NH3)2-)NH2(CH2)6-NH2 diamine chain [9], [10], [11], [12], designated as BBR3464, (iii) trans-PtCl2 complexes with imino ether ligands as inert groups [13], [14], [15], [16], and (iv) trans-[PtCl2(amine′)(isopropylamine)], where (amine′) may be dimethylamine, methylamine, propylamine, or butylamine [17], [18].

We recently reported that several trans-platinum(II) compounds with mixed aliphatic amines exhibit remarkable cytotoxic activity against tumor cell lines, both sensitive and resistant to cisplatin [17]. Because of these interesting biological properties, it was decided to compare the cytotoxicity of the trans-Pt(II) compounds with that of their corresponding cis analogues [19]. Thus, we have synthesized and characterized several cis-Pt(II) complexes of general formula cis-[PtCl2(NH2CH(CH3)2)(amine′)], where the unchanged amine is isopropylamine and amine′ can be either dimethylamine, propylamine, butylamine, or methylamine. The results reported in this paper show that the compounds of formula cis-[PtCl2(NH2CH(CH3)2)(methylamine)] (2a), cis-[PtCl2(NH2CH(CH3)2)(dimethylamine)] (2b), cis-[PtCl2(NH2CH(CH3)2)(propylamine)] (2c) and cis-[PtCl2(NH2CH(CH3)2)(butylamine)] (2d), show a lower cytotoxic activity than both cisplatin and their corresponding trans isomers.

The consensus of opinion is that genomic DNA is the primary pharmacological target of cisplatin and related analogues [20], [21]. In addition, it is also generally accepted that the cytotoxic activity of platinum complexes may be a consequence of the formation of DNA adducts. Although, cisplatin may form several types of DNA adducts, the 1,2-d(GG) intrastrand cross-link is the major one and therefore has been considered as the main DNA lesion responsible for the biochemical mechanism of cytotoxic activity of the drug [20], [21], [22], [23]. The N7 atom of guanine in the major groove has been described as the most electronegative site in double-stranded DNA [24] and has been the most reactive site toward the positively-charged, aquated cisplatin intermediates. In order to shed light on the differences observed in cytotoxic activity between the cis- and trans-[PtCl2(amine)(amine′)] complexes, we have compared the kinetics of formation of the reaction products of these compounds with 5′-GMP. The Pt binding to 5′-GMP has been studied by proton nuclear magnetic resonance in dilute solution, using a fourfold excess of GMP. With this technique the Pt–GMP interaction can be followed, because it is possible to observe simultaneously the formation and disappearance of several platinum–GMP species. The chemical shift of the H(8) proton of GMP fortunately is very sensitive to the geometry and the composition of the complex [25], [26], [27] and is a very useful signal to monitor. To mimic biological conditions, experiments were performed in neutral aqueous solutions. Rather low concentrations of the reactants were used to allow ready dissolution of the platinum chloride compounds. These condition also prevent the polymerization reactions and precipitation, as found earlier [25] in more concentrated solutions.

Section snippets

Infrared spectroscopy

Infrared spectra have been recorded in Nujol mulls and KBr pellets in the 4000–200 cm−1 region using a Perkin–Elmer model 283 spectrophotometer.

Elemental analysis

The microanalytical laboratory of the SIDI (Universidad Autónoma de Madrid, Spain) performed C, H, and N determinations, using a Carlo Erba Strumentazione element analyzer (Model 1106).

NMR measurements

1H spectra were recorded on a Bruker DPX-300 spectrometer operating at a frequency of 300 MHz. 13C spectra were recorded on a Bruker DPX-300 spectrometer operating at a

Synthesis and characterization of the cis-[PtCl2(NH2CH(CH3)2)(amine′)] compounds

The synthesis takes place in four steps as it is seen in Scheme 1 [28], [29]. Preparation of the cis-Pt(II) compounds involves obtaining the iodine-bridged dimer with isopropylamine and the subsequent breaking of the bridge with the different aliphatic amines [28]. Elemental analysis, infrared spectra and 1H, 13C and 195Pt NMR spectra confirm with the compound structures. The microanalytical data are consistent with the empirical formulas C4H14N2PtCl2 (2a), C5H16N2PtCl2 (2b), C6H18N2PtCl2 (2c),

Concluding remarks

The results described and discussed above have clearly shown that both cis- and trans-isomers of complexes of general formula PtCl2(L1)(L2) with L1=isopropylamine and L2=another secondary amine, do react with comparable rates with 5′GMP. On the other hand, the antitumor activity of the cis isomers is significantly lower than that of the trans isomers.

Further studies with other N-donor ligands L1 and L2 should prove whether or not this observation has a more general value.

Acknowledgements

This work was supported by the Spanish CICYT (Grant No. SAF00-0029) and European COST Actions D20/0001/00 and D20/0003/00. A training grant from the EU (Medicinor) under contract (HPMT-CT-2000-00192) is highly appreciated. We thank Johnson & Matthey for a loan scheme of K2PtCl4.

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    EU Training fellow at Leiden University, 2001–2002.

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