Synthesis of (N,N'-Bis(2-Hydroxyethyl)Ethane-1,2-Diamine)Malonatoplatinum(II) and X-Ray Crystal Structure of the Cis-R,S-Isomer

Hydroxyethyl substituted amineplatinum(II) and (IV) complexes are an interesting class of platinum based antitumour compounds due to their uncoordinated hydroxy groups. These hydroxy groups could play an important role in the mode of action of such complexes with respect to their ability to act as donor or acceptor for hydrogen bonds. Moreover, their chemistry in solution is of interest because it was found that there is the possibility of an intramolecular attack to form ethanolatoamine chelated species which are responsible for very stable monoadducts with 5'-GMP. Furthermore, there is the possibility of derivatisation at the OH site to form a new series of platinum compounds which may be used for a carrier mediated transport to tumour tissues. In this context a series of (N,N'-bis(2-hydroxyethyl)ethane-l,2-diamine)-platinum(II) complexes has been synthesised. During purification of one of the platinum based compounds, it was possible to isolate (SP-4-3)-R,S-(N,N'-bis(2-hydroxyethyl)ethane-l,2-diamine)malonatoplatinum(ll) and to resolve the structure by single crystal structure analysis. Intra- and intermolecular hydrogen bonds have been found which may explain the spontaneous crystallisation of the cis-R,S isomer and the stabilisation of the boat conformation of the malonatoplatinum(II) six-membered ring.


INTRODUCTION
Since the discovery of cisplatin, (NH3)2PtCI2 t'2j, as anticancer drug and its subsequent worldwide clinical application for the treatment of different types of tumoursE31, the synthesis and investigation of platinum compounds have become of interest. DNA is assumed to be the major target of a platinum based chemotherapyt41. After DNA platination (clear preference for N7 of guanine) replication and transcription are inhibited and apoptosis is induced. The application of cisplatin in therapy is limited by a variety of side effects including dose dependent nephrotoxicityESI. During the last decades, different strategies have been used to develop new platinum based anticancer compounds. Central points are reduction of toxicity and side effects, to increase the activity spectrum and to circumvent acquired cisplatin resistance of cells [6'7'8'9]. Therefore, thousands of platinum compounds have been synthesised and tested with respect to their anticancer activity. Nearly 30 entered clinical trials, but only carboplatin achieved worldwide approval and use. Based on a more detailed understanding of the mode of action of cisplatin and analogues, a rational drug design has started resulting in new platinum compounds and complexes which even violate the structure activity relationship" orally administrable platinum(IV) compounds, di-and trinuclear complexes, sterically hindered Pt coordination compounds, trans complexes and complexes with three nitrogen ligands.
In this context, we have synthesised mono-and bis(hydroxyethyl)substituted dianaineplatintm(ll/IV) I''-'l complexes which can be used for further derivatisation at the OH-group with respect to a carrier mediated transport of the cytotoxic moiety. Furthermore, the complexes themselves are very interesting because of their hydroxy-groups as a potential acceptor and/or donor for hydrogen bonds which could play an important role in the binding of platinum complexes to DNA. In addition, such complexes recently have shown an interesting behaviour in solution which resulted in very stable monoadducts with 5'-GMP ..41.

Chemicals
All chemicals obtained from commercial suppliers were used as received and were of analytical grade. Water was used bidistilled. The synthetic procedures were carried out in a light protected environment. B.K. Keppler et al.
Synthesis of (N,N'-Bi(2-Hydroxyethyl)Ethane-1,2-Diamine) Malonatoplatinum(II) and X-ray Crystal Structure of the Cis-R, S-Isomer NMR Spectra tH-, 13Cand 2D NMR experiments were performed at 400.13 MHz (1H) and 100.61 MHz (13C) on a Bruker DPX 400 spectrometer (UltraShield TM Magnet) at 24C. The gradient selected 1H,Hand 13C,H shift correlation experiments were performed using standard Bruker pulse programs. X-Ray Structure Determination The single crystal data were collected on a Nonius Kappa CCD diffractometer at room temperature. The measured intensities were corrected for Lorentzand polarisation effects. The crystal structure was determined by direct methods (SHELXS-97, Sheldrick, 1997a) [15] and subsequent Fourier and difference Fourier syntheses. Final structure parameters of the compound were obtained by full-matrix least squares techniques on F (SHELXL-97, Sheldrick, 1997b) [161. X-ray structure analysis data are given in Table I. Crystallographic data for the structure reported in this paper flare been deposited with the Cambridge Crystallographic Data Center as supplementary publication no. CCDC 155444 [171.

Preparation of Platinum Complexes
The synthesis of the title compound (N,N'-bis(2-hydroxyethyl)ethane-l,2-diamine)malonatoplatinum(II) (Scheme 1) starts from potassium tetrachloroplatinate(II)and N,N'-bis(2-hydroxyethyl)ethane-l,2-diamine. After activation of the resulting platinum(II) complex with silver sulfate, the aquasulfato species was then reacted with the in situ formed sodium salt of malonic acid. After addition of acetone and filtration the solution was left at 4C to crystallize. Dichloro(N,N'-bis(2-hydroxyethyl)ethane-l,2-diamine)platinum(II). A solution of N,N'-bis(2-hydroxyethyl)ethane-l,2-diamine (1.7916 g, 12.09 mmol) in 60 ml of ethanol was treated with K_PtCI4 (5.0176 g, 12.09 mmol). After addition of 115 ml of bidistilled water the pH was adjusted to 7 using diluted hydrochloric acid and stirred at room temperature. The precipitates were collected over a period of 20 hours.
During this time the pH was kept constant at 7 using diluted NaOH. The yellow precipitates were washed with water and dried over P4Ol0. Anal    On the other hand the spontaneous crystallisation of the cis-R,S isomer could be explained by the intra-and intermolecular hydrogen bonds as possible driving force. Moreover, a nearly linear arrangement of C3-H3 04 could be found with an angle of 172.17. The distance between C3 and 04 is found to be 3.532(8) A which is not in the range of C-H O hydrogen bonds (donor acceptor contacts around 3.2 A) but may indicate a very weak attractive interaction further stabilising the structure of found in the crystal.