Preparation and Crystal Structure of a Platinum(II) Complex of [CH2N(CH2COOH)CH2CONH2]2, the Hydrolysis Product of an Anti-Tumour Bis(3,5-Dioxopiperazin-1-YL)Alkane

The synthesis and crystal and molecular structures of the platinum(II) complex Pt(HL)Cl where H2L is the diacid diamide –[CH2N(CH2COOH)CH2CONH2]2, a hydrolytic metabolite of an antitumour active bis(3,5-dioxopiperazin-1-yl)alkane are reported. The complex is square planar and contains HL– as a tridentate 2N (amino), O (carboxylate) donor. The metal to ligand bond distances are Pt-Cl 2.287(1) Å, Pt-O 2.002 (1) Å, Pt-Ntrans Cl 2.014(1) Å and Pt-Ntrans O 2.073 Å. There is extensive hydrogen bonding, each molecule of Pt(HL)Cl being intermolecularly hydrogen bonded to ten others giving a 3-dimensional network. There is also one intramolecular H-bond.


Introduction
The bis(3,5-dioxopiperazin-l-yl)alkanes (i) are a family of antitumour drugs of which the propane derivative is the most effective and is marketed under the name Razoxane, R Me. [1][2][3] These drugs were synthesised in the expectation that they would enter cells and then undergo intracellular hydrolytic metabolism to chelating agents which would interfere with metalloenzymes essential for tumour cell growth. There are a number of possible hydrolytic metabolites one of which is the bis-acid, bis-amide, H2NOCCH2(HOOCCH2)NCH2CH(R)N(CH2COOH)CH2CONH2, H2L.
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Preparation and Crystal Structure of a Platinum(11) Complex of [-CH2N(CH2COOH)CH2CONH2J2, the Hydrolysis Product of an Anti.TumourBis (3,5.Dioxopiperazin-1-yl)Alkane We decided to synthesise platinum(If) complexes of ligands of this type for testing as antitumour agents and in this paper report on the preparation, properties and crystal structure of Pt(HL)CI, where R H. o,, /C-CH2\ / k/CH2-C\ The ligand H2L, N,N'-dicarboxamidomethyl-N,N'-dicarboxymethyl-1,2-diaminoethane, was prepared by a literature reported method for similar compounds, 4 as follows.
1.2-Bis(3,5-dioxopiperazin-l-yl)ethane (20.0 g, 79 mmol),5 and copper(II) acetate monohydrate (15.0 g, 75 mmol) in water (20 cm3) were stirred together at room temperature for 2 days to give a blue solution which was then heated under reflux for 4 hours. The solution was evaporated under reduced pressure until 10 cm3 remained and this on standing at room temperature gave a blue crystalline complex. This was collected by suction filtration and dried at room temperature. The product (17.5 g, 50 mmol) which is the copper(II) complex of the title ligand, was dissolved in hot water (250 cm3) and acetic acid (5.00 cm3) was added to the solution which was then saturated with hydrogen sulphide. The precipitated cupric sulphide was removed by gravity filtration. The filtrate was passed through a column containing Kieselguhr and evaporated under reduced pressure to give a yellow oil. The oil was triturated and twice reerystallised from aqueous methanol-isopropanol to give H2L as a colourless solid. Yield 9.9 g (34.1 mmol), 69% from the copper(II) complex, m.p. 168 C (dec). Spectroscopy IR spectra were recorded as Nujol mulls between NaC1 plates on a Philips PU 9714 spectrophotometer and UV-VIS spectra were recorded on a Philips 89730 UV/VIS scanning spectrophotometer.

X-ray Crystallography
A rectangular shaped crystal measuring 0.32 x 0.25 x 0.33 mm was selected and used for data collection, the results of which are summarised in Table 1. X-ray data were obtained on an Enraf-Nonius CAD4F diffractometer using monochromated MoKa radiation Z.= 0.7093 A,. The structure was solved by direct methods, SHELX 86, 6 and refined by full matrix least squares using SHELX 76.7 Data were corrected for Lorentz and polarization effects and for absorption.8 Hydrogen atoms were included in calculated positions with fixed thermal parameters on the methylene carbon atoms only. The non-hydrogen atoms were refined anisotropically. The atomic scattering factors for non-hydrogen and hydrogen atoms and the anomalous dispersion correction factors for non-hydrogen atoms were taken from the literature. [9][10][11] All calculations were performed on a VAX 6610 computer. The ORTEP program was used to obtain the drawings. 12

Results and Discussion
The addition of a solution K2[PtCI4] to a solution of H2L produced crystals of the complex Pt(HL)C1, the crystal and molecular structure of which shows that the geometry around the metal is approximately square planar and that HL is present as a tridentate 2N (amine), O (carboxylate) ligand. The IR spectrum of the complex in the C=O stretching region shows bands at 1730 em -1 (unionized COOH group), 1670 cm -1 (amide I band) and 1630 cm -1 (coordinated COO-). 13 The UV spectrum of an aqueous solution of the complex shows bands at 350 (15.3), 24.6 (93) and 230 (344) nm with e values in din3 mol-1 em-1 given in parenthesis. COO-. Since the nitrogen atoms are very similar, both being tertiary and both attached to three CH2 groups the difference in bond distances may be partly due to the higher trans influence of COOrelative to CIand also to the fact that the N trans to CIis part of two chelate rings while the other N is involved in only one such ring. The molecular structure of Pt(HL)C1 shows that there is extensive hydrogen bonding, each molecule being involved in intermolecular hydrogen bonds to ten other molecules, giving rise to a 3-dimensional network. In Fig 2 is shown a typical molecule viewed down the x-axis and for clarity shows its contacts with only 8 other molecules. The remaining two contacted molecules lie above and below the plane. There is one intramolecular hydrogen bond formed between N(2) and 0(6) which has a distance of 3.086 A,. The hydrogen bonds distances are shown in the Table 3.  (6) Pt (1) The fractional atomic coordinates for the non-hydrogen atoms are listed in Table 4. Additional material available from the Cambridge Crystallographic data centre includes a full listing of the remaining bond angles, H-atom coordinates and thermal parameters.