Six novel platinum(II) intercalators of the form [Pt(AL)(IL)]Cl2, where AL = ethylenediamine (en), 1R,2R-diaminocyclohexane (R,R-dach), or 1S,2S-diaminocyclohexane (S,S-dach) and IL = 4,7-dihydroxy-1,10-phenanthroline (4,7-dhp) or 4,7-dicarboxy-1,10-phenanthroline (4,7-dcp), were synthesised. All complexes were prepared by the addition of the intercalating ligand followed by the addition of the diamine ancillary ligand. The complexes with 4,7-dhp were soluble in DMSO and were characterised by 1H, 13C, and 195Pt NMR, elemental analysis, UV-vis, ESI-MS, and CD. The complexes with 4,7-dcp were only soluble in a highly acidic solution and, therefore, were characterised only by 1H NMR and elemental analysis. The cytotoxicity of the 4,7-dhp complexes was tested in the L1210 murine leukaemia cell line. [Pt(S,S-dach)(4,7-dhp)]Cl2 showed an IC50 value of > 80 μM. The antitumour and antibacterial activities of all six complexes were tested in vitro using the Kirby-Bauer disc diffusion method with Staphylococcus aureus and Agrobacterium tumefaciens. The 4,7-dhp complexes showed no activity to these bacteria strains. The activities of the 4,7-dcp complexes were not able to be tested due to their solubility only in acidic solutions, which itself inhibits cell growth. The diffusion coefficients of the Pt(II) intercalators of the form [Pt(AL)(IL)]Cl2, where AL = en, R,R-dach, or S,S-dach and IL = phen, 4-mp, 4,7-dmp, 4,7-dhp, 4,7-dcp or 3,4,7,8-tmp and various starting materials used during the synthesis of these complexes were measured using pulsed gradient spin-echo (PGSE) NMR. The diffusion coefficients of both 4,7-dcp and [Pt(4,7-dcp)Cl2] were observed to be lower than other compounds with similar molecular weights indicating dimerisation of the compounds. The binding studies of the systems, [Pt(en)(phen)]Cl2 to (i) BSA, (ii) delipidated BSA, and (iii) d(GTCGAC)2 were studied using a simple two-site binding model with diffusion NMR. The binding of [Pt(en)(phen)]Cl2 – BSA was well described by the model giving the values Kd = 0.0021 ± 0.0002 M and n = 5.85 ± 0.31. On the contrary, the binding of [Pt(en)(phen)]Cl2 – delipidated BSA showed a poor fit to the model. From the poor fit of the data, it was speculated that the transverse relaxation of BSA largely affected the system. The binding of [Pt(en)(phen)]Cl2 – d(GTCGAC)2 showed results where the diffusion coefficient decreases as the concentration of the drug increases but an opposite effect was observed from the point where the drug reached equimolar concentrations to d(GTCGAC)2. It was speculated that the drug undergoes allosteric binding to the biomolecule or that a conformational change occurred as the drug concentration increases in the system. A further study of [Pt(en)(phen)]Cl2 and K2PtCl4 using 195Pt diffusion NMR was conducted giving a diffusion coefficient of 3.08 ± 0.04 × 10-10 m2 s-1 for K2PtCl4. The diffusion coefficient of [Pt(en)(phen)]Cl2, however, were unobtainable due to the short transverse relaxation of the Pt complex. / Master of Science (M.Sc.) (Hons)
| Identifer | oai:union.ndltd.org:ADTP/204266 |
| Date | January 2008 |
| Creators | Miyoshi, Emi, University of Western Sydney, College of Health and Science, School of Biomedical and Health Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
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