Four tumour active trinuclear complexes: DH4Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd( NH3)2(H2N(CH2)4NH2)2]Cl4, DH5Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd( NH3)2(H2N(CH2)5NH2)2]Cl4, DH6Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd( NH3)2(H2N(CH2)6NH2)2]Cl4, DH7Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd(NH3)2-( H2N(CH2)7NH2)2]Cl4 and one dinuclear complex DHD: [{trans-PtCl(NH3)2}�-{ H2N(CH2)6NH2}{trans-PdCl(NH3)2]Cl(NO3), have been prepared and characterised based on elemental analyses, IR, Raman, mass and 1 H NMR spectral measurements. For the trinuclear complexes, the synthesis has been carried out using a step-up method branching out from the central palladium unit. A purity of about 95% has been obtained by repeated dissolution and precipitation. The activity against human cancer cell lines including ovary cell lines: A2780, A2780 cisR , A2780 ZD0473R , non small lung cell line: NCI-H640 and melanoma: Me-10538 have been determined based on MMT assay. Cell uptakes, DNA-binding have been determined for ovary cell lines: A2780, A2780 cisR . The nature of interaction with pBR322 plasmid DNA and ssDNA has been studied for trinuclear complexes DH4Cl, DH5Cl, DH6Cl and DH7Cl and the dinuclear complex DHD. Interaction of DH6Cl with adenine and guanine has also been studied by HPLC. The compounds are found to exhibit significant anticancer activity against cancer cell lines especially ovarian cancer cell lines: A2780, A2780 cisR and A2780 ZD0473R . DH6Cl in which the linking diamine has six carbon atoms is found to be the most active compound. As the number of carbon atoms in thelinking diamine is changed from the optimum value of six, the activity is found to decrease, illustrating the structure-activity relationship. The increase in uptake of the trinuclear complexes in A2780 cell line with the increase in size of the linking diamine coupled with the low molar conductivity values found for the solutions of the compounds suggest that the compounds would remain in solution as undissociated �molecules� and hence could cross the cell membrane by passive diffusion. Much lower resistance factors for the all the multinuclear compounds including DHD as applied to A2780 cisR cell line, as compared to that for cisplatin, suggest that the compounds are able to overcome multiple mechanisms of resistance operating in the cell line. All of the multinuclear complexes are expected to form long-range interstrand GG adducts with DNA, causing irreversible global changes in the DNA conformation but unlike cisplatin do not cause sufficient DNA bending to be recognized by HMG 1 protein. Increasing prevention of BamH1 digestion with the increase in concentration of the multinuclear compounds also provide support to the idea that the compounds because of the formation of a plethora of interstrand GG adducts are able to cause irreversible changes in DNA conformation. The results of the study show that indeed new trinuclear tumour active compounds can be found by replacing the central platinum unit in BBR3464 with other suitable metal units.
| Identifer | oai:union.ndltd.org:ADTP/283021 |
| Date | January 2004 |
| Creators | Daghriri, Hassan |
| Publisher | University of Sydney. Biomedical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English, en_AU |
| Detected Language | English |
| Rights | Copyright Daghriri, Hassan;http://www.library.usyd.edu.au/copyright.html |
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