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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
Synthesis and cytotoxicity of three trans-palladium complexes containing planaramine ligands in human ovarian tumor
Mohammed Ehsanul Hoque Mazumder1, Philip Beale, Charles Chan
1Discipline of Biomedical Science, School of Medical Sciences, Faculty of Medicine, The University of Sydney, P.O. Box 170, 75 East Street, Lidcombe, NSW 1825, Australia.
Abstract:
The present study deals with the synthesis, characterization, and activity against human ovarian cancer cell lines A2780, A2780(cisR), A2780(ZD0473R), and SKOV-3 of three trans-planaramine-palladium(II) complexes of the form trans-PdL(2)Cl(2), coded as EH1, EH3, and EH4, for which L = 2-methylpyridine, imidazole, and 1,2-α-imidazopyridine, respectively. The cellular accumulation of palladium, palladium-DNA binding levels, and the nature of interactions of the compounds with salmon sperm and pBR322 plasmid DNA were also determined. All three compounds were found to be less active than cisplatin, but unlike cisplatin they were found to be equally or more active against the resistant cell lines A2780(cisR) and A2780(ZD0473R) than against the parent cell line A2780. Among the three palladium complexes, EH4 (which has the bulkiest carrier ligand) was found to be most active, in line with the highest cellular accumulation of palladium and highest level of palladium-DNA binding resulting from the compound. EH4 was also found to cause the greatest conformational change to pBR322 plasmid DNA. The results of this study illustrate structure-activity relationships; in particular, they support the idea that the decreased reactivity of trans-palladium complexes through the introduction of bulky ligands can make them more active against tumors.
Insights
Three new palladium(II) complexes show activity against ovarian cancer cell lines. The complex EH4, with a bulky ligand, demonstrated the highest activity and palladium-DNA binding, suggesting potential for overcoming cisplatin resistance.
Area of Science:
- Inorganic Chemistry
- Medicinal Chemistry
- Cancer Research
Background:
- Cisplatin is a widely used chemotherapy drug for ovarian cancer.
- Drug resistance is a significant challenge in ovarian cancer treatment.
- Palladium(II) complexes are being investigated as alternative anticancer agents.
Purpose of the Study:
- To synthesize and characterize three trans-planaramine-palladium(II) complexes.
- To evaluate their anticancer activity against human ovarian cancer cell lines, including cisplatin-resistant ones.
- To investigate their cellular accumulation, DNA binding, and DNA interaction mechanisms.
Main Methods:
- Synthesis and characterization of palladium(II) complexes (EH1, EH3, EH4).
- In vitro anticancer activity assays against A2780, A2780(cisR), A2780(ZD0473R), and SKOV-3 cell lines.
- Measurement of cellular palladium accumulation and palladium-DNA binding levels.
- DNA interaction studies using salmon sperm and pBR322 plasmid DNA.
Main Results:
- All synthesized palladium(II) complexes exhibited anticancer activity.
- Complexes showed comparable or greater activity against cisplatin-resistant cell lines than the parent cell line.
- EH4, featuring the bulkiest ligand, displayed the highest activity, correlating with increased palladium cellular uptake and DNA binding.
- EH4 induced significant conformational changes in pBR322 plasmid DNA.
Conclusions:
- The study highlights structure-activity relationships for trans-planaramine-palladium(II) complexes.
- Bulky ligands in palladium complexes can enhance anticancer activity, potentially by reducing reactivity.
- These findings suggest that palladium complexes like EH4 could be promising candidates for overcoming cisplatin resistance in ovarian cancer.
