PhD student, Monash University
Platinum complexes are known for there activity as anticancer drugs. In order to develop compounds with less side effects, new complexes were synthesised and tested against some cancer cells and DNA to investigate the interaction of those drugs with them.
Abstract: The two six-coordinate Pt(IV) complexes, containing bidentate nitrogen donor/methyl ligands with general formula [Pt(X)2Me2((t)bu2bpy)], where (t)bu2bpy = 4,4'-ditert-butyl-2,2'-bipyridine and X = Cl (C1) or Br (C2), serving as the leaving groups were synthesized for evaluation of their anticancer activities and DNA binding properties. To examine anticancer activities of the synthetic complexes, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ethidium bromide/acridine orange (EB/AO) staining method were performed. The binding properties of these complexes to DNA and purine nucleotides were examined, using different spectroscopic techniques. These complexes demonstrated significant anticancer activities against three cancer cell lines Jurkat, K562, and MCF-7. On the basis of the results of EB/AO staining, C1 and C2 were also capable to induce apoptosis in cancer cells. These complexes comprise halide leaving groups, displaying different departure rates; accordingly, they demonstrated slightly dissimilar anticancer activity and significantly different DNA/purine nucleotide binding properties. The results of DNA interaction studies of these complexes suggest a mixed-binding mode, comprising partial intercalation and groove binding. Overall, the results presented herein indicate that the newly synthesized Pt(IV) complexes are promising class of the potential anticancer agents which can be considered as molecular templates in designing novel platinum anticancer drugs. This study also highlights the importance of leaving group in anticancer activity and DNA binding properties of Pt(IV) complexes.
Pub.: 15 Jan '14, Pinned: 19 Jun '17
Abstract: The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-threat agents, and photoactivatable platinum(IV) complexes. Nanoparticles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations, including supramolecular self-assembled structures, proteins, peptides, metal–organic frameworks, and coordination polymers, will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also will reflect our optimism that the next generation of approved platinum cancer drugs is about to arrive.
Pub.: 11 Feb '16, Pinned: 19 Jun '17
Abstract: Publication date: 1 March 2017 Source:Inorganica Chimica Acta, Volume 457 Author(s): Urszula Śliwińska-Hill, Lilianna Trynda-Lemiesz Cytochrome c is an important electron transfer carrier in mitochondrial electron transfer and is essential for apoptosis. In the present work we have examined the effect of platinum (II) complexes (cisplatin, transplatin and carboplatin) on the conformation of cytochrome c and the state of heme moiety. For this purpose, UV–VIS spectroscopy, circular dichroism (CD) and absorption second derivative spectroscopy methods have been used. Moreover, the amount of platinum per mole of cytochrome c and stability of carboplatin–cytochrome c system have been determined by ICP-AES and zeta potential measurements, respectively. The present data has revealed that binding of platinum (II) complexes to cytochrome c induces a conformation of the protein with less organized tertiary structure. Determination of tyrosine exposure by second-derivative spectroscopy indicates changes occurring in the tyrosyl microenvironment, which becomes more polar following the more open conformation compared to that of a native protein. The reaction of cytochrome c with platinum complexes led to the changes in spectral properties, most notably the decreases in intensity of the absorption band at 695nm, indicating that platinum complexes may affect coordination Met-80 with the heme iron. Under physiological conditions the carboplatin-cytochrome c system shows instability, what is desired effect from the pharmacological point of view. Graphical abstract
Pub.: 26 Dec '16, Pinned: 19 Jun '17
Abstract: A joint theoretical and experimental investigation of the influence that protonation can have on the reactivity of the anticancer prodrug satrapaltin and of analogous octahedral Pt(IV) complexes having two carboxylates as axial ligands has been carried out. Such a study sheds some light on the fate of the drugs, synthesized to be orally administered, after their consumption.For the synthesis and selection of active platinum-based anticancer drugs that perform better than cisplatin and its analogues, six-coordinate octahedral Pt(IV) complexes appear to be promising candidates as, being kinetically more inert and more resistant to ligand substitution than four-coordinate Pt(II) centers, they are able to minimize unwanted side reactions with biomolecules prior to DNA binding. Due to their kinetic inertness, Pt(IV) complexes have also been exploited to bypass inconvenient intravenous administration. The most prominent example is satraplatin (Sat.) which is the first platinum antineoplastic agent reported to have oral activity. The present paper deals with a theoretical DFT investigation of the influence that the acidity of the biological environment can have on the activity of satraplatin and analogous octahedral Pt(IV) complexes having two carboxylates as axial ligands. Moreover, here the outcomes of a joint electrospray ionization mass spectrometry and DFT investigation of the fragmentation pathways of the protonated satraplatin are reported. Calculations show that the simulated acidic environment has an important impact on the satraplatin reactivity causing a significant lowering of the barrier that is necessary to overcome for the hydrolysis of the first acetate ligand to occur. Data from electrospray ionization mass spectrometry, 1H NMR, and potentiometric experiments strongly suggest that the loss of CH3COOH from the protonated satraplatin ion [Sat. + H]+ takes place almost immediately upon dissolution of satraplatin in methanol–water, D2O, and water solutions, respectively, at room temperature.
Pub.: 28 Apr '17, Pinned: 19 Jun '17