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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
Novel platinum(II) compounds with O,S bidentate ligands: synthesis, characterization, antiproliferative properties
Carolin Mügge1, Ruiqi Liu, Helmar Görls
1Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller-University Jena, Humboldtstraße 8, 07743 Jena, Germany. wolfgang.weigand@uni-jena.de.
Abstract:
Cisplatin and its analogues are first-line chemotherapeutic agents for the treatment of numerous human cancers. A major inconvenience in their clinical use is their strong tendency to link to sulfur compounds, especially in kidney, ultimately leading to severe nephrotoxicity. To overcome this drawback we prepared a variety of platinum complexes with sulfur ligands and analyzed their biological profiles. Here, a series of six platinum(II) compounds bearing a conserved O,S binding moiety have been synthesized and characterized as experimental anticancer agents. The six compounds differ in the nature of the O,S bidentate β-hydroxydithiocinnamic alkyl ester ligand where both the substituents on the aromatic ring and the length of the alkyl chain may be varied. The two remaining coordination positions at the square-planar platinum(II) center are occupied by a chloride ion and a DMSO molecule. These novel platinum compounds showed an acceptable solubility profile in mixed DMSO-buffer solutions and an appreciable stability at physiological pH as judged from analysis of their time-course UV-visible absorption spectra. Their anti-proliferative and pro-apoptotic activities were tested against the cisplatin-resistant lung cancer cell line A549. Assays revealed significant effects of the sample drugs at low concentrations (in the μmolar range); initial structure-activity-relationships are proposed. The activity of the apoptosis-promoting protein caspase 3/7 was determined; results proved that these novel platinum compounds, under the chosen experimental conditions, preferentially induce apoptosis over necrosis. Reactions with the model proteins cytochrome c, lysozyme and albumin were studied by ESI MS and ICP-OES to gain preliminary mechanistic information. The tested compounds turned out to metalate the mentioned proteins to a large extent. In view of the obtained results these novel platinum complexes qualify themselves as promising cytotoxic agents and merit, in our opinion, a deeper pharmacological evaluation as prospective anticancer agents.
Insights
New platinum compounds with sulfur ligands show promise as anticancer agents, effectively targeting lung cancer cells and inducing apoptosis while minimizing kidney toxicity associated with cisplatin.
Area of Science:
- Medicinal Chemistry
- Oncology
- Materials Science
Background:
- Cisplatin is a key chemotherapy drug but causes severe kidney toxicity due to sulfur compound interactions.
- Developing platinum-based anticancer agents with reduced nephrotoxicity is a critical clinical need.
Purpose of the Study:
- To synthesize and evaluate novel platinum(II) complexes with sulfur ligands as potential anticancer agents.
- To investigate the anti-proliferative and pro-apoptotic effects of these compounds on cisplatin-resistant lung cancer cells.
Main Methods:
- Synthesis and characterization of six novel platinum(II) compounds with O,S bidentate ligands.
- Assessment of anti-proliferative and pro-apoptotic activity against A549 lung cancer cells.
- Analysis of protein metalation using ESI-MS and ICP-OES.
Main Results:
- The novel platinum compounds demonstrated significant anti-proliferative and pro-apoptotic activity at low micromolar concentrations.
- Compounds preferentially induced apoptosis over necrosis.
- Extensive metalation of model proteins (cytochrome c, lysozyme, albumin) was observed.
Conclusions:
- The synthesized platinum(II) complexes exhibit promising cytotoxic and apoptosis-inducing properties.
- These novel sulfur-ligated platinum compounds represent potential candidates for further pharmacological evaluation as anticancer therapeutics.
- The findings suggest a potential mechanism involving protein metalation.
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