Synthesis and in vitro Anticancer Activity of Octahedral Platinum(IV) Complexes with Cyclohexyl‐Functionalized Ethylenediamine‐N,N′‐Diacetate‐Type Ligands

• DOI: 10.1002/cmdc.201000058
• Publication Date: 2010-04-20T17:52:38Z
• Authors: Jelena M. Lazić; Ljubica Vučićević; Sanja Grgurić‐Šipka; Kristina Janjetović; Goran N. Kaluđerović; Maja Misirkić; Maja Gruden‐Pavlović; Dušan Popadić; Reinhard Paschke; Vladimir Trajković; Tibor J. Sabo
• Keywords: autophagy; apoptosis; 610; Antineoplastic Agents; Apoptosis; 540; Ethylenediamines; Ligands; 01 natural sciences; Rats; 0104 chemical sciences; 3. Good health; Mice; Coordination Complexes; Cell Line, Tumor; cancer; oxidative stress; Animals; Humans; platinum; Cisplatin; Platinum

AbstractThe present study describes the synthesis and anticancer activity of novel octahedral PtIV complexes with cyclohexyl functionalized ethylenediamine‐N,N′‐diacetate‐type ligands. Molecular mechanics calculations and density functional theory analysis revealed that s‐cis is the preferred geometry of these PtIV complexes with tetradentate‐coordinated (S,S)‐ethylenediamine‐N,N′‐di‐2‐(3‐cyclohexyl)propanoate. The viability of cancer cell lines (U251 human glioma, C6 rat glioma, L929 mouse fibrosarcoma, and B16 human melanoma) was assessed by measuring mitochondrial dehydrogenase activity and lactate dehydrogenase release. Cell‐cycle distribution, oxidative stress, caspase activation, and induction of autophagy were analyzed by flow cytometry using appropriate fluorescent reporter dyes. The cytotoxic activity of novel PtIV complexes against various cancer cell lines (IC50 range: 1.9–8.7 μM) was higher than that of cisplatin (IC50 range: 10.9–67.0 μM) and proceeded through completely different mechanisms. Cisplatin induced caspase‐dependent apoptosis associated with the cytoprotective autophagic response. In contrast, the new PtIV complexes caused rapid, caspase‐independent, oxidative stress‐mediated non‐apoptotic cell death characterized by massive cytoplasmic vacuolization, cell membrane damage, and the absence of protective autophagy.