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Synthesis and in vitro Anticancer Activity of Octahedral Platinum(IV) Complexes with Cyclohexyl‐Functionalized Ethylenediamine‐ N , N ′‐Diacetate‐Type Ligands
Author(s) -
Lazić Jelena M.,
Vučićević Ljubica,
GrgurićŠipka Sanja,
Janjetović Kristina,
Kaluđerović Goran N.,
Misirkić Maja,
GrudenPavlović Maja,
Popadić Dušan,
Paschke Reinhard,
Trajković Vladimir,
Sabo Tibor J.
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000058
Subject(s) - chemistry , apoptosis , lactate dehydrogenase , viability assay , cancer cell , oxidative stress , cisplatin , ethylenediamine , stereochemistry , biochemistry , enzyme , biology , cancer , inorganic chemistry , chemotherapy , genetics
The present study describes the synthesis and anticancer activity of novel octahedral Pt IV 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 Pt IV 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 Pt IV complexes against various cancer cell lines (IC 50 range: 1.9–8.7 μ M ) was higher than that of cisplatin (IC 50 range: 10.9–67.0 μ M ) and proceeded through completely different mechanisms. Cisplatin induced caspase‐dependent apoptosis associated with the cytoprotective autophagic response. In contrast, the new Pt IV 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.