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J Biol Inorg Chem. 2014 Aug;19(6):967-79. doi: 10.1007/s00775-014-1133-6. Epub 2014 Apr 16.

Synthesis, characterization, and evaluation of cis-diphenyl pyridineamine platinum(II) complexes as potential anti-breast cancer agents.

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1
Department of Chemistry, The University of Texas at El Paso, El Paso, TX, 79968, USA.

Abstract

Although cisplatin is considered as an effective anti-cancer agent, it has shown limitations and may produce toxicity in patients. Therefore, we synthesized two cis-dichlorideplatinum(II) compounds (13 and 14) composed of meta- and para-N,N-diphenyl pyridineamine ligands through a reaction of the amine precursors and PtCl2 with respective yields of 16 and 47 %. We hypothesized that compounds 13 and 14, with lipophilic ligands, should transport efficiently in cancer cells and demonstrate more effectiveness than cisplatin. When tested for biological activity, compounds 13 and 14 were found to inhibit the growth of MCF 7 and MDA-MB-231 cells (IC50s 1 ± 0.4 µM and 1 ± 0.2 µM for 13 and 14, respectively, and IC50 7.5 ± 1.3 µM for compound 13 and 1 ± 0.3 µM for compound 14). Incidentally, these doses were found to be lower than cisplatin doses (IC50 5 ± 0.7 µM for MCF 7 and 10 ± 1.1 µM for MDA-MB-231). Similar to cisplatin, 13 and 14 interacted with DNA and induced apoptosis. However, unlike cisplatin, they blocked the migration of MDA-MB-231 cells suggesting that in addition to apoptotic and DNA-binding capabilities, these compounds are useful in blocking the metastatic migration of breast cancer cells. To delineate the mechanism of action, computer-aided analyses (DFT calculations) were conducted for compound 13. Results indicate that in vivo, the pyridineamine ligands are likely to dissociate from the complex, forming a platinum DNA adduct with anti-proliferative activity. These results suggest that complexes 13 and 14 hold promise as potential anti-cancer agents.

PMID:
24737042
PMCID:
PMC4641452
DOI:
10.1007/s00775-014-1133-6
[Indexed for MEDLINE]
Free PMC Article
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